Principles of neural science

Contents Front Matter 1 The Brain and Behavior 2 Nerve Cells and Behavior 3 Genes and Behavior I The Neurobiology of Behavior 4 The Cytology of Neurons 5 Synthesis and Trafficking of Neuronal Protein 6 Ion Channels 7 Membrane Potential 8 Local Signaling: Passive Electrical Properties of the Neuron 9 Propagated Signaling: The Action Potential II Cell and Molecular Biology of the Neuron 10 Overview of Synaptic Transmission 11 Signaling at the Nerve-Muscle Synapse: Directly Gated Transmission 12 Synaptic Integration 13 Modulation of Synaptic Transmission: Second Messengers 14 Transmitter Release 15 Neurotransmitters 16 Diseases of Chemical Transmission at the Nerve-Muscle Synapse: Myasthenia Gravis III Elementary Interactions Between Neurons: Synaptic Transmission 17 The Anatomical Organization of the Central Nervous System 18 The Functional Organization of Perception and Movement 19 Integration of Sensory and Motor Function: The Association Areas of the Cerebral Cortex and the Cognitive Capabilities of the Brain 20 From Nerve Cells to Cognition: The Internal Cellular Representation Required or Perception and Action IV The Neural Basis of Cognition 21 Coding of Sensory Information 22 The Bodily Senses 23 Touch 24 The Perception of Pain 25 Constructing the Visual Image 26 Visual Processing by the Retina 27 Central Visual Pathways 28 Perception of Motion, Depth, and Form 29 Color Vision 30 Hearing 31 Sensory Transduction in the Ear 32 Smell and Taste: The Chemical Senses V Preception 33 The Organization of Movement 34 The Motor Unit and Muscle Action 35 Diseases of the Motor Unit 36 Spinal Reflexes

37 Locomotion 38 Voluntary Movement 39 The Control of Gaze 40 The Vestibular System 41 Posture 42 The Cerebellum 43 The Basal Ganglia VI Movement 44 Brain Stem, Reflexive Behavior, and the Cranial Nerves 45 Brain Stem Modulation of Sensation, Movement, and Consciousness 46 Seizures and Epilepsy 47 Sleep and Dreaming 48 Disorders of Sleep and Wakefulness 49 The Autonomic Nervous System and the Hypothalamus 50 Emotional States and Feelings 51 Motivational and Addictive States VII Arousal, Emotion, and Behavioral Homeostasis 52 The Induction and Patterning of the Nervous System 53 The Generation and Survival of Nerve Cells 54 The Guidance of Axons to Their Targets 55 The Formation and Regeneration of Synapses 56 Sensory Experience and the Fine-Tuning of Synaptic Connections 57 Sexual Differentiation of the Nervous System 58 Aging of the Brain and Dementia of the Alzheimer Type VIII The Development of the Nervous System 59 Language and the Aphasias 60 Disorders of Thought and Volition: Schizophrenia 61 Disorders of Mood: Depression, Mania, and Anxiety Disorders 62 Learning and Memory 63 Cellular Mechanisms of Learning and the Biological Basis of Individuality IX Language, Thought, Mood, Learning, and Memory Appendix A Current Flow in Neurons Appendix B Ventricular Organization of Cerebrospinal Fluid: Blood-Brain Barrier, Brain Edema, and Hydrocephalus Appendix C Circulation of the Brain Appendix D Consciousness and the Neurobiology of the Twenty-First Century Index

Contents: ●

Front Matter

●

ChapterDA1-C1)

●

ChapterDA1-C2)

●

ChapterDA1-C3)

●

ChapterDA1-CI)

●

ChapterDA2-C4)

●

ChapterDA2-C5)

●

ChapterDA2-C6)

●

ChapterDA2-C7)

●

ChapterDA2-C8)

●

ChapterDA2-C9)

●

ChapterDA2-CII)

●

ChapterDA3-C10)

●

ChapterDA3-C11)

●

ChapterDA3-C12)

●

ChapterDA3-C13)

●

ChapterDA3-C14)

●

ChapterDA3-C15)

●

ChapterDA3-C16)

●

ChapterDA3-CIII)

●

ChapterDA4-C17)

●

ChapterDA4-C18)

●

ChapterDA4-C19)

●

ChapterDA4-C20)

●

ChapterDA4-CIV)

●

ChapterDA5-C21)

●

ChapterDA5-C22)

●

ChapterDA5-C23)

●

ChapterDA5-C24)

●

ChapterDA5-C25)

●

ChapterDA5-C26)

●

ChapterDA5-C27)

●

ChapterDA5-C28)

●

ChapterDA5-C29)

●

ChapterDA5-C30)

●

ChapterDA5-C31)

●

ChapterDA5-C32)

●

ChapterDA5-CV)

●

ChapterDA6-C33)

●

ChapterDA6-C34)

●

ChapterDA6-C35)

●

ChapterDA6-C36)

●

ChapterDA6-C37)

●

ChapterDA6-C38)

●

ChapterDA6-C39)

●

ChapterDA6-C40)

●

ChapterDA6-C41)

●

ChapterDA6-C42)

●

ChapterDA6-C43)

●

ChapterDA6-CVI)

●

ChapterDA7-C44)

●

ChapterDA7-C45)

●

ChapterDA7-C46)

●

ChapterDA7-C47)

●

ChapterDA7-C48)

●

ChapterDA7-C49)

●

ChapterDA7-C50)

●

ChapterDA7-C51)

●

ChapterDA7-CVII)

●

ChapterDA8-C52)

●

ChapterDA8-C53)

●

ChapterDA8-C54)

●

ChapterDA8-C55)

●

ChapterDA8-C56)

●

ChapterDA8-C57)

●

ChapterDA8-C58)

●

ChapterDA8-CVIII)

●

ChapterDA9-C59)

●

ChapterDA9-C60)

●

ChapterDA9-C61)

●

ChapterDA9-C62)

●

ChapterDA9-C63)

●

ChapterDA9-CIX)

●

Appendices)

Back

Principles of Neural Science 4th_Edition 3 Clinical Medicine Life Sciences Neurology Neuroscience Text/Reference

Editors Eric R. Kandel James H. Schwartz Thomas M. Jessell Center for Neurobiology and Behavior, College of Physicians & Surgeons of Columbia University and The Howard Hughes Medical Institute

Secondary Editors Sarah Mack Art Direction Jane Dodd Art Direction John Butler Editor Harriet Lebowitz Editor Shirley Dahlgren Production Supervisor Eve Siegel Art Manager Joellen Ackerman Designer Judy Cuddihy Index Precision Graphics Illustrators.

R. R. Donnelley & Sons, Inc. Printer and Binder.

CONTRIBUTORS David G. Amaral PhD Professor Department of Psychiatry, Center for, Neuroscience, University of California, Davis

Allan I. Basbaum PhD Professor and Chair Department of Anatomy, University of California, San Francisco; Member W.M., Keck Foundation Center for Integrative

Neuroscience

John C. M. Brust MD Professor Department of Neurology, Columbia, University College of Physicians & Surgeons; Director; of Neurology Service, Harlem Hospital

Linda Buck PhD Associate Professor Department of Neurobiology, Harvard Medical School; Associate Investigator, Howard Hughes Medical Institute

Pietro De Camilli MD Professor and Chairman Department of Cell Biology, Yale University Medical School

Antonio R. Damasio MD, PhD M.W. Van Allen Professor and Head Department of, Neurology, University of Iowa College of Medicine; Adjunct Professor Salk Institute for Biological Studies

Mahlon R. DeLong MD Professor and Chairman Department of Neurology, Emory University School of Medicine

Nina F. Dronkers PhD Chief Audiology and Speech Pathology VA Northern, California Health Care System; Departments of Neurology and Linguistics, University of California, Davis

Richard S. J. Frackowiak MD, DSc Dean Institute of Neurology, University College, London; Chair, Wellcome Department of Cognitive, Neurology; The National Hospital for Neurology & Neurosurgery, London

Esther P. Gardner PhD Professor Department of Physiology and Neuroscience, New York University School of Medicine

Claude P. J. Ghez MD Professor Department of Neurology and Department of Physiology and Cellular Biophysics; Center for Neurobiology and Behavior; Columbia University, College of Physicians & Surgeons; New York State, Psychiatric Institute

T. Conrad Gilliam PhD Professor Department of Genetics and Development, Columbia University College of Physicians & Surgeons

Michael E. Goldberg MD Chief Section of Neuro-opthalmological Mechanisms, Laboratory of Sensorimotor Research; National Eye, Institute, National Institutes of Health

Gary W. Goldstein MD President The Kennedy Krieger Research Institute; Professor, Neurology and Pediatrics, The Johns, Hopkins University School of

Medicine

James Gordon EdD Professor of Practice Program Director, Physical, Therapy, Graduate School of Health Sciences, New York Medical College

Roger A. Gorski PhD Professor Department of Neurobiology, UCLA School of Medicine

A. J. Hudspeth MD, PhD Professor and Head Laboratory of Sensory, Neuroscience, Rockefeller University; Investigator, Howard Hughes Medical Institute

Leslie L. Iversen PhD Professor Department of Pharmacology, Oxford University

Susan D. Iversen PhD Professor Department of Experimental Psychology, Oxford University

Thomas M. Jessell PhD Professor Department of Biochemistry and Molecular, Biophysics; Center for Neurobiology and Behavior; Investigator, The Howard Hughes Medical Institute, Columbia University College of Physicians & Surgeons

Eric R. Kandel MD University Professor Departments of Biochemistry and Molecular Biophysics, Physiology and Cellular Biophysics, and Psychiatry; Center for Neurobiology and Behavior; Senior Investigator, The Howard Hughes, Medical Institute, Columbia University College of Physicians & Surgeons

John Koester PhD Professor of Clinical Neurobiology and Behavior in Psychiatry Acting Director, Center for Neurobiology and Behavior, New York State Psychiatric Institute, Columbia University College of Physicians & Surgeons

John Krakauer MD Assistant Professor Department of Neurology, Columbia University College of Physicians & Surgeons

Irving Kupfermann PhD Professor Department of Psychiatry and Department of Physiology and Cellular Biophysics, Center for Neurobiology and Behavior, Columbia University, College of Physicians & Surgeons

John Laterra MD, PhD Associate Professor of Neurology Oncology, and Neuroscience; The Kennedy Krieger Research Institute, Johns Hopkins University School of Medicine

Peter Lennie PhD Professor of Neural Science Center for Neural Science, New York University

Gerald E. Loeb MD Professor Department of Physiology, Member, MRC, Group in Sensory-Motor Neuroscience, Queen's University, Canada

John H. Martin PhD Associate Professor Department of Psychiatry; Center for Neurobiology and Behavior, Columbia University College of Physicians & Surgeons

Geoffrey Melvill Jones MD Professor Department of Clinical Neurosciences, Faculty of Medicine, University of Calgary, Canada

Keir Pearson PhD Professor Department of Physiology, University of Alberta

Steven Pinker PhD Professor Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology; Director, McDonnell-Pew Center for Cognitive, Neuroscience

Donald L. Price MD Professor Neuropathology Laboratory, The Johns, Hopkins University School of Medicine

Allan Rechtshaffen PhD Professor Emeritus Department of Psychiatry, and Department of Psychology, University of Chicago

Timothy Roehrs PhD Director of Research Henry Ford Sleep Disorders Center

Thomas Roth PhD Director , Sleep Disorders and Research Center, Henry, Ford Hospital; University of Michigan

Lewis P. Rowland MD Professor Department of Neurology; Columbia, University College of Physicians & Surgeons

Joshua R. Sanes PhD Professor Department of Anatomy and Neurobiology; Washington University School of Medicine

Clifford B. Saper MD, PhD Professor and Chairman Department of Neurology; Beth Israel Deaconess Medical Center, Harvard, Medical School

James H. Schwartz MD PhD Professor Departments of Physiology and Cellular, Biophysics, Neurology and Psychiatry, Center for, Neurobiology and Behavior,

Columbia University, College of Physicians and Surgeons.

Jerome M. Siegel PhD Professor of Psychiatry UCLA Medical Center; Chief Neurobiology Research, Sepulveda VA Medical Center

Steven A. Siegelbaum PhD Professor Department of Pharmacology, Center for, Neurobiology and Behavior Investigator, Howard, Hughes Medical Institute, Columbia University, College of Physicians and Surgeons

Marc T. Tessier-Lavigne PhD Professor Departments of Anatomy and of, Biochemistry and Biophysics, University of California, San Francisco; Investigator, Howard Hughes Medical Institute

W. Thomas Thach Jr. MD Professor Department of Anatomy and Neurobiology, Washington University School of Medicine

Gary L. Westbrook MD Senior Scientist and Professor of Neurology Vollum Institute, Oregon Health Sciences University

Robert H. Wurtz PhD Chief Laboratory of Sensorimotor Research, National, Eye Institute; National Institutes of Health

2000 McGraw-Hill New York United States of America 0-8385-7701-6

Principles of Neural Science, 4/e Copyright © 2000 by The McGraw-Hill Companies, Inc. All rights reserved. Printed in the United States of America. Except as permitted under the United States Copyright Act of 1976, no part of this publication may be reproduced or distributed in any form or by any means, or stored in a data base or retrieval system, without the prior written permission of the publisher. Previous edition copyright © 1991 by Appleton & Lange 4567890 DOWDOW 09876543 ISBN 0-8385-7701-6 This book was set in Palatino by Clarinda Prepress, Inc. This book is printed on acid-free paper. Cataloging-in-Publication Data is on file for this title at the Library of Congress.

Cover image: The autoradiograph illustrates the widespread localization of mRNA encoding the NMDA-R1 receptor subtype determined by in situ hybridization. Areas of high NMDA receptor expression are shown as light regions in this horizontal section of an adult rat brain.

From Moriyoshi K, Masu M, Ishi T, Shigemoto R, Mizuno N, Nakanishi S. 1991. Molecular cloning and characterization of the rat NMDA receptor. Nature 354:31-37.

Note

Columns II of the Edwin Smith Surgical Papyrus

This papyrus, written in the seventeenth century B.C., contains the earliest reference to the brain anywhere in human records. According to James Breasted, who translated and published the document in 1930, the word brain

occurs only eight times in ancient Egyptian records, six of them in these pages, which describe the symptoms, diagnosis, and prognosis of two patients, with compound fractures of the skull. The entire treatise is now in the Rare Book Room of the New York Academy of Medicine. From James Henry Breasted, 1930. The Edwin Smith Surgical Papyrus, 2 volumes, Chicago: The University of Chicago Press. From James Henry Breasted, 1930. The Edwin Smith Surgical Papyrus, 2 volumes, Chicago: The University of Chicago Press.

Columns IV of the Edwin Smith Surgical Papyrus

Men ought to know that from the brain, and from the brain only, arise our pleasures, joys, laughter and jests, as well as our sorrows, pains, griefs and tears. Through it, in particular, we think, see, hear, and distinguish the ugly from the beautiful, the bad from the good, the pleasant from the unpleasant…. It is the same thing which makes us mad or delirious, inspires us with dread and fear, whether by night or by day, brings sleeplessness, inopportune mistakes, aimless anxieties, absent-mindedness, and acts that are contrary to habit. These things that we suffer all come from the brain, when it is not healthy, but becomes abnormally hot, cold, moist, or dry, or suffers any other unnatural affection to which it was not accustomed. Madness comes from its moistness. When the brain is abnormally moist, of necessity it moves, and when it moves neither sight nor hearing are still, but we see or hear now one thing and now another, and the tongue speaks in accordance with the things seen and heard on any occasion. But when the brain is still, a man can think properly. attributed to Hippocrates Fifth Century, B.C. From Hippocrates, Vol.2, translated by W.H.S. Jones, London and New York: William Heinemann and Harvard University Press. 1923.

Notice Medicine is an ever-changing science. As new research and clinical experience broaden our knowledge, changes in treatment and drug therapy are required. The editors and the publisher of this work have checked with sources believed to be reliable in their efforts to provide information that is complete and generally in accord with the standards accepted at the time of publication. However, in view of the possibility of human error or changes in medical sciences, neither the editors nor the publisher nor any other party who has been involved in the preparation or publication of this work warrants that the information contained herein is in every respect accurate or complete, and they are not responsible for any errors or omissions or for the results obtained from use of such information. Readers are encouraged to confirm the information contained herein with other sources. For example and in particular, readers are advised to check the product information sheet included in the package of each drug they plan to administer to be certain that the information contained in this book is accurate and that changes have not been made in the recommended dose or in the contraindications for administration. This recommendation is of particular importance in connection with new or infrequently used drugs.

Preface The goal of neural science is to understand the mind—how we perceive, move, think, and remember. As in the earlier editions of this book, in this fourth edition we emphasize that behavior can be examined at the level of individual nerve cells by seeking answers to five basic questions: How does the brain develop? How do nerve cells in the brain communicate with one another? How do different patterns of interconnections give rise to different perceptions and motor acts? How is communication between neurons modified by experience? How is that communication altered by diseases? When we published the first edition of this book in 1981, these questions could be addressed only in cell biological terms. By the time of the third edition in 1991, however, these same problems were being explored effectively at the molecular level. In the eight years intervening between the third and the present edition, molecular biology has continued to facilitate the analysis of neurobiological problems. Initially molecular biology enriched our understanding of ion channels and receptors important for signaling. We now have obtained the first molecular structure of an ion channel, providing us with a threedimensional understanding of the ion channel pore. Structural studies also have deepened our understanding of the membrane receptors coupled to intracellular second-messenger systems and of the role of these systems in modulating the physiological responses of nerve cells. Molecular biology also has greatly expanded our understanding of how the brain develops and how it generates behavior. Characterizations of the genes encoding growth factors and their receptors, transcriptional regulatory factors, and cell and substrate adhesion molecules have changed the study of neural development from a descriptive discipline into a mechanistic one. We have even begun to define the molecular mechanisms underlying the developmental processes responsible for assembling functional neural circuits. These processes include the specification of cell fate, cell migration, axon growth, target recognition, and synapse formation. In addition, the ability to develop genetically modified mice has allowed us to relate single genes to signaling in nerve cells and to relate both of these to an organism's behavior. Ultimately, these experiments will make it possible to study emotion, perception, learning, memory, and other cognitive processes on both a cellular and a molecular level. Molecular biology has also made it possible to probe the pathogenesis of many diseases that affect neural function, including several

devastating genetic disorders: muscular dystrophy, retinoblastoma, neurofibromatosis, Huntington disease, and certain forms of Alzheimer disease. Finally, the 80,000 genes of the human genome are nearly sequenced. With the possible exception of trauma, every disease that affects the nervous system has some inherited component. Information about the human genome is making it possible to identify which genes contribute to these disorders and thus to predict an individual's susceptibility to particular illnesses. In the long term, finding these genes will radically transform the practice of medicine. Thus we again stress vigorously our view, advocated since the first edition of this book, that the future of clinical neurology and psychiatry depends on the progress of molecular neural science. Advances in molecular neural science have been matched by advances in our understanding of the biology of higher brain functions. The present-day study of visual perception, emotion, motivation, thought, language, and memory owes much to the collaboration of cognitive psychology and neural science, a collaboration at the core of the new cognitive neural science. Not long ago, ascribing a particular aspect of behavior to an unobservable mental process—such as planning a movement or remembering an event—was thought to be reason for removing the problem from experimental analysis. Today our ability to visualize functional changes in the brain during normal and abnormal mental activity permits even complex cognitive processes to be studied directly. No longer are we constrained simply to infer mental functions from observable behavior. As a result, neural science during the next several decades may develop the tools needed to probe the deepest of biological mysteries—the biological basis of mind and consciousness. Despite the growing richness of neural science, we have striven to write a coherent introduction to the nervous system for students of behavior, biology, and medicine. Indeed, we think this information is even more necessary now than it was two decades ago. Today neurobiology is central to the biological sciences—students of biology increasingly want to become familiar with neural science, and more students of psychology are interested in the biological basis of behavior. At the same time, progress in neural science is providing clearer guidance to clinicians, particularly in the treatment of behavioral disorders. Therefore we believe it is particularly important to clarify the major principles and mechanisms governing the functions of the nervous system without becoming lost in details. Thus this book provides the detail necessary to meet the interests of students in particular fields. It is organized in such a way, however, that excursions into special topics are not necessary for grasping the major principles of neural science. Toward that end, we have completely redesigned the illustrations in the book to provide accurate, yet vividly graphic, diagrams that allow the reader to understand the fundamental concepts of neural science. With this fourth and millennial edition, we hope to encourage the next generation of undergraduate, graduate, and medical students to approach the study of behavior in a way that unites its social and its biological dimensions. From ancient times, understanding human behavior has been central to civilized cultures. Engraved at the entrance to the Temple of Apollo at Delphi was the famous maxim “Know thyself.” For us, the study of the mind and consciousness defines the frontier of biology. Throughout this book we both document the central principle that all behavior is an expression of neural activity and illustrate the insights into behavior that neural science provides. Eric R. Kandel James H. Schwartz Thomas M. Jessell

Acknowledgments We are again fortunate to have had the creative editorial assistance of Howard Beckman, who read several versions of the text, demanding clarity of style and logic of argument. We owe a special debt to Sarah Mack, who rethought the whole art program and converted it to color. With her extraordinary insights into science, she produced remarkably clear diagrams and figures. In this task, she was aided by our colleague Jane Dodd, who as art editor supervised the program both scientifically and artistically. We again owe much to Seta Izmirly: she undertook the demanding task of coordinating the production of this book at Columbia as she did its predecessor. We thank Harriet Ayers and Millie Pellan, who typed the many versions of the manuscript; Veronica Winder and Theodore Moallem, who checked the bibliography; Charles Lam, who helped with the art program; Lalita Hedge who obtained permissions for figures; and Judy Cuddihy, who prepared the index. We also are indebted to Amanda Suver and Harriet Lebowitz, our development editors, and to the manager of art services, Eve Siegel, for their help in producing this edition. Finally we want to thank John Butler, for his consistent and thoughtful support of this project throughout the work on this fourth edition. Many colleagues have read portions of the manuscript critically. We are especially indebted to John H. Martin for helping us, once again, with the anatomical drawings. In addition, we thank the following colleagues, who made constructive comments on various chapters: George Aghajanian, Roger Bannister, Robert Barchi, Cornelia Bargmann, Samuel Barondes, Elizabeth Bates, Dennis Baylor, Ursula Bellugi, Michael V.L. Bennett, Louis Caplan, Dennis Choi, Patricia Churchland, Bernard Cohen, Barry Connors, W. Maxwell Cowan, Hanna Damasio, Michael Davis, Vincent Ferrera, Hans

Christian Fibinger, Mark Fishman, Jeff Friedman, Joacquin M. Fuster, Daniel Gardner, Charles Gilbert, Mirchell Glickstein, Corey Goodman, Jack Gorman, Robert Griggs, Kristen Harris, Allan Hobson, Steven Hyman, Kenneth Johnson, Edward Jones, John Kalaska, Maria Karayiorgou, Frederic Kass, Doreen Kimura, Donald Klein, Arnold Kriegstein, Robert LaMotte, Peretz Lavie, Joseph LeDoux, Alan Light, Rodolfo Llinas, Shawn Lockery, John Mann, Eve Marder, C.D. Marsden, Richard Masland, John Maunsell, Robert Mc-Carley, David McCormick, Chris Miller, George Miller, Adrian Morrison, Thomas Nagel, William Newsome, Roger Nicoll, Donata Oertel, Richard Palmiter, Michael Posner, V.S. Ramachandran, Elliott Ross, John R. Searle, Dennis Selkoe, Carla Shatz, David Sparks, Robert Spitzer, Mircea Steriade, Peter Sterling, Larry Swanson, Paula Tallal, Endel Tulving, Daniel Weinberger, and Michael Young.

Back

1 The Brain and Behavior Eric R. Kandel THE LAST FRONTIER OF THE biological sciences—their ultimate challenge—is to understand the biological basis of consciousness and the mental processes by which we perceive, act, learn, and remember.In the last two decades a remarkable unity has emerged within biology. The ability to sequence genes and infer the amino acid sequences for the proteins they encode has revealed unanticipated similarities between proteins in the nervous system and those encountered elsewhere in the body. As a result, it has become possible to establish a general plan for the function of cells, a plan that provides a common conceptual framework for all of cell biology, including cellular neurobiology. The next and even more challenging step in this unifying process within biology, which we outline in this book, will be the unification of the study of behavior—the science of the mind—and neural science, the science of the brain. This last step will allow us to achieve a unified scientific approach to the study of behavior. Such a comprehensive approach depends on the view that all behavior is the result of brain function. What we commonly call the mind is a set of operations carried out by the brain. The actions of the brain underlie not only relatively simple motor behaviors such as walking or eating, but all the complex cognitive actions that we believe are quintessentially human, such as thinking, speaking, and creating works of art. As a corollary, all the behavioral disorders that characterize psychiatric illness—disorders of affect (feeling) and cognition (thought)—are disturbances of brain function. The task of neural science is to explain behavior in terms of the activities of the brain. How does the brain marshal its millions of individual nerve cells to produce behavior, and how are these cells influenced by the environment, which includes the actions of other people? The progress of neural science in explaining human behavior is a major theme of this book. Like all science, neural science must continually confront certain fundamental questions. Are particular mental processes localized to specific regions of the brain, or does the mind represent a collective and emergent property of the whole brain? If specific mental processes can be localized to discrete brain regions, what is the relationship between the anatomy and physiology of one region and its specific function in perception, thought, or movement? Are such relationships more likely to be revealed by examining the region as a whole or by studying its individual nerve cells? In this chapter we consider to what degree mental functions are located in specific regions of the brain and to what degree such local mental processes can be understood in terms of the properties of specific nerve cells and their interconnections. To answer these questions, we look at how modern neural science approaches one of the most elaborate cognitive behaviors—language. In doing so we necessarily P.6 focus on the cerebral cortex, the part of the brain concerned with the most evolved human behaviors. Here we see how the brain is organized into regions or brain compartments, each made up of large groups of neurons, and how highly complex behaviors can be traced to specific regions of the brain and understood in terms of the functioning of groups of neurons. In the next chapter we consider how these neural circuits function at the cellular level, using a simple reflex behavior to examine the way sensory signals are transformed into motor acts.

Two Opposing Views Have Been Advanced on the Relationship Between Brain and Behavior Our current views about nerve cells, the brain, and behavior have emerged over the last century from a convergence of five experimental traditions: anatomy, embryology, physiology, pharmacology, and psychology. Before the invention of the compound microscope in the eighteenth century, nervous tissue was thought to function like a gland—an idea that goes back to the Greek physician Galen, who proposed that nerves convey fluid secreted by the brain and spinal cord to the body's periphery. The microscope revealed the true structure of the cells of nervous tissue. Even so, nervous tissue did not become the subject of a special science until the late 1800s, when the first detailed descriptions of nerve cells were undertaken by Camillo Golgi and Santiago Ramón y Cajal. Golgi developed a way of staining neurons with silver salts that revealed their entire structure under the microscope. He could see clearly that neurons had cell bodies and two major types of projections or processes: branching dendrites at one end and a long cable-like axon at the other. Using Golgi's technique, Ramón y Cajal was able to stain individual cells, thus showing that nervous tissue is not one continuous web but a network of discrete cells. In the course of this work, Ramón y Cajal developed some of the key concepts and much of the early evidence for the neuron doctrine—the principle that individual neurons are the elementary signaling elements of the nervous system. Additional experimental support for the neuron doctrine was provided in the 1920s by the American embryologist Ross Harrison, who demonstrated that the two major projections of the nerve cell—the dendrites and the axon—grow out from the cell body and that they do so even in tissue culture in which each neuron is isolated from other neurons. Harrison also confirmed Ramón y Cajal's suggestion that the tip of the axon gives rise to an expansion called the growth cone, which leads the developing axon to its target (whether to other nerve cells or to muscles). Physiological investigation of the nervous system began in the late 1700s when the Italian physician and physicist Luigi Galvani discovered that living excitable muscle and nerve cells produce electricity. Modern electrophysiology grew out of work in the nineteenth century by three German physiologists—Emil DuBoisReymond, Johannes Müller, and Hermann von Helmholtz—who were able to show that the electrical activity of one nerve cell affects the activity of an adjacent cell in predictable ways. Pharmacology made its first impact on our understanding of the nervous system and behavior at the end of the nineteenth century, when Claude Bernard in France, Paul Ehrlich in Germany, and John Langley in England demonstrated that drugs do not interact with cells arbitrarily, but rather bind to specific receptors typically located in the membrane on the cell surface. This discovery became the basis of the all-important study of the chemical basis of communication between nerve cells. The psychological investigation of behavior dates back to the beginnings of Western science, to classical Greek philosophy. Many issues central to the modern investigation of behavior, particularly in the area of perception, were subsequently reformulated in the seventeenth century first by René Descartes and then by John Locke, of whom we shall learn more later. In the midnineteenth century Charles Darwin set the stage for the study of animals as models of human actions and behavior by publishing his observations on the continuity of species in evolution. This new approach gave rise to ethology, the study of animal behavior in the natural environment, and later to experimental psychology, the study of human and animal behavior under controlled conditions. In fact, by as early as the end of the eighteenth century the first attempts had been made to bring together biological and psychological concepts in the study of behavior. Franz Joseph Gall, a German physician and neuroanatomist, proposed three radical new ideas. First, he advocated that all behavior emanated from the brain. Second, he argued that particular regions of the cerebral cortex controlled specific functions. Gall asserted that the cerebral cortex did not act as a single organ but was divided into at least 35 organs (others were added later), each corresponding to a specific mental faculty. Even the most abstract of human behaviors, such as generosity, secretiveness, and religiosity were assigned their spot in the brain. Third, Gall proposed that the center for each mental function grew with use, much as a muscle bulks up with exercise. As each center P.7

grew, it purportedly caused the overlying skull to bulge, creating a pattern of bumps and ridges on the skull that indicated which brain regions were most developed (Figure 1-1). Rather than looking within the brain, Gall sought to establish an anatomical basis for describing character traits by correlating the personality of individuals with the bumps on their skulls. His psychology, based on the distribution of bumps on the outside of the head, became known as phrenology. In the late 1820s Gall's ideas were subjected to experimental analysis by the French physiologist Pierre Flourens. By systematically removing Gall's functional centers from the brains of experimental animals, Flourens attempted to isolate the contributions of each “cerebral organ” to behavior. From these experiments he concluded that specific brain regions were not responsible for specific behaviors, but that all brain regions, especially the cerebral hemispheres of the forebrain, participated in every mental operation. Any part of the cerebral hemisphere, he proposed, was able to perform all the functions of the hemisphere. Injury to a specific area of the cerebral hemisphere would therefore affect all higher functions equally. In 1823 Flourens wrote: “All perceptions, all volitions occupy the same seat in these cerebral) organs; the faculty of perceiving, of conceiving, of willing merely constitutes therefore a faculty which is essentially one.” The rapid acceptance of this belief (later called the aggregate-field view of the brain) was based only partly on Flourens's experimental work. It also represented a cultural reaction against the reductionist view that the human mind has a biological basis, the notion that there was no soul, that all mental processes could be reduced to actions within different regions in the brain! The aggregate-field view was first seriously challenged in the mid-nineteenth century by the British neurologist J. Hughlings Jackson. In his studies of focal epilepsy, a disease characterized by convulsions that begin in a particular part of the body, Jackson showed that different motor and sensory functions can be traced to different parts of the cerebral cortex. These studies were later refined by the German neurologist Karl Wernicke, the English physiologist Charles Sherrington, and Ramón y Cajal into a view of brain function called cellular connectionism. According to this view, individual neurons are the signaling units of the brain; they are generally arranged in functional groups and connect to one another in a precise fashion. Wernicke's work in particular showed that different behaviors are produced by different brain regions interconnected by specific neural pathways. The differences between the aggregate-field theory and cellular-connectionism can best be illustrated by an analysis of how the brain produces language. Before we consider the relevant clinical and anatomical studies concerned with the localization of language, let us briefly look at the overall structure of the brain. (The anatomical organization of the nervous system is described in detail in Chapter 17.)

Figure 1-1 According to the nineteenth-century doctrine of phrenology, complex traits such as combativeness, spirituality, hope, and conscientiousness are controlled by specific areas in the brain, which expand as the traits develop. This enlargement of local areas of the brain was thought to produce characteristic bumps and ridges on the overlying skull, from which an individual's character could be determined. This map, taken from a drawing of the early 1800s, purports to show 35 intellectual and emotional faculties in distinct areas of the skull and the cerebral cortex underneath.

The Brain Has Distinct Functional Regions The central nervous system is a bilateral and essentially symmetrical structure with seven main parts: the spinal cord, medulla oblongata, pons, cerebellum, midbrain, diencephalon, and the cerebral hemispheres (Box 1-1 and Figures 1-2A,1-2B and 1-3). Radiographic imaging techniques have made it possible to visualize these structures in living subjects. Through a variety of experimental methods, such images of the brain can be made while subjects are engaged in specific tasks, which then can be related to the activities of discrete regions of the brain. As a result, Gall's original idea that different regions are P.8 P.9 specialized for different functions is now accepted as one of the cornerstones of modern brain science.

Box 1-1 The Central Nervous System The central nervous system has seven main parts (Figure 1-2A).

●

The spinal cord, the most caudal part of the central nervous system, receives and processes sensory information from the skin, joints, and muscles of the limbs and trunk and controls movement of the limbs and the trunk. It is subdivided into cervical, thoracic, lumbar, and sacral regions. The spinal cord continues rostrally as the brain stem, which consists of the medulla, pons, and midbrain (see below). The brain stem receives sensory information from the skin and muscles of the head and provides the motor control for the muscles of the head. It also conveys information from the spinal cord to the brain and from the brain to the spinal cord, and regulates levels of arousal and awareness, through the reticular formation. The brain stem contains several collections of cell bodies, the cranial nerve nuclei. Some of these nuclei receive information from the skin and muscles of

the head; others control motor output to muscles of the face, neck, and eyes. Still others are specialized for information from the special senses: hearing, balance, and taste. ●

The medulla oblongata, which lies directly above the spinal cord, includes several centers responsible for vital autonomic functions, such as digestion, breathing, and the control of heart rate. ●

The pons, which lies above the medulla, conveys information about movement from the cerebral hemisphere to the cerebellum. ●

The cerebellum lies behind the pons and is connected to the brain stem by several major fiber tracts called peduncles. The cerebellum modulates the force and range of movement and is involved in the learning of motor skills.

Figure 1-2A The central nervous system can be divided into seven main parts.

●

The midbrain, which lies rostral to the pons, controls many sensory and motor functions, including eye movement and the coordination of visual and auditory reflexes. ●

The diencephalon lies rostral to the midbrain and contains two structures. One, the thalamus, processes most of the information reaching the cerebral cortex from the rest of the central nervous system. The other, the hypothalamus, regulates autonomic, endocrine, and visceral function. ●

The cerebral hemispheres consist of a heavily wrinkled outer layer—the cerebral cortex —and three deep-lying structures: the basal ganglia, the hippocampus, and the amygdaloid nuclei. The basal ganglia participate in regulating motor performance; the hippocampus is involved with aspects of memory storage; and the amygdaloid nuclei coordinate the autonomic and endocrine responses of emotional states. The cerebral cortex is divided into four lobes: frontal, parietal, temporal, and occipital (Figure 1-2B).

The brain is also commonly divided into three broader regions: the hindbrain (the medulla, pons, and cerebellum), midbrain, and forebrain (diencephalon and cerebral hemispheres). The hindbrain (excluding the cerebellum) and midbrain comprise the brain stem.

Figure 1-2B The four lobes of the cerebral cortex.

Figure 1-3 The main divisions are clearly visible when the brain is cut down the midline between the two hemispheres. A. This schematic drawing shows the position of major structures of the brain in relation to external landmarks. Students of brain anatomy quickly learn to distinguish the major internal landmarks, such as the corpus callosum, a large bundle of nerve fibers that connects the left and right hemispheres. B. The major brain divisions drawn in A are also evident here in a magnetic resonance image of a living human brain.

One reason this conclusion eluded investigators for so many years lies in another organizational principle of the nervous system known as parallel distributed processing. As we shall see below, many sensory, motor, and cognitive functions are served by more than one neural pathway. When one functional region or pathway is damaged, others may be able to compensate partially for the loss, thereby obscuring the behavioral evidence for localization. Nevertheless, the neural pathways for certain higher functions have been precisely mapped in the brain.

Cognitive Functions Are Localized Within the Cerebral Cortex The brain operations responsible for our cognitive abilities occur primarily in the cerebral cortex —the furrowed gray matter covering the cerebral hemispheres. In each of the brain's two hemispheres the overlying cortex is divided into four anatomically distinct lobes: frontal, parietal, temporal, and occipital (see Figure 12B), originally named for the skull bones that encase them. These lobes have specialized functions. The frontal lobe is largely concerned with planning future action and with the control of movement; the parietal lobe with somatic sensation, with forming a body image, and with relating one's body image with extrapersonal space; the occipital lobe with vision; the temporal lobe with hearing; and through its deep structures—the hippocampus and the amygdaloid nuclei—with aspects of learning, memory, and emotion. Each lobe has several characteristic deep infoldings (a favored evolutionary strategy for packing in more cells in a limited space). The crests of these convolutions are called gyri, while the intervening grooves are called sulci or fissures. The more prominent gyri and sulci are quite similar in everyone and have specific names. For example, the central sulcus separates the precentral gyrus, which is concerned with motor function, from the postcentral gyrus, which is concerned with sensory function (Figure 1-4A). The organization of the cerebral cortex is characterized by two important features. First, each hemisphere is concerned primarily with sensory and motor processes on the contralateral (opposite) side of the body. Thus sensory information that arrives at the spinal cord from the left side of the body—from the left hand, say—crosses over to the right side of the nervous system (either within the spinal cord or in the brain stem) on its way to the cerebral cortex. Similarly, the motor areas in the right hemisphere exert control over the movements of the left half P.10 of the body. Second, although the hemispheres are similar in appearance, they are not completely symmetrical in structure nor equivalent in function. To illustrate the role of the cerebral cortex in cognition, we will trace the development of our understanding of the neural basis of language, using it as an example of how we have progressed in localizing mental functions in the brain. The neural basis of language is discussed more fully in Chapter 59. Much of what we know about the localization of language comes from studies of aphasia, a language disorder found most often in patients who have suffered a stroke (the occlusion or rupture of a blood vessel supplying blood to a portion of the cerebral hemisphere). Many of the important discoveries in the study of aphasia occurred in rapid succession during the last half of the nineteenth century. Taken together, these advances form one of the most exciting chapters in the study of human behavior, because they offered the first insight into the biological basis of a complex mental function. The French neurologist Pierre Paul Broca was much influenced by Gall and by the idea that functions could be localized. But he extended Gall's thinking in an important way. He argued that phrenology, the attempt to localize the functions of the mind, should be based on examining damage to the brain produced by clinical lesions rather than by examining the distribution of bumps on the outside of the head. Thus he wrote in 1861: “I had thought that if there were ever a phrenological science, it would be the phrenology of convolutions (in the cortex), and not the phrenology of bumps (on the head).” Based on this insight Broca founded neuropsychology, a new science of mental processes that he was to distinguish from the phrenology of Gall. In 1861 Broca described a patient named Leborgne, who could understand language but could not speak. The patient had none of the conventional motor deficits (of the tongue, mouth, or vocal cords) that would affect speech. In fact, he could utter isolated words, whistle, and sing a melody without difficulty. But he could not speak grammatically or create complete sentences, nor could he express ideas in writing. Postmortem examination of this patient's brain showed a lesion in the posterior region of the frontal lobe (now called Broca's area; Figure 1-4B). Broca studied eight similar patients, all with lesions in this region, and in each case found that the lesion was located in the left cerebral hemisphere. This discovery led Broca to announce in 1864 one of the most famous principles of brain function: “Nous parlons avec l'hémisphère gauche!” (“We speak with the left hemisphere!”) Broca's work stimulated a search for the cortical sites of other specific behavioral functions—a search soon rewarded. In 1870 Gustav Fritsch and Eduard Hitzig galvanized the scientific community by showing that characteristic and discrete limb movements in dogs, such as extending a paw, can be produced by electrically stimulating a localized region of the precentral gyrus of the brain. These discrete regions were invariably located in the contralateral motor cortex. Thus, the right hand, the one most humans use for writing and skilled movements, is controlled by the left hemisphere, the same hemisphere that controls speech. In most people, therefore, the left hemisphere is regarded as dominant.

Figure 1-4 The major areas of the cerebral cortex are shown in this lateral view of the of the left hemisphere. A. Outline of the left hemisphere. B. Areas involved in language. Wernicke's area processes the auditory input for language and is important to the understanding of speech. It lies near the primary auditory cortex and the angular gyrus, which combines auditory input with information from other senses. Broca's area controls the production of intelligible speech. It lies near the region of the motor area that controls the mouth and tongue movements that form words. Wernicke's area communicates with Broca's area by a bidirectional pathway, part of which is made up of the arcuate fasciculus. (Adapted from Geschwind 1979.)

The next step was taken in 1876 by Karl Wernicke. At age 26 Wernicke published a now classic paper, “The P.11 Symptom-Complex of Aphasia: APsychological Study on an Anatomical Basis.” In it he described another type of aphasia, one involving a failure to comprehend language rather than to speak (a receptive as opposed to an expressive malfunction). Whereas Broca's patients could understand language but not speak, Wernicke's patient could speak but could not understand language. Moreover, the locus of this new type of aphasia was different from that described by Broca: the critical cortical lesion was located in the posterior part of the temporal lobe where it joins the parietal and occipital lobes (Figure 1-4B). On the basis of this discovery, and the work of Broca, Fritsch, and Hitzig, Wernicke formulated a theory of language that attempted to reconcile and extend the two theories of brain function holding sway at that time. Phrenologists argued that the cortex was a mosaic of functionally specific areas, whereas the aggregatefield school argued that mental functions were distributed homogeneously throughout the cerebral cortex. Wernicke proposed that only the most basic mental functions, those concerned with simple perceptual and motor activities, are localized to single areas of the cortex. More complex cognitive functions, he argued, result from interconnections between several functional sites. In placing the principle of localized function within a connectionist framework, Wernicke appreciated that different components of a single behavior are processed in different regions of the brain. He was thus the first to advance the idea of distributed processing, now central to our understanding of brain function. Wernicke postulated that language involves separate motor and sensory programs, each governed by separate cortical regions. He proposed that the motor program, which governs the mouth movements for speech, is located in Broca's area, suitably situated in front of the motor area that controls the mouth, tongue, palate, and vocal cords (Figure 1-4B). And he assigned the sensory program, which governs word perception, to the temporal lobe area he discovered (now called Wernicke's area). This area is conveniently surrounded by the auditory cortex as well as by areas collectively known as association cortex, areas that integrate auditory, visual, and somatic sensation into complex perceptions. Thus Wernicke formulated the first coherent model for language organization that (with modifications and elaborations we shall soon learn about) is still of some use today. According to this model, the initial steps in the processing of spoken or written words by the brain occur in separate sensory areas of the cortex specialized for auditory or visual information. This information is then conveyed to a cortical association area specialized for both visual and auditory information, the angular gyrus. Here, according to Wernicke, spoken or written words are transformed into a common neural representation shared by both speech and writing. From the angular gyrus this representation is conveyed to Wernicke's area, where it is recognized as language and associated with meaning. Without that association, the ability to comprehend language is lost. The common neural representation is then relayed from Wernicke's to Broca's area, where it is transformed from a sensory (auditory or visual) representation into a motor representation that can potentially lead to spoken or written language. When the laststage transformation from sensory to motor representation cannot take place, the ability to express language (either as spoken words or in writing) is lost. Based on this premise, Wernicke correctly predicted the existence of a third type of aphasia, one that results from disconnection. Here the receptive and motor speech zones themselves are spared but the neuronal fiber pathways that connect them are destroyed. This conduction aphasia, as it is now called, is characterized by an incorrect use of words (paraphasia). Patients with conduction aphasia understand words that they hear and read and have no motor difficulties when they speak. Yet they cannot speak coherently; they omit parts of words or substitute incorrect sounds. Painfully aware of their own errors, they are unable to put them right. Inspired in part by Wernicke, a new school of cortical localization arose in Germany at the beginning of the twentieth century led by the anatomist Korbinian Brodmann. This school sought to distinguish different functional areas of the cortex based on variations in the structure of cells and in the characteristic arrangement of these cells into layers. Using this cytoarchitectonic method, Brodmann distinguished 52 anatomically and functionally distinct areas in the human cerebral cortex (Figure 1-5). Thus, by the beginning of the twentieth century there was compelling biological evidence for many discrete areas in the cortex, some with specialized roles in

behavior. Yet during the first half of this century the aggregate-field view of the brain, not cellular connectionism, continued to dominate experimental thinking and clinical practice. This surprising state of affairs owed much to the arguments of several prominent neural scientists, among them the British neurologist Henry Head, the German neuropsychologist Kurt Goldstein, the Russian behavioral physiologist Ivan Pavlov, and the American psychologist Karl Lashley, all advocates of the aggregate-field view. The most influential of this group was Lashley, who was deeply skeptical of the cytoarchitectonic approach to functional delineation of the cortex. “The ‘ideal’ architectonic map is nearly worthless,” Lashley wrote. P.12 “The area subdivisions are in large part anatomically meaningless, and misleading as to the presumptive functional divisions of the cortex.” Lashley's skepticism was reinforced by his attempts, in the tradition of Flourens's work, to find a specific seat of learning by studying the effects of various brain lesions on the ability of rats to learn to run a maze. But Lashley found that the severity of the learning defect seemed to depend on the size of the lesions, not on their precise site. Disillusioned, Lashley—and, after him, many other psychologists —concluded that learning and other mental functions have no special locus in the brain and consequently cannot be pinned down to specific collections of neurons. On the basis of his observations, Lashley reformulated the aggregate-field view into a theory of brain function called mass action, which further belittled the importance of individual neurons, specific neuronal connections, and brain regions dedicated to particular tasks. According to this view, it was brain mass, not its neuronal components, that was crucial to its function. Applying this logic to aphasia, Head and Goldstein asserted that language disorders could result from injury to almost any cortical area. Cortical damage, regardless of site, caused patients to regress from a rich, abstract language to the impoverished utterances of aphasia. Lashley's experiments with rats, and Head's observations on human patients, have gradually been reinterpreted. A variety of studies have demonstrated that the maze-learning task used by Lashley is unsuited to the study of local cortical function because the task involves so many motor and sensory capabilities. Deprived of one sensory capability (such as vision), a rat can still learn to run a maze using another (by following tactile or olfactory cues). Besides, as we shall see, many mental functions are handled by more than one region or neuronal pathway, and a single lesion may not eliminate them all. In addition, the evidence for the localization of function soon became overwhelming. Beginning in the late 1930s, Edgar Adrian in England and Wade Marshall and Philip Bard in the United States discovered that applying a tactile stimulus to different parts of a cat's body elicits electrical activity in distinctly different subregions of the cortex, allowing for the establishment of a precise map of the body surface in specific areas of the cerebral cortex described by Brodmann. These studies established that cytoarchitectonic areas of cortex can be defined unambiguously according to several independent criteria, such as cell type and cell layering, connections, and—most important—physiological function. As we shall see in later chapters, local functional specialization has emerged as a key principle of cortical organization, extending even to individual columns of cells within a functional area. Indeed, the brain is divided into many more functional regions than even Brodmann envisaged!

Figure 1-5 In the early part of the twentieth century Korbinian Brodmann divided the human cerebral cortex into 52 discrete areas on the basis of distinctive nerve cell structures and characteristic arrangements of cell layers. Brodmann's scheme of the cortex is still widely used today and is continually updated. In this drawing each area is represented by its own symbol and is assigned a unique number. Several areas defined by Brodmann have been found to control specific brain functions. For instance, area 4, the motor cortex, is responsible for voluntary movement. Areas 1, 2, and 3 comprise the primary somatosensory cortex, which receives information on bodily sensation. Area 17 is the primary visual cortex, which receives signals from the eyes and relays them to other areas for further deciphering. Areas 41 and 42 comprise the primary auditory cortex. Areas not visible from the outer surface of the cortex are not shown in this drawing.

More refined methods have made it possible to learn even more about the function of different brain regions involved in language. In the late 1950s Wilder Penfield, and more recently George Ojemann used small electrodes to stimulate the cortex of awake patients during brain surgery for epilepsy (carried out under local anesthesia), in search of areas that produce language. Patients were asked to name objects or use language in other ways while different areas of the cortex were stimulated. If the area of the cortex was critical for language, application of the electrical stimulus blocked the patient's ability to name objects. In this way Penfield and Ojemann were able to confirm—in the living conscious brain—the language areas of the cortex described by Broca and Wernicke. In addition, Ojemann discovered other sites essential for language, indicating P.13 that the neural networks for language are larger than those delineated by Broca and Wernicke. Our understanding of the neural basis of language has also advanced through brain localization studies that combine linguistic and cognitive psychological approaches. From these studies we have learned that a brain area dedicated to even a specific component of language, such as Wernicke's area for language comprehension, is further subdivided functionally. These modular subdivisions of what had previously appeared to be fairly elementary operations were first discovered in the mid 1970s by Alfonso Caramazza and Edgar Zurif. They found that different lesions within Wernicke's area give rise to different failures to comprehend. Lesions of the frontal-temporal region of Wernicke's area result in failures in lexical processing, an inability to understand the meaning of words. By contrast, lesions in the parietal-temporal region of Wernicke's area result in failures in syntactical processing, the ability to understand the relationship between the words of a sentence. (Thus syntactical knowledge allows one to appreciate that the sentence “Jim is in love with Harriet” has a different meaning from “Harriet is in love with Jim.”) Until recently, almost everything we knew about the anatomical organization of language came from studies of patients who had suffered brain lesions. Positron emission tomography (PET) and functional magnetic resonance imaging (MRI) have extended this approach to normal people (Chapter 20). PET is a noninvasive imaging technique for visualizing the local changes in cerebral blood flow and metabolism that accompany mental activities, such as reading, speaking, and thinking. In 1988, using this new imaging form, Michael Posner, Marcus Raichle, and their colleagues made an interesting discovery. They found that the

incoming sensory information that leads to language production and understanding is processed in more than one pathway. Recall that Wernicke believed that both written and spoken words are transformed into a representation of language by both auditory and visual inputs. This information, he thought, is then conveyed to Wernicke's area, where it becomes associated with meaning before being transformed in Broca's area into output as spoken language. Posner and his colleagues asked: Must the neural code for a word that is read be translated into an auditory representation before it can be associated with a meaning? Or can visual information be sent directly to Broca's area with no involvement of the auditory system? Using PET, they determined how individual words are coded in the brain of normal subjects when the words are read on a screen or heard through earphones. Thus, when words are heard Wernicke's area becomes active, but when words are seen but not heard or spoken Wernicke's area is not activated. The visual information from the occipital cortex appears to be conveyed directly to Broca's area without first being transformed into an auditory representation in the posterior temporal cortex. Posner and his colleagues concluded that the brain pathways and sensory codes used to see words are different from those used to hear words. They proposed, therefore, that these pathways have independent access to higher-order regions of the cortex concerned with the meaning of words and with the ability to express language (Figure 1-6). Not only are reading and listening processed separately, but the act of thinking about a word's meaning (in the absence of sensory inputs) activates a still different area in the left frontal cortex. Thus language processing is parallel as well as serial; as we shall learn in Chapter 59, it is considerably more complex than initially envisaged by Wernicke. Indeed, similar conclusions have been reached from studies of behavior other than language. These studies demonstrate that information processing requires many individual cortical areas that are appropriately interconnected—each of them responding to, and therefore coding for, only some aspects of specific sensory stimuli or motor movement, and not for others. Studies of aphasia afford unusual insight into how the brain is organized for language. One of the most impressive insights comes from a study of deaf people who lost their ability to speak American Sign Language after suffering cerebral damage. Unlike spoken language, American signing is accomplished with hand gestures rather than by sound and is perceived by visual rather than auditory pathways. Nonetheless, signing, which has the same structural complexities characteristic of spoken languages, is also localized to the left hemisphere. Thus, deaf people can become aphasic for sign language as a result of lesions in the left hemisphere. Lesions in the right hemisphere do not produce these defects. Moreover, damage to the left hemisphere can have quite specific consequences, affecting either sign comprehension (following damage in Wernicke's area) or grammar (following damage in Broca's area) or signing fluency. These observations illustrate three points. First, the cognitive processing for language occurs in the left hemisphere and is independent of pathways that process the sensory or motor modalities used in language. Second, speech and hearing are not necessary conditions for the emergence of language capabilities in the left hemisphere. Third, spoken language represents only one of a family of cognitive skills mediated by the left hemisphere.

Figure 1-6 Specific regions of the cortex involved in the recognition of a spoken or written word can be identified with PET scanning. Each of the four images of the human brain shown here (from the left side of the cortex) actually represents the averaged brain activity of several normal subjects. (In these PET images white represents the areas of highest activity, red and yellow quite high activity, and blue and gray the areas of minimal activity.) The “input” component of language (reading or hearing a word) activates the regions of the brain shown in A and B. The motor “output” component of language (speech or thought) activates the regions shown in C and D. (Courtesy of Cathy Price.) A. The reading of a single word produces a response both inthe primary visual cortex and in the visual association cortex (see Figure 1-5). B. Hearing a word activates an entirely different set of areas in the temporal cortex and at the junction of the temporalparietal cortex. (To control for irrelevant differences, the same list of words was used in both the reading and listening tests.) A and B show that the brain uses several discrete pathways for processing language and does not transform visual signals for processing in the auditory pathway. C. Subjects were asked to repeat a word presented either through earphones or on a screen. Speaking a word activates the supplementary motor area of the medial frontal cortex. Broca's area is activated whether the word is presented orally or visually. Thus both visual and auditory pathways converge on Broca's area, the common site for the motor articulation of speech. D. Subjects were asked to respond to the word “brain” with an appropriate verb (for example, “to think”). This type of thinking activates the frontal cortex as well as Broca's and Wernicke's areas. These areas play a role in all cognition and abstract representation.

P.14

Affective Traits and Aspects of Personality Are Also Anatomically Localized Despite the persuasive evidence for localized languagerelated functions in the cortex, the idea nevertheless persisted that affective (emotional) functions are not localized. Emotion, it was believed, must be an expression of whole-brain activity. Only recently has this view been modified. Although the emotional aspects of behavior have not been as precisely mapped as sensory, motor, and cognitive functions, distinct emotions can be elicited by stimulating specific parts of the brain in humans or experimental animals. The localization of affect has been dramatically demonstrated in patients with certain language disorders and those with a particular type of epilepsy. Aphasia patients not only manifest cognitive defects in language, but also have trouble with the affective aspects of language, such as intonation (or prosody). These affective aspects are represented in the right P.15 hemisphere and, rather strikingly, the neural organization of the affective elements of language mirrors the organization of the logical content of language in the left hemisphere. Damage to the right temporal area corresponding to Wernicke's area in the left temporal region leads to disturbances in comprehending the emotional quality of language, for example, appreciating from a person's tone of voice whether he is describing a sad or happy event. In contrast, damage to the right frontal area corresponding to Broca's area leads to difficulty in expressing emotional aspects of language. Thus some linguistic functions also exist in the right hemisphere. Indeed, there is now considerable evidence that an intact right hemisphere may be necessary to an appreciation of subtleties of language, such as irony, metaphor, and wit, as well as the emotional content of speech. Certain disorders of affective language that are localized to the right hemisphere, called aprosodias, are classified as sensory, motor, or conduction aprosodias, following the classification used for aphasias. This pattern of localization appears to be inborn, but it is by no means completely determined until the age of about seven or eight. Young children in whom the left cerebral hemisphere is severely damaged early in life can still develop an essentially normal grasp of language. Further clues to the localization of affect come from patients with chronic temporal lobe epilepsy. These patients manifest characteristic emotional changes, some of which occur only fleetingly during the seizure itself and are called ictal phenomena (Latin ictus, a blow or a strike). Common ictal phenomena include feelings of unreality and déjàvu (the sensation of having been in a place before or of having had a particular experience before); transient visual or auditory hallucinations; feelings of depersonalization, fear, or anger; delusions; sexual feelings; and paranoia. More enduring emotional changes, however, are evident when patients are not having seizures. These interictal phenomena are interesting because they represent a true psychiatric syndrome. A detailed study of such patients indicates they lose all interest in sex, and the decline in sexual interest is often paralleled by a rise in social aggressiveness. Most exhibit one or more distinctive personality traits: They can be intensely emotional, ardently religious, extremely moralistic, and totally lacking in humor. In striking contrast, patients with epileptic foci outside the temporal lobe show no abnormal emotion and behavior. One important structure for the expression and perception of emotion is the amygdala, which lies deep within the cerebral hemispheres. The role of this structure in emotion was discovered through studies of the effects of the irritative lesions of epilepsy within the temporal lobe. The consequences of such irritative lesions are exactly the opposite of those of destructive lesions resulting from a stroke or injury. Whereas destructive lesions bring about loss of function, often through the disconnection of specialized areas, the electrical storm of epilepsy can increase activity in the regions affected, leading to excessive expression of emotion or over-elaboration of ideas. We consider the neurobiology of emotion in Part VIII of this book.

Mental Processes Are Represented in the Brain by Their Elementary Processing Operations Why has the evidence for localization, which seems so obvious and compelling in retrospect, been rejected so often in the past? The reasons are several. First, phrenologists introduced the idea of localization in an exaggerated form and without adequate evidence. They imagined each region of the cerebral cortex as an independent mental organ dedicated to a complete and distinct mental function (much as the pancreas and the liver are independent digestive organs). Flourens's rejection of phrenology and the ensuing dialectic between proponents of the aggregate-field view (against localization) and the cellular connectionists (for localization) were responses to a theory that was simplistic and overweening. The concept of localization that ultimately emerged—and prevailed—is more subtle by far than anything Gall (or even Wernicke) ever envisioned. In the aftermath of Wernicke's discovery that there is a modular organization for language in the brain consisting of a complex of serial and parallel processing centers with more or less independent functions, we now appreciate that all cognitive abilities result from the interaction of many simple processing mechanisms distributed in many different regions of the brain. Specific brain regions are not concerned with faculties of the mind, but with elementary processing operations. Perception, movement, language, thought, and memory are all made possible by the serial and parallel interlinking of several brain regions, each with specific functions. As a result, damage to a single area need not result in the loss of an entire faculty as many earlier neurologists predicted. Even if a behavior initially disappears, it may partially return as undamaged parts of the brain reorganize their linkages. Thus, it is not useful to represent mental processes as a series of links in a chain, for in such an arrangement the entire process breaks down when a single link is disrupted. The better, more realistic metaphor is to think of mental processes as several railroad lines that all feed P.16 into the same terminal. The malfunction of a single link on one pathway affects the information carried by that pathway, but need not interfere permanently with the system as a whole. The remaining parts of the system can modify their performance to accommodate extra traffic after the breakdown of a line. Models of localized function were slow to be accepted because it is enormously difficult to demonstrate which components of a mental operation are represented by a particular pathway or brain region. Nor has it been easy to analyze mental operations and come up with testable components. Only during the last decade, with the convergence of modern cognitive psychology and the brain sciences, have we begun to appreciate that all mental functions are divisible into subfunctions. One difficulty with breaking down mental processes into analytical categories or steps is that our cognitive experience consists of instantaneous, smooth operations. Actually, these processes are composed of numerous independent information-processing components, and even the simplest task requires coordination of several distinct brain areas. To illustrate this point, consider how we learn about, store, and recall the knowledge that we have in our mind about objects, people, and events in our world. Our common sense tell us that we store each piece of our knowledge of the world as a single representation that can be recalled by memory-jogging stimuli or even by the imagination alone. Everything we know about our grandmother, for example, seems to be stored in one complete representation of “grandmother” that is equally accessible to us whether we see her in person, hear her voice, or simply think about her. Our experience, however, is not a faithful guide to the knowledge we have stored in memory. Knowledge is not stored as complete representations but rather is subdivided into distinct categories and stored separately. For example, the brain stores separately information about animate and inanimate objects. Thus selected lesions in the left temporal lobe's association areas can obliterate a patient's knowledge of living things, especially people, while leaving the patient's knowledge of inanimate objects quite intact. Representational categories such as “living people” can be subdivided even further. A small lesion in the left temporal lobe can destroy a patient's ability to recognize people by name without affecting the ability to recognize them by sight. The most astonishing example of the modular nature of representational mental processes is the finding that our very sense of ourselves as a self-conscious coherent being—the sum of what we mean when we say “I”—is achieved through the connection of independent circuits, each with its own sense of awareness, that carry out separate operations in our two cerebral hemispheres. The remarkable discovery that even consciousness is not a unitary process was made by Roger Sperry and Michael Gazzaniga in the course of studying epileptic patients in whom the corpus callosum—the major tract connecting the two hemispheres—was severed as a treatment for epilepsy. Sperry and Gazzaniga found that each hemisphere had a consciousness that was able to function independently of the other. The right hemisphere, which cannot speak, also cannot understand language that is well-understood by the isolated left hemisphere. As a result, opposing commands can be issued by each hemisphere—each hemisphere has a mind of its own! While one patient was holding a favorite book in his left hand, the right hemisphere, which controls the left hand but cannot read, found that simply looking at the book was boring. The right hemisphere commanded the left hand to put the book down! Another patient would put on his clothes with the left hand, while taking them off with the other. Thus in some

commissurotomized patients the two hemispheres can even interfere with each other's function. In addition, the dominant hemisphere sometimes comments on the performance of the nondominant hemisphere, frequently exhibiting a false sense of confidence regarding problems in which it cannot know the solution, since the information was projected exclusively to the nondominant hemisphere. Thus the main reason it has taken so long to appreciate which mental activities are localized within which regions of the brain is that we are dealing here with biology's deepest riddle: the neural representation of consciousness and self-awareness. After all, to study the relationship between a mental process and specific brain regions, we must be able to identify the components of the mental process that we are attempting to explain. Yet, of all behaviors, higher mental processes are the most difficult to describe, to measure objectively, and to dissect into their elementary components and operations. In addition, the brain's anatomy is immensely complex, and the structure and interconnections of its many parts are still not fully understood. To analyze how a specific mental activity is represented in the brain, we need not only to determine which aspects of the activity are represented in which regions of the brain, but also how they are represented and how such representations interact. Only in the last decade has that become possible. By combining the conceptual tools of cognitive psychology with new physiological techniques and brain imaging methods, we are beginning to visualize the regions of the brain involved in particular behaviors. And we are P.17 just beginning to discern how these behaviors can be broken down into simpler mental operations and mapped to specific interconnected modules of the brain. Indeed, the excitement evident in neural science today is based on the conviction that at last we have in hand the proper tools to explore the extraordinary organ of the mind, so that we can eventually fathom the biological principles that underlie human cognition.

Selected Readings Bear DM. 1979. The temporal lobes: an approach to the study of organic behavioral changes. In: MS Gazzaniga (ed). Handbook of Behavioral Neurobiology, Vol. 2, Neuropsychology. pp. 75–95. New York: Plenum.

Caramazza A. 1995. The representation of lexical knowledge in the brain. In: RD Broadwell (ed). Neuroscience, Memory, and Language, Vol. 1, Decade of the Brain, pp. 133–147. Washington, DC: Library of Congress.

Churchland PS. 1986. Neurophilosophy, Toward a Unified Science of the Mind-Brain. Cambridge, MA: MIT Press.

Cooter R. 1984. The Cultural Meaning of Popular Science: Phrenology and the Organization of Consent in Nineteenth-Century Britain. Cambridge: Cambridge Univ. Press.

Cowan WM. 1981. Keynote. In: FO Schmitt, FG Worden, G Adelman, SG Dennis (eds). The Organization of the Cerebral Cortex: Proceedings of a Neurosciences Research Program Colloquium, pp. xi–xxi. Cambridge, MA: MIT Press.

Ferrier D. 1890. The Croonian Lectures on Cerebral Localisation. London: Smith, Elder.

Geschwind N. 1974. Selected Papers on Language and the Brain. Dordrecht, Holland: Reidel.

Harrington A. 1987. Medicine, Mind, and the Double Brain: A Study in Nineteenth-Century Thought. Princeton, NJ: Princeton Univ. Press.

Harrison RG. 1935. On the origin and development of the nervous system studied by the methods of experimental embryology. Proc R Soc Lond B Biol Sci 118:155–196.

Jackson JH. 1884. The Croonian lectures on evolution and dissolution of the nervous system. Br Med J 1:591–593; 660–663; 703–707.

Kandel ER. 1976. The study of behavior: the interface between psychology and biology. In: Cellular Basis of Behavior: An Introduction to Behavioral Neurobiology, pp. 3–27. San Francisco: Freeman.

Kosslyn SM. 1988. Aspects of a cognitive neuroscience of mental imagery. Science 240:1621–1626.

Marshall JC. 1988. Cognitive neurophysiology: the lifeblood of language. Nature 331:560–561.

Marshall JC. 1988. Cognitive neuropsychology: sensation and semantics. Nature 334:378.

Ojemann GA. 1995. Investigating language during awake neurosurgery. In: RD Broadwell (ed). Neuroscience, Memory, and Language, Vol. 1, Decade of the Brain, pp. 117–131. Washington, DC: Library of Congress.

Petersen SE. 1995. Functional neuroimaging in brain areas involved in language. In: RD Broadwell (ed). Neuroscience, Memory, and Language, Vol. 1, Decade of the Brain, pp. 109–116. Washington DC: Library of Congress.

Posner MI, Petersen SE, Fox PT, Raichle ME. 1988. Localization of cognitive operations in the human brain. Science 240:1627–1631.

Ross ED. 1984. Right hemisphere's role in language, affective behavior and emotion. Trends Neurosci 7:342–346.

Shepherd GM. 1991. Foundations of the Neuron Doctrine. New York: Oxford Univ. Press.

Sperry RW. 1968. Mental unity following surgical disconnection of the cerebral hemispheres. Harvey Lect 62:293–323.

Young RM. 1970. Mind, Brain and Adaptation in the Nineteenth Century. Oxford: Clarendon.

References Adrian ED. 1941. Afferent discharges to the cerebral cortex from peripheral sense organs. J Physiol (Lond) 100: 159–191.

Bernard C. 1878–1879. Leçons sur les Phénomènes de la vie Communs aux Animaux et aux Végétaux. Vols. 1, 2. Paris: Baillière.

Boakes R. 1984. From Darwin to Behaviourism: Psychology and the Minds of Animals. Cambridge, England: Cambridge Univ. Press.

Broca P. 1865. Sur le siége de la faculté du langage articulé. Bull Soc Anthropol 6:377–393.

Brodmann K. 1909. Vergleichende Lokalisationslehre der Grosshirnrinde in ihren Prinzipien dargestellt auf Grund des Zeelenbaues. Leipzig: Barth.

Darwin C. 1872. The Expression of the Emotions in Man and Animals. London: Murray.

Descartes R. [1649] 1984. The Philosophical Writings of Descartes. Cambridge: Cambridge Univ. Press.

DuBois-Reymond E. 1848–1849. Untersuchungen über thierische Elektrizität. Vols. 1, 2. Berlin: Reimer.

Ehrlich P. 1913. Chemotherapeutics: scientific principles, methods, and results. Lancet 2:445–451.

Flourens P. 1824. Recherches expérimentales. Archiv Méd 2:321–370; Cited and translated by P Flourens, JMD Olmsted. In: EA Underwood (ed). 1953. Science, Medicine and History, 2:290–302. London: Oxford Univ. Press.

Flourens P. 1824. Recherches Expérimentales sur les Propriétés et les Fonctions du Système Nerveux, dans les Animaux Vertébrés. Paris: Chez Crevot.

Fritsch G, Hitzig E. 1870. Über die elektrische Erregbarkeit des Grosshirns. Arch Anat Physiol Wiss Med, pp. 300–332; 1960. Reprinted in: G. von Bonin (transl). Some Papers on the Cerebral Cortex, pp. 73–96. Springfield, IL: Thomas. P.18

Gall FJ, Spurzheim G. 1810. Anatomie et Physiologie du Système Nerveux en Général, et du Cerveau en Particulier, avec des Observations sur la Possibilité de Reconnoitre Plusieurs Dispositions Intellectuelles et Morales de l'Homme et des Animaux, par la Configuration de leurs Tetes. Paris: Schoell.

Galvani L. [1791] 1953. Commentary on the Effect of Electricity on Muscular Motion. RM Green (transl). Cambridge, MA: Licht.

Gazzaniga MS, LeDoux JE. 1978. The Integrated Mind. New York: Plenum.

Geschwind N. 1979. Specializations of the human brain. Sci Am 241(3):180–199.

Goldstein K. 1948. Language and Language Disturbances: Aphasic Symptom Complexes and Their Significance for Medicine and Theory of Language. New York: Grune & Stratton.

Golgi C. [1906] 1967. The neuron doctrine: theory and facts. In: Nobel Lectures: Physiology or Medicine, 1901–1921, pp. 189–217. Amsterdam: Elsevier.

Head H. 1921. Release of function in the nervous system. Proc R Soc Lond B Biol Sci 92:184–209.

Head H. 1926. Aphasia and Kindred Disorders of Speech. Vols. 1, 2. Cambridge: Cambridge Univ. Press; 1963. Reprint. New York: Hafner.

Heilman KM, Scholes R, Watson RT. 1975. Auditory affective agnosia. Disturbed comprehension of affective speech. J Neurol Neurosurg Psychiatry 38:69–72.

Langley JN. 1906. On nerve endings and on special excitable substances in cells. Proc R Soc Lond B Biol Sci 78:170–194.

Lashley KS. 1929. Brain Mechanisms and Intelligence: A Quantitative Study of Injuries to the Brain. Chicago: Univ. Chicago Press.

Lashley KS, Clark G. 1946. The cytoarchitecture of the cerebral cortex of Ateles: a critical examination of architectonic studies. J Comp Neurol 85:223–305.

Locke J. 1690. An essay concerning humane understanding. In: Four Books. London.

Loeb J. 1918. Forced Movements, Tropisms and Animal Conduct. Philadelphia: Lippincott.

Marshall WH, Woolsey CN, Bard P. 1941. Observations on cortical somatic sensory mechanisms of cat and monkey. J Neurophysiol 4:1–24.

McCarthy RA, Warrington EK. 1988. Evidence for modalityspecific meaning systems in the brain. Nature 334: 428–430.

Müller J. 1834–1840. Handbuch der Physiologie des Menschen für Vorlesungen. Vols 1, 2. Coblenz: Hölscher.

Nieuwenhuys R, Voogd J, van Huijzen, Chr. 1988. The Human Central Nervous System: A Synopsis and Atlas, 3rd rev. ed. Berlin: Springer.

Pavlov IP. 1927. Conditioned Reflexes: An Investigation of the Physiological Activity of the Cerebral Cortex. GV Anrep (transl). London: Oxford Univ. Press.

Penfield W. 1954. Mechanisms of voluntary movement. Brain 77:1–17.

Penfield W, Rasmussen T. 1950. The Cerebral Cortex of Man: A Clinical Study of Localization of Function. New York: Macmillan.

Penfield W, Roberts L. 1959. Speech and Brain-Mechanisms. Princeton, NJ: Princeton Univ. Press.

Petersen SE, Fox PT, Posner MI, Mintun M, Raichle ME. 1989. Positron emission tomographic studies of the processing of single words. J Cogn Neurosci 1 (2):153–170.

Posner MI, Carr TH. 1992. Lexical access and the brain: anatomical constraints on cognitive models of word recognition. Am J Psychol 105:1–26.

Ramón y Cajal S. [1892] 1977. Anew concept of the histology of the central nervous system. DA Rottenberg (transl). (See also historical essay by SL Palay, preceding Ramón y Cajal's paper.) In: DA Rottenberg, FH Hochberg (eds). Neurological Classics in Modern Translation, pp. 7–29. New York: Hafner.

Ramón y Cajal S. [1906] 1967. The structure and connexions of neurons. In: Nobel Lectures: Physiology or Medicine, 1901–1921, pp. 220–253. Amsterdam: Elsevier.

Ramón y Cajal S. [1908] 1954. Neuron Theory or Reticular Theory? Objective Evidence of the Anatomical Unity of Nerve Cells. MU Purkiss, CA Fox (transl). Madrid: Consejo Superior de Investigaciones Científicas Instituto Ramón y Cajal.

Ramón y Cajal S. 1937. 1852–1934. Recollections of My Life. EH Craigie (transl). Philadelphia: American Philosophical Society; 1989. Reprint. Cambridge, MA: MIT Press.

Rose JE, Woolsey CN. 1948. Structure and relations of limbic cortex and anterior thalamic nuclei in rabbit and cat. J Comp Neurol 89:279–347.

Ross ED. 1981. The aprosodias: functional-anatomic organization of the affective components of language in the right hemisphere. Arch Neurol 38:561–569.

Sherrington C. 1947. The Integrative Action of the Nervous System, 2nd ed. Cambridge: Cambridge Univ. Press.

Spurzheim JG. 1825. Phrenology, or the Doctrine of the Mind, 3rd ed. London: Knight.

Swazey JP. 1970. Action proper and action commune: the localization of cerebral function. J Hist Biol 3:213–234.

von Helmholtz H. 1850. On the rate of transmission of the nerve impulse. Monatsber Preuss Akad Wiss Berlin, pp. 14–15. Translated in: W Dennis (ed). 1948. Readings in the History of Psychology, pp. 197–198. New York: Appleton-Century-Crofts.

Wernicke C. 1908. The symptom-complex of aphasia. In: A Church (ed), Diseases of the Nervous System, pp. 265–324. New York: Appleton.

Zurif E. 1974. Auditory lateralization, prosodic and syntactic factors. Brain Lang 1:391–401.

Back

2 Nerve Cells and Behavior Eric R. Kandel HUMANS ARE VASTLY superior to other animals in their ability to exploit their physical environment. The remarkable range of human behavior—indeed, the complexity of the environment humans have been able to create for themselves—depends on a sophisticated array of sensory receptors connected to a highly flexible neural machine—a brain—that is able to discriminate an enormous variety of events in the environment. The continuous stream of information from these receptors is organized by the brain into perceptions (some of which are stored in memory for future reference) and then into appropriate behavioral responses. All of this is accomplished by the brain using nerve cells and the connections between them. Individual nerve cells, the basic units of the brain, are relatively simple in their morphology. Although the human brain contains an extraordinary number of these cells (on the order of 1011 neurons), which can be classified into at least a thousand different types, all nerve cells share the same basic architecture. The complexity of human behavior depends less on the specialization of individual nerve cells and more on the fact that a great many of these cells form precise anatomical circuits. One of thekey organizational principles of the brain, therefore, is that nerve cellswith basically similar properties can nevertheless produce quite differentactions because of the way they are connected with each other and with sensory receptors and muscle. Since relatively few principles of organization give rise to considerable complexity, it is possible to learn a great deal about how the nervous system produces behavior by focusing on four basic features of the nervous system:

●

The mechanisms by which neurons produce signals. ●

The patterns of connections between nerve cells. ●

The relationship of different patterns of interconnection to different types of behavior. ●

The means by which neurons and their connections are modified by experience.

In this chapter we introduce these four features by first considering the structural and functional properties P.20 of neurons and the glial cells that surround and support them. We then examine how individual cells organize and transmit signals and how signaling between a few interconnected nerve cells produces a simple behavior, the knee jerk reflex. Finally, we consider how changes in the signaling ability of specific cells can modify behavior.

The Nervous System Has Two Classes of Cells There are two main classes of cells in the nervous system: nerve cells (neurons) and glial cells (glia).

Glial Cells Are Support Cells Glial cells far outnumber neurons—there are between 10 and 50 times more glia than neurons in the central nervous system of vertebrates. The name for these cells derives from the Greek for glue, although in actuality glia do not commonly hold nerve cells together. Rather, they surround the cell bodies, axons, and dendrites of neurons. As far as is known, glia are not directly involved in information processing, but they are thought to have at least seven other vital roles:

●

Glial cells support neurons, providing the brain with structure. They also separate and sometimes insulate neuronal groups and synaptic connections from each other. ●

Two types of glial cells (oligodendrocytes and Schwann cells) produce the myelin used to insulate nerve cell axons, the cell outgrowths that conduct electrical signals. ●

Some glial cells are scavengers, removing debris after injury or neuronal death. ●

Glial cells perform important housekeeping chores that promote efficient signaling between neurons (Chapter 14). For example, some glia also take up chemical transmitters released by neurons during synaptic transmission. ●

During the brain's development certain classes of glial cells (“radial glia”) guide migrating neurons and direct the outgrowth of axons. ●

In some cases, as at the nerve-muscle synapse of vertebrates, glial cells actively regulate the properties of the presynaptic terminal. ●

Some glial cells (astrocytes) help form an impermeable lining in the brain's capillaries and venules— the blood-brain barrier—that prevents toxic substances in the blood from entering the brain (Appendix B). ●

Other glial cells apparently release growth factors and otherwise help nourish nerve cells, although this role has been difficult to demonstrate conclusively.

Glial cells in the vertebrate nervous system are divided into two major classes: microglia and macroglia.

Microglia are phagocytes that are mobilized after injury, infection, or disease. They arise from macrophages outside the nervous system and are physiologically and embryologically unrelated to the other cell types of the nervous system. Not much is known about what microglia do in the resting state, but they become activated and recruited during infection, injury, and seizure. The activated cell has a process that is stouter and more branched than that of inactivated cells, and it expresses a range of antigens, which suggests that it may serve as the major antigen presenting cell in the central nervous system. Microglia are thought to become activated in a number of diseases including multiple sclerosis and AIDS-related dementia, as well as various chronic neurodegenerative diseases such as Parkinson's disease and Alzheimer's disease. Three types of macroglial cells predominate in the vertebrate nervous system: oligodendrocytes, Schwann cells, and astrocytes. Oligodendrocytes and Schwann cells are small cells with relatively few processes. Both types carry out the important job of insulatingaxons, forming a myelin sheath by tightly winding their membranous processes around the axon in a spiral. Oligodendrocytes, which are found in the central nervous system, envelop an average of 15 axonal internodes each (Figure 2-1A). By contrast, Schwann cells, which occur in the peripheral nervous system, each envelop just one internode of only one axon (Figure 2-1B). The types of myelin produced by oligodendrocytes and Schwann cells differ to some degree in chemical makeup. Astrocytes, the most numerous of glial cells, owe their name to their irregular, roughly star-shaped cell bodies (Figure 2-1C). They tend to have rather long processes, some of which terminate in end-feet. Some astrocytes form end-feet on the surfaces of nerve cells in the brain and spinal cord and may play a role in bringing nutrients to these cells. Other astrocytes place end-feet on the brain's blood vessels and cause the vessel's endothelial (lining) cells to form tight junctions, thus creating the protective blood-brain barrier (Figure 2-1C). Astrocytes also help to maintain the right potassium ion concentration in the extracellular space between neurons. As we shall learn below and in Chapter 7, when a nerve cell fires, potassium ions flow out of the cell. Repetitive firing may create an excess of extracellular potassium that could interfere with signaling between cells in the vicinity. Because astrocytes are highly P.21 permeable to potassium, they can take up the excess potassium and so protect those neighboring neurons. In addition, astrocytes take up neurotransmitters from synaptic zones after release and thereby help regulate synaptic activities by removing transmitters. But the role of astrocytes is largely a supporting one.

Figure 2-1 The principal types of glial cells in the central nervous system are astrocytes and oligodendrocytes and in the peripheral nervous system, Schwann cells. A. Oligodendrocytes are small cells with relatively few processes. In white matter (left) they provide the myelin, and in gray matter (right) perineural oligodendrocytes surround and support the cell bodies of neurons. A single oligodendrocyte can wrap its membranous processes around many axons, insulating them with a myelin sheath. B. Schwann cells furnish the myelin sheaths that insulate axons in the peripheral nervous system. Each of several Schwann cells, positioned along the length of a single axon, forms a segment of myelin sheath about 1 mm long. The sheath assumes its form as the inner tongue of the Schwann cell turns around the axon several times, wrapping it in concentric layers of membrane. The intervals between segments of myelin are known as the nodes of Ranvier. In living cells the layers of myelin are more compact than what is shown here. (Adapted from Alberts et al. 1994.) C. Astrocytes, the most numerous of glial cells in the central nervous system, are characterized by their star-like shape and the broad end-feet on their processes. Because these endfeet put the astrocyte into contact with both capillaries and neurons, astrocytes are thought to have a nutritive function. Astrocytes also play an important role in forming the bloodbrain barrier.

There is no evidence that glia are directly involved in electrical signaling. Signaling is the function of nerve cells.

Nerve Cells Are the Main Signaling Units of the Nervous System A typical neuron has four morphologically defined regions: the cell body, dendrites, the axon, and presynaptic terminals (Figure 2-2). As we shall see later, each of these regions has a distinct role in the generation of signals and the communication of signals between nerve cells. The cell body (soma) is the metabolic center of the cell. It contains the nucleus, which stores the genes of the cell, as well as the endoplasmic reticulum, an extension of the nucleus where the cell's proteins are synthesized. The cell body usually gives rise to two kinds of processes: several short dendrites and one, long, tubular axon. Dendrites branch out in tree-like fashion and are the main apparatus for receiving incoming signals from other nerve cells. In contrast, the axon extends away from the cell body and is the main conducting unit for carrying signals to other neurons. An axon can convey electrical signals along distances ranging from 0.1 mm to 3 m. These electrical signals, called action potentials, are rapid, transient, all-or-none nerve impulses, with an amplitude of 100 mV and a duration of about 1 ms (Figure 2-3). Action potentials are initiated at a specialized trigger region at the origin of the axon called the axon hillock (or initial segment of the axon); from there they are conducted down the axon without failure or distortion at rates of 1–100 m per second. The amplitude of an action potential traveling down the axon remains constant because the action potential is an all-or-none impulse that is regenerated at regular intervals along the axon. P.22 Action potentials constitute the signals by which the brain receives, analyzes, and conveys information. These signals are highly stereotyped throughout the

nervous system, even though they are initiated by a great variety of events in the environment that impinge on our bodies—from light to mechanical contact, from odorants to pressure waves. Thus, the signals that convey information about vision are identical to those that carry information about odors. Here we encounter another key principle of brain function. The information conveyed by an action potential is determined not by the form of the signal but by the pathway the signal travels in the brain. The brain analyzes and interprets patterns of incoming electrical signals and in this way creates our everyday sensations of sight, touch, taste, smell, and sound. To increase the speed by which action potentials are conducted, large axons are wrapped in a fatty, insulating sheath of myelin. The sheath is interrupted at regular intervals by the nodes of Ranvier. It is at these uninsulated spots on the axon that the action potential becomes regenerated. We shall learn more about myelination in Chapter 4 and about action potentials in Chapter 9. Near its end, the tubular axon divides into fine branches that form communication sites with other neurons. The point at which two neurons communicate is known as a synapse. The nerve cell transmitting a signal is called the presynaptic cell. The cell receiving the signal is P.23 the postsynaptic cell. The presynaptic cell transmits signals from the swollen ends of its axon's branches, called presynaptic terminals. However, a presynaptic cell does not actually touch or communicate anatomically with the postsynaptic cell since the two cells are separated by a space, the synaptic cleft. Most presynaptic terminals end on the postsynaptic neuron's dendrites, but the terminals may also end on the cell body or, less often, at the beginning or end of theaxon of the receiving cell (Figure 2-2).

Figure 2-2 Structure of a neuron. Most neurons in the vertebrate nervous system have several main features in common. The cell body contains the nucleus, the storehouse of genetic information, and gives rise to two types of cell processes, axons and dendrites. Axons, the transmitting element of neurons, can vary greatly in length; some can extend more than 3 m within the body. Most axons in the central nervous system are very thin (between 0.2 and 20 µm in diameter) compared with the diameter of the cell body (50 µm or more). Many axons are insulated by a fatty sheath of myelin that is interrupted at regular intervals by the nodes of Ranvier. The action potential, the cell's conducting signal, is initiated either at the axon hillock, the initial segment of the axon, or in some cases slightly farther down the axon at the first node of Ranvier. Branches of the axon of one neuron (the presynaptic neuron) transmit signals to another neuron (the postsynaptic cell) at a site called the synapse. The branches of a single axon may form synapses with as many as 1000 other neurons. Whereas the axon is the output element of the neuron, the dendrites (apical and basal) are input elements of the neuron. Together with the cell body, they receive synaptic contacts from other neurons.

Figure 2-3 This historic tracing is the first published intracellular recording of an action potential. It was obtained in 1939 by Hodgkin and Huxley from the squid giant axon, using glass capillary electrodes filled with sea water. Time marker is 500 Hz. The vertical scale indicates the potential of the internal electrode in millivolts, the sea water outside being taken as zero potential. (From Hodgkin and Huxley 1939.)

As we saw in Chapter 1, Ramón y Cajal provided much of the early evidence for the now basic understanding that neurons are the signaling units of the nervous system and that each neuron is a discrete cell with distinctive processes arising from its cell body (the neuron doctrine). In retrospect, it is hard to appreciate how difficult it was to persuade scientists of this elementary idea. Unlike other tissues, whose cells have simple shapes and fit into a single field of the light microscope, nerve cells have complex shapes; the elaborate patterns of dendrites and the seemingly endless course of some axons made it extremely difficult initially to establish a relationship between these elements. Even after the anatomists Jacob Schleiden and Theodor Schwann put forward the cell theory in the early 1830s—when the idea that cells are the structural units of all living matter became a central dogma of biology—most anatomists would not accept that the cell theory applied to the brain, which they thought of as a continuous web-like reticulum. The coherent structure of the neuron did not become clear until late in the nineteenth century, when Ramón y Cajal began to use the silver staining method introduced by Golgi. This method, which continues to be used today, has two advantages. First, in a random manner that is still not understood, the silver solution stains only about 1% of the cells in any particular brain region, making it possible to study a single nerve cell in isolation from its neighbors. Second, the neurons that do take up the stain are delineated in their entirety, including the cell body, axon, and full dendritic tree. The stain shows that (with rare exceptions we shall consider later) there is no cytoplasmic continuity between neurons, even at the synapse between two cells. Thus, neurons do not form a syncytium; each neuron is clearly segregated from every other neuron. Ramón y Cajal applied Golgi's method to the embryonic nervous systems of many animals, including the human brain. By examining the structure of neurons in almost every region of the nervous system and tracing the contacts they made with one another, Ramón y Cajal was able to describe the differences between classes of nerve cells and to map the precise connections between a good many of them. In this way Ramón y Cajal grasped, in addition to the neuron doctrine, two other principles of neural organization that would prove particularly valuable in studying communication in the nervous system. The first of these has become known as the principle of dynamic polarization. It states that electrical signals within a nerve cell flow only in one direction: from the receiving sites of the neuron (usually the dendrites and cell body) to the trigger region at the axon. From there, the action potential is propagated unidirectionally along the entire length of the axon to the cell's presynaptic terminals. Although neurons vary in shape and function, the operation of most follows this rule of information flow. Later in this chapter we shall describe the physiological basis of this principle. The second principle, the principle of connectional specificity, states that nerve cells do not connect indiscriminately with one another to form random networks; rather each cell makes specific connections—at particular contact points—with certain postsynaptic target cells but not with others. Taken together, the principles of dynamic polarization and connectional specificity form the cellular basis of the modern connectionist approach to the brain discussed in Chapter 1. Ramón y Cajal was also among the first to realize that the feature that most distinguishes one neuron from another is shape—specifically, the number and form of the processes arising from the cell body. On the basis of shape, neurons are classified into three large groups: unipolar, bipolar, and multipolar.

Figure 2-4 Neurons can be classified as unipolar, bipolar, or multipolar according to the number of processes that originate from the cell body. A. Unipolar cells have a single process, with different segments serving as receptive surfaces or releasing terminals. Unipolar cells are characteristic of the invertebrate nervous system. B. Bipolar cells have two processes that are functionally specialized: the dendrite carries information to the cell, and the axon transmits information to other cells. C. Certain neurons that carry sensory information, such as information about touch or stretch, to the spinal cord belong to a subclass of bipolar cells designated as pseudo-unipolar. As such cells develop, the two processes of the embryonic bipolar cell become fused and emerge from the cell body as a single process. This outgrowth then splits into two processes, both of which function as axons, one going to peripheral skin or muscle, the other going to the central spinal cord. D. Multipolar cells have an axon and many dendrites. They are the most common type of neuron in the mammalian nervous system. Three examples illustrate the large diversity of these cells. Spinal motor neurons (left) innervate skeletal muscle fibers. Pyramidal cells (middle) have a roughly triangular cell body; dendrites emerge from both the apex (the apical dendrite) and the base (the basal dendrites). Pyramidal cells are found in the hippocampus and throughout the cerebral cortex. Purkinje cells of the cerebellum (right) are characterized by the rich and extensive dendritic tree in one plane. Such a structure permits enormous synaptic input. (Adapted from Ramón y Cajal 1933.)

P.24 Unipolar neurons are the simplest nerve cells because they have a single primary process, which usually gives rise to many branches. One branch serves as the axon; other branches function as dendritic receiving structures (Figure 2-4A). These cells predominate in the nervous systems of invertebrates; in vertebrates they occur in the autonomic nervous system. Bipolar neurons have an oval-shaped soma that gives rise to two processes: a dendrite that conveys information from the periphery of the body, and an axon that carries information toward the central nervous system (Figure 2-4B). Many sensory cells are bipolar cells, including those in the retina of the eye and in the olfactory epithelium of the nose. The mechanoreceptors that convey touch, pressure, and pain to the spinal cord are variants of bipolar cells called pseudounipolar cells. These cells develop initially as bipolar cells; later the two cell processes fuse to form one axon that emerges from the cell body. The axon then splits into two; one branch runs to the periphery (to sensory receptors in the skin, joints, and muscle), the other to the spinal cord (Figure 2-4C). Multipolar neurons predominate in the nervous system of vertebrates. They have a single axon and, typically, many dendrites emerging from various points around the cell body (Figure 2-4D). Multipolar cells vary greatly in shape, especially in the length of their P.25 axons and in the number, length, and intricacy of dendrite branching. Usually the number and extent of their dendrites correlate with the number of synaptic contacts that other neurons make onto them. A spinal motor cell with a relatively modest number of dendrites receives about 10,000 contacts—2000 on its cell body and 8000 on its dendrites. The dendritic tree of a Purkinje cell in the cerebellum is much larger and bushier, as well it might be—it receives approximately 150,000 contacts! Neurons are also commonly classified into three major functional groups: sensory, motor, and interneuronal. Sensory neurons carry information from the body's periphery into the nervous system for the purpose of both perception and motor coordination.1 Motor neurons carry commands from the brain or spinal cord to muscles and glands. Interneurons constitute by far the largest class, consisting of all nerve cells that are not specifically sensory or motor. Interneurons are subdivided into two classes. Relay or projection interneurons have long axons and convey signals over considerable distances, from one brain region to another. Local interneurons have short axons and process information within local circuits.

Nerve Cells Form Specific Signaling Networks That Mediate Specific Behaviors All the behavioral functions of the brain—the processing of sensory information, the programming of motor and emotional responses, the vital business of storing information (memory)—are carried out by specific sets of interconnected neurons. Here we shall examine in general terms how a behavior is produced by considering a simple stretch reflex, the knee jerk. We shall see how a transient imbalance of the body, which puts a stretch on the extensor muscles of the leg, produces sensory information that is conveyed to motor cells, which in turn convey commands to the extensor muscles to contract so that balance will be restored. The anatomical components of the knee jerk are shown in Figure 2-5. The tendon of the quadriceps femoris, an extensor muscle that moves the lower leg, is attached to the tibia through the tendon of the kneecap, the patellar tendon. Tapping this tendon just below the patella will pull (stretch) the quadriceps femoris. This initiates a reflex contraction of the quadriceps muscle to produce the familiar knee jerk, an extension of the leg smoothly coordinated with a relaxation of the hamstrings, the opposing flexor muscles. By increasing the tension of a selected group of muscles, the stretch reflex changes the position of the leg, suddenly extending it outward. (The regulation of movement by the nervous system is discussed in Section VI.)

Figure 2-5 The knee jerk is an example of a monosynaptic reflex system, a simple behavior controlled by directconnections between sensory and motor neurons. Tapping the kneecap with a reflex hammer pulls on the tendon of the quadriceps femoris, an extensor muscle that extends the lower leg. When the muscle stretches in response to the pull of the tendon, information regarding this change in the muscle is conveyed by afferent (sensory) neurons to the central nervous system. In the spinal cord the sensory neurons act directly on extensor motor neurons that contract the quadriceps, the muscle that was stretched. In addition, the sensory neurons act indirectly, through interneurons, to inhibit flexor motor neurons that would otherwise contract the opposing muscle, the hamstring. These actions combine to produce the reflex behavior. In this schematic drawing each extensor and flexor motor neuron represents a population of many cells.

Stretch reflexes like the knee jerk are a special type of reflex called spinal reflexes, behaviors mediated by neural circuits that are entirely confined to the spinal P.26 cord. As we shall see later in the book, such spinal circuits relieve the major motor systems of the brain of having to micromanage elementary behavioral actions. Stretch reflexes are mediated in good part by monosynaptic circuits, in which the sensory neurons and motor neurons executing the action are directly connected to one another, with no interneuron intervening between them. Most other reflexes, including most spinal reflexes, use polysynaptic circuits that include one or more sets of interneurons. Polysynaptic circuits are more amenable to modification by the brain's higher processing centers. The cell bodies of the mechanoreceptor sensory neurons involved in the knee jerk are clustered near the spinal cord in a dorsal root ganglion (Figure 2-5). They are pseudo-unipolar cells; one branch of the cell's axongoes to the quadriceps muscle at the periphery, while the other runs centrally into the spinal cord. The branch that innervates the quadriceps makes contact with stretchsensitive receptors called muscle spindles and is excited when the muscle is stretched. The branch in the spinal cord forms excitatory connections with the motor neurons that innervate the quadriceps and control its contraction. In addition, this branch contacts local interneurons that inhibit the motor neurons controlling the opposing flexor muscles. These local interneurons are not involved in the stretch reflex itself, but by coordinating motor action they increase the stability of the reflex response. Thus, the electrical signals that produce the stretch reflex convey four kinds of information:

●

Sensory information is conveyed to the central nervous system (the spinal cord) from the body's surface. ●

Motor commands from the central nervous system are issued to the muscles that carry out the knee jerk. ●

Complementary, inhibitory commands are issued to motor neurons that innervate opposing muscles, providing coordination of muscle action. ●

Information about local neuron activity related to the knee jerk is conveyed to higher centers of the central nervous system, thus permitting the brain to coordinate behavioral commands.

The stretching of just one muscle, the quadriceps, activates several hundred sensory neurons, each of which makes direct contact with 100–150 motor neurons (Figure 2-6A). This pattern of connection, in which one neuron activates many target cells, is called neuronal divergence; it is especially common in the input stages of the nervous system. By distributing its signals to many target cells, a single neuron can exert wide and diverse influence. For example, sensory neurons involved in a stretch reflex also contact projection interneurons that transmit information about the local neural activity to higher brain regions concerned with coordinating movements. In contrast, because there are usually five to 10 times more sensory neurons than motor neurons, a single motor cell typically receives input from many sensory cells (Figure 2-6B). This pattern of connection, called convergence, is common at the output stages of the nervous system. By receiving signals from numerous neurons, the target motor cell is able to integrate diverse information from many sources.

Figure 2-6 Diverging and convergingneuronal connections are a key organizational feature of the brain. A. In the sensory systems receptor neurons at the input stage usually branch out and make multiple, divergent connections with neurons that represent the second stage of processing. Subsequent connections diverge even more. B. By contrast, motor neurons are the targets of progressively converging connections. With convergence, the target cell receives the sum of information from many presynaptic cells.

A stretch reflex such as the knee jerk is a simple behavior produced by two classes of neurons connecting at excitatory synapses. But not all important signals in the brain are excitatory. In fact, half of all neurons produce inhibitory signals. Inhibitory neurons release a transmitter that reduces the likelihood of firing. As we have seen, even in the knee-jerk reflex, the sensory neurons make both excitatory connections and connections through inhibitory interneurons. Excitatory connections with the leg's extensor muscles cause these muscles to contract, while connections with certain inhibitory interneurons prevent the antagonist flexor muscles from being called to action. This feature of the circuit is an example of feed-forward inhibition (Figure 2-7A). Feedforward inhibition in the knee-jerk reflex is reciprocal, ensuring that the flexor and extensor pathways always P.27 inhibit each other, so only muscles appropriate for the movement, and not those that oppose it, are recruited.

Figure 2-7 Inhibitory interneurons can produce either feed forward or feedback inhibition. A. Feed-forward inhibition is common in monosynaptic reflex systems, such as the knee-jerk reflex (see Figure 2-5). Afferent neurons from extensor muscles excite not only the extensor motor neurons, but also inhibitory neurons that prevent the firing of the motor cells in the opposingflexor muscles. Feedforward inhibition enhances the effect of the active pathway by suppressing the activity of other, opposing, pathways. B. Negative feedback inhibition is a self-regulating mechanism. The effect is to dampen activity within the stimulated pathway and prevent it from exceeding a certain critical maximum. Here the extensor motor neurons act on inhibitory interneurons, which feed back to the extensor motor neurons themselves and thus reduce the probability of firing by these cells.

Neurons can also have connections that provide feedback inhibition. For example, an active neuron may have excitatory connections withboth a target cell and an inhibitory interneuron that has its own feedbackconnection with the active neuron. In this way signals from the active neuron simultaneously excite the target neuron and the inhibitory interneuron, which thus is able to limit the ability of the active neuron to excite its target (Figure 2-7B). We will encounter many examples of feed-forward and feedback inhibition when we examine more complex behaviors in later chapters.

Signaling Is Organized in the Same Way in All Nerve Cells To produce a behavior, a stretch reflex for example, each participating sensory and motor nerve cell sequentially generates four different signals at different sites within the cell: an input signal, a trigger signal, a conducting signal, and an output signal. Regardless of cell size and shape, transmitter biochemistry, or behavioral function, almost all neurons can be described by a model neuron that has four functional components, or regions, that generate the four types of signals (Figure 2-8): a local input (receptive) component, a trigger (summing or integrative) component, a long-range conducting (signaling) component, and an output (secretory) component. This model neuron is the physiological representation of Ramón y Cajal's principle of dynamic polarization. The different types of signals used by a neuron are determined in part by the electrical properties of the cell membrane. At rest, all cells, including neurons, maintain a difference in the electrical potential on either side of the plasma (external) membrane. This is called the resting membrane potential. In a typical resting neuron the electrical potential difference is about 65 mV. Because the net charge outside of the membrane is arbitrarily defined as zero, we say the resting membrane potential is -65 mV. (In different nerve cells it may range from about -40 to -80 mV; in muscle cells it is greater still, about -90 mV.) As we shall see in Chapter 7, the difference in electrical potential when the cell is at rest results from two factors: (1) the unequal distribution of electrically charged ions, in particular, the positively charged Na+ and K+ ions and the negatively charged amino acids and proteins on either side of the cell membrane, and (2) the selective permeability of the membrane to just one of these ions, K+. The unequal distribution of positively charged ions on either side of the cell membrane is maintained by a membrane protein that pumps Na+ out of the cell and K +

back into it. This Na+-K+ pump, which we shall learn more about in Chapter 7, keeps the Na+ ion concentration in the cell low (about 10 times lower than that

outside the cell) and the K+ ion concentration high (about 20 times higher than that outside). At the same time, the cell membrane is selectively permeable to K+ because the otherwise impermeable membrane contains ion channels, pore-like structures that span the membrane and are highly permeable to K+ but considerably less permeable to Na+. When the cell is at rest, these channels are open and K+ ions tend to leak out. As K+ ions leak from the cell, they leave behind a cloud of unneutralized negativecharge on the inner surface of the membrane, so that the net charge inside P.28 the membrane is more negative than on the outside (Figure 2-9).

Figure 2-8 Most neurons, regardlessof type, have four functional regions in common: an input component, a trigger or integrative component, a conductile component, and an output component. Thus, the functional organization of most neurons can be schematically represented by a model neuron. Each component produces a characteristic signal: the input, integrative, and conductile signals are all electrical, while the output signal consists of the release of a chemical transmitter into the synaptic cleft. Not all neurons share all these features; for example, local interneurons often lack a conductile component.

Excitable cells, such as nerve and muscle cells, differ from other cells in that their membrane potential can be significantly and quickly altered; this change can serve as a signaling mechanism. Reducing the membrane potential by say 10 mV (from -65 mV to -55 mV) makes the membrane much more permeable to Na+ than to K+. This influx of positively charged Na+ ions tends to neutralize the negative charge inside the cell and results in an even greater reduction in membrane potential— the action potential. The action potential is conducted down the cell's axon to the axon's terminals which end on other cells (neurons or muscle), where the action potential initiates communication with the other cells. As noted earlier, the action potential is an all-or-none impulse that is actively propagated along the axon, so that its amplitude is not diminished by the time it reaches the axon terminal. Typically, an action potential lasts about one millisecond, after which the membrane returns to its resting state, with its normal separation of charges and higher permeability to K+ than to Na+. We shall learn more about the mechanisms underlying the resting potential and action potential in Chapters 6,7,8,9.

In addition to the long-range signal of the action potential, nerve cells also produce local signals, such as receptor potentials and synaptic potentials, that are not actively propagated and therefore typically decay within just a few millimeters. Both long-range and local signals result from changes in the membrane potential, either a decrease or increase from the resting potential. The resting membrane potential therefore provides the baseline against which all signals are expressed. A reduction in membrane potential (eg, from -65 mV to -55 mV) is called depolarization. Because depolarization enhances a cell's ability to generate an action potential, it is excitatory. In contrast, an increase in membrane potential (eg, from about -65 mV to -75 mV) is called hyperpolarization. Hyperpolarization makes a cell less likely to generate an action potential and is therefore inhibitory.

The Input Component Produces Graded Local Signals In most neurons at rest no current flows from one part of the neuron to another, so the resting potential is the same throughout the cell. In sensory neurons current flow is typically initiated by a sensory stimulus, which activates specialized receptor proteins at the neuron's receptive surface. In our example of the knee jerk, P.29 stretch of the quadriceps muscle activates specific proteins that are sensitive to stretch of the sensory neuron. The specialized receptor protein forms ion channels in the membrane, through which Na+ and K+ flow. These channels open when the cell is stretched, as we shall learn in Chapters 7 and 9, permitting a rapid influx of ions into the sensory cell. This ionic current disturbs the resting potential of the cell membrane, driving the membrane potential to a new level called the receptor potential. The amplitude and duration of the receptor potential depends on the intensity of the muscle stretch. The larger or longer-lasting the stretch, the larger and longer-lasting the resulting receptor potential (Figure 2-10A). Most receptor potentials are depolarizing (excitatory). However, hyperpolarizing (inhibitory) receptor potentials are found in the retina of the eye, as we shall learn in Chapter 26.

Figure 2-9 The membrane potential of a cell results from a difference in the net electrical charge on either side of its membrane. When a neuron is at rest there is an excess of positive charge outside the cell and an excess of negative charge inside it.

The receptor potential is the first representation of stretch to be coded in the nervous system. It is, however, a purely local signal. The receptor potential—the electrical activity in the sensory neuron initiated by a stimulus —spreads only passively along the axon. It therefore decreases in amplitude with distance and cannot be conveyed much farther than 1 or 2 mm. In fact, at about 1 mm down the axon the amplitude of the signal is only about one-third what it was at the site of generation. To be carried successfully to the rest of the nervous system, the local signal must be amplified—it must generate an action potential. In the knee jerk the receptor potential in the sensory neuron propagates to the first node of Ranvier in the axon, where, if it is large enough, it generates an action potential, which then propagates without failure (by a regenerative mechanism discussed in Chapter 9) to the axon terminals in the spinal cord. Here, at the synapse, between the sensory neuron and a motor neuron activating the leg muscles, the action potential produces a chain of events that result in an input signal to the motor neuron. In our example of the knee jerk, the action potential in the sensory neuron releases a chemical signal (a neurotransmitter) across the synaptic cleft. The transmitter binds to receptor proteins on the motor neuron, and the resulting reaction transduces the potential chemical energy of the transmitter into electrical energy. This in turn alters the membrane potential of the motor cell, a change called the synaptic potential. Like the receptor potential, the synaptic potential is graded. The amplitude of the synaptic potential depends on how much chemical transmitter is released, and its duration on how long the transmitter is active. The synaptic potential can be either depolarizing or hyperpolarizing, depending on the type of receptor molecule that is activated. Synaptic potentials, like receptor potentials, are local changes in membrane potential that spread passively along the neuron. The signal does not reach beyond the axon's initial segment unless it gives rise to an action potential. The features ofreceptor and synaptic potentials are summarized in Table 2-1.

The Trigger Component Makes the Decision to Generate an Action Potential Charles Sherrington first pointed out that the quintessential action of the nervous system is its ability to weigh the consequences of different types of information and then decide on appropriate responses. This integrative action of the nervous system is clearly seen in the actions of the trigger component of the neuron. Action potentials are generated by a sudden influx of Na+ ions through voltage-sensitive channels in the cell membrane. When an input signal (a receptor potential or synaptic potential) depolarizes the cell membrane, the change in membrane potential opens the Na+ ion channels, allowing Na+ to flow down its concentration gradient, from outside the cell where the Na+ con-

P.30 centration is high to inside the cell where it is low. These voltage-sensitive Na+ channels are concentrated at the initial segment of the axon, an uninsulated portion of the axon just beyond the neuron's input region. In sensory neurons the highest density of Na+ channels occurs at the myelinated axon's first node of Ranvier; in interneurons and motor neurons the highest density occurs at the axon hillock, where the axon emerges from the cell body.

Figure 2-10 A sensory neuron transforms a physical stimulus (in our example, a stretch) into electrical activity in the cell. Each of the neuron's four signaling components produces a characteristic signal. A. The input signal (a receptor or synaptic potential) is graded in amplitude and duration, proportional to the amplitude and duration of the stimulus. B. The trigger zone integrates the input signal—the receptor potential in sensory neurons, or synaptic potential in motor neurons—into a trigger action that produces action potentials that will be propagated along the axon. An action potential is generated only if the input signal is greater than a certain spike threshold. Once the input signal surpasses this threshold, any further increase in amplitude of the input signal increases the frequency with which the action potentials are generated, not their amplitude. The duration of the input signal determines the number of action potentials. Thus, the graded nature of input signals is translated into a frequency code of action potentials at the trigger zone. C. Action potentials are all-or-none. Every action potential has the same amplitude and duration, and thus the same wave form on an oscilloscope. Since action potentials are conducted without fail along the full length of the axon to the synaptic terminals, the information in the signal is represented only by the frequency and number of spikes, not by the amplitude. D. When the action potential reaches the synaptic terminal, the cell releases a chemical neurotransmitter that serves as the output signal. The total number of action potentials in a given period of time determines exactly how much neurotransmitter will be released by the cell.

Because it has the highest density of voltagesensitive Na+ channels, the initial segment of the axon has the lowest threshold for generating an action potential. Thus, an input signal spreading passively along the cell membrane is more likely to give rise to an action potential at the initial segment of the axon than at other sites in the cell. This part of the axon is therefore known as the impulse initiation zone, or trigger zone. It is here that the activity of all receptor (or synaptic) potentials is summed and where, if the size of the input signal reaches threshold, the neuron fires an action potential. Table 2-1 Comparison of Local (Passive) and Propagated Signals Signal type

Amplitude (mV)

Duration

Summation

Effect of signal

Type of propagation

Local (passive) signals Receptor potentials

Small (0.1–10)

Brief (5–100 ms)

Graded

Hyperpolarizing or depolarizing

Passive

Synaptic potentials

Small (0.1–10)

Brief to long (5 ms to 20 min)

Graded

Hyperpolarizing or depolarizing

Passive

Brief (1–10 ms)

All-or-none

Depolarizing

Active

Propagated (active) signals Action potentials

Large (70–110)

P.31

The Conductile Component Propagates an All-or-None Action Potential The action potential, the conducting signal of the neuron, is all-or-none. This means that while stimuli below the threshold will not produce a signal, all stimuli

above the threshold produce the same signal. However much the stimuli vary in intensity or duration, the amplitude and duration of each action potential are pretty much the same. In addition, unlike receptor and synaptic potentials, which spread passively and decrease in amplitude, the action potential does not decay as it travels along the axon to its target—a distance that can measure 3 m in length—because it is periodically regenerated. This conducting signal can travel at rates as fast as 100 meters per second. The remarkable feature of action potentials is that they are highly stereotyped, varying only subtly (although in some cases importantly) from one nerve cell to another. This feature was demonstrated in the 1920s by Edgar Adrian, who was one of the first to study the nervous system at the cellular level. Adrian found that all action potentials have a similar shape or wave form on the oscilloscope (see Figure 2-3). Indeed, the voltage signals of action potentials carried into the nervous system by a sensory axon often are indistinguishable from those carried out of the nervous system to the muscles by a motor axon. Only two features of the conducting signal convey information: the number of action potentials and the time intervals between them (Figure 2-10C). As Adrian put it in 1928, summarizing his work on sensory fibers: “… all impulses are very much alike, whether the message is destined to arouse the sensation of light, of touch, or of pain; if they are crowded together the sensation is intense, if they are separated by long intervals the sensation is correspondingly feeble.” Thus, what determines the intensity of sensation or speed of movement is not the magnitude or duration of individual action potentials, but their frequency. Likewise, the duration of a sensation or movement is determined by the period over which action potentials are generated. If signals are stereotyped and do not reflect the properties of the stimulus, how do neural signals carry specific behavioral information? How is a message that carries visual information distinguished from one that carries pain information about a bee sting, and how do both of these signals differ from messages that send commands for voluntary movement? As we have seen, and will learn to appreciate even more in later chapters, the message of an action potential is determined by the neural pathway that carries it. The visual pathways activated by receptor cells in the retina that respond to light are completely distinct from the somatic sensory pathways activated by sensory cells in the skin that respond to touch or to pain. The function of the signal—be it visual, tactile, or motor—is determined not by the signal itself but by the pathway along which it travels.

The Output Component Releases Neurotransmitter When an action potential reaches a neuron's terminal it stimulates the release of a chemical transmitter from the cell. Transmitters can be small molecules, such as L-glutamate and acetylcholine, or they can be peptides like enkephalin (Chapter 15). Transmitter molecules are held in subcellular organelles called synaptic vesicles, which are loaded into specialized release sites in the presynaptic terminals called active zones. To unload their transmitter, the vesicles move up to and fuse with the neuron's plasma membrane, a process known as exocytosis. (We shall consider neurotransmitter release in Chapter 14.) The release of chemical transmitter serves as a neuron's output signal. Like the input signal, the output signal is graded. The amount of transmitter released is P.32 determined by the number and frequency of the action potentials in the presynaptic terminals (see Figure 2-10). After the transmitter is released from the presynaptic neuron, it diffuses across the synaptic cleft to receptors in the membrane of the postsynaptic neuron. The binding of transmitter to receptors causes the postsynaptic cell to generate a synaptic potential. Whether the synaptic potential has an excitatory or inhibitory effect will depend on the type of receptors in the postsynaptic cell, not on the particular neurotransmitter. The same transmitter can have different effects on different types of receptors.

Figure 2-11 The sequence of signals that produces a reflex action. 1. The stretching of a muscle produces a receptor potential in the terminal fibers of the sensory neuron (the dorsal root ganglion cell). The amplitude of the receptor potential is proportional to the intensity of the stretch. This potential then spreads passively to the integrative segment, or trigger zone, at the first node of Ranvier. There, if the receptor potential is sufficiently large, it triggers an action potential, which then propagates actively and without change along the axon to the terminal region. At the terminal the action potential leads to an output signal: the release of a chemical neurotransmitter. The transmitter diffuses across the synaptic cleft and interacts with receptor molecules on the external membranes of the motor neurons that innervate the stretched muscle. 2. This interaction initiates a synaptic potential in the motor cell. The synaptic potential then spreads passively to the trigger zone of the motor neuron axon, where it initiates an action potential that propagates actively to the terminal of the motor neuron. The action potential releases transmitter at the nerve-muscle synapse. 3. The binding of the neurotransmitter with receptors in the muscle triggers a synaptic potential in the muscle. This signal produces an action potential in the muscle, causing con-traction of the muscle fiber.

The Transformation of the Neural Signal From Sensory to Motor Is Illustrated by the Stretch Reflex Pathway We have seen that a signal is transformed as it is conveyed from one component of the neuron to the next and from one neuron to the next. This transformation— from input to output—can be seen in perspective by tracing the relay of signals for the stretch reflex. When a muscle is stretched, the features of the stimulus —its amplitude and duration—are reflected in the amplitude and duration of the receptor potential in the sensory neuron. If the receptor potential exceeds the threshold for action potentials in that cell, the graded signal is transformed at the trigger component into an action potential, an all-or-none signal. The more the receptor potential exceeds threshold, the greater the depolarization and consequently the greater the frequency of action potentials in the axon; likewise, the duration of the input signal determines the number of action potentials. (Several action potentials together are called a train of action potentials.) This information—the frequency and number of action potentials—is then faithfully conveyed along the entire axon's length to its terminals, where the frequency of action potentials determines how much transmitter is released. These stages of transformation have their counterparts in the motor neuron. The transmitter released by a sensory neuron interacts with receptors on the motor neuron to initiate a graded synaptic potential, which spreads to the initial segment of the motor axon. If the membrane potential of the motor neuron reaches a

critical threshold, an action potential will be generated and propagate without fail to the motor cell's presynaptic terminals. There the action potential causes transmitter release, which triggers a synaptic potential in the muscle. That in turn produces an action potential in the leg muscle, which leads to the final transformation —muscle contraction and an overt behavior. The sequence of transformations of a signal from senP.33 sory neuron to motor neuron to muscle is illustrated in Figure 2-11.

Nerve Cells Differ Most at the Molecular Level The model of neuronal signaling we have outlined is a simplification that applies to most neurons, but there are some important variations. For example, some neurons do not generate action potentials. These are typically local interneurons without a conductile component—they have no axon, or such a short one that a conducted signal is not required. In these neurons the input signals are summed and spread passively to the nearby terminal region, where transmitter is released. There are also neurons that lack a steady resting potential and are spontaneously active. Even cells with similar organization can differ in important molecular details, expressing different combinations of ion channels, for example. As we shall learn in Chapters 6 and 9, different ion channels provide neurons with various thresholds, excitability properties, and firing patterns. Thus, neurons with different ion channels can encode the same class of synaptic potential into different firing patterns and thereby convey different signals. Neurons also differ in the chemical transmitters they use to transmit information to other neurons, and in the receptors they have to receive information from other neurons. Indeed, many drugs that act on the brain do so by modifying the actions of specific chemical transmitters or a particular subtype of receptor for a given transmitter. These differences not only have physiological importance for day-to-day functioning of the brain, but account for the fact that a disease may affect one class of neurons but not others. Certain diseases, such as amyotrophic lateral sclerosis and poliomyelitis, strike only motor neurons, while others, such as tabes dorsalis, a late stage of syphilis, affect primarily sensory neurons. Parkinson's disease, a disorder of voluntary movement, damages a small population of interneurons that use dopamine as a chemical transmitter. Some diseases are selective even within the neuron, affecting only the receptive elements, the cell body, or the axon. In Chapter 16 we shall see how research into myasthenia gravis, caused by a faulty transmitter receptor in the muscle membrane, has provided important insights into synaptic transmission. Indeed, because the nervous system has so many cell types and variations at the molecular level, it is susceptible to more diseases (psychiatric as well as neurological) than any other organ of the body. Despite the differences among nerve cells, the basic mechanisms of electrical signaling are surprisingly similar. This simplicity is fortunate for those who study the brain. By understanding the molecular mechanisms that produce signaling in one kind of nerve cell, we are well on the way to understanding these mechanisms in many other nerve cells.

Nerve Cells Are Able to Convey Unique Information Because They Form Specific Networks The stretch reflex illustrates how just a few types of nerve cells can interact to produce a simple behavior. But even the stretch reflex involves populations of neurons— perhaps a few hundred sensory neurons and a hundred motor neurons. Can the individual neurons implicated in a complex behavior be identified with the same precision? In invertebrate animals, and in some lower vertebrates, a single cell (the so-called command cell) can initiate a complex behavioral sequence. But, as far as we know, no complex human behavior is initiated by a single neuron. Rather, each behavior is generated by the actions of many cells. Broadly speaking, as we have seen, there are three neural components of behavior: sensory input, intermediate (interneuronal) processing, and motor output. Each of these components is mediated by a single group or several distinct groups of neurons. As discussed in Chapter 1, one of the key strategies of the nervous system is localization of function: specific types of information are processed in particular brain regions. Thus, information for each of our senses is processed in a distinct brain region where the afferent connections typically form a precise map of the pertinent receptor sheet on the body surface—the skin (touch), the retina (sight), the basilar membrane of the cochlea (hearing), or the olfactory epithelium (smell). These maps are the first stage in creating a representation in the brain of the outside world in which we live. Similarly, areas of the brain concerned with movement contain an orderly arrangement of neural connections representing the musculature and specific movements. The brain, therefore, contains at least two types of neural maps: one for sensory perceptions and another for motor commands. The two maps are interconnected in ways we do not yet fully understand. The neurons that make up these maps—motor, sensory, and interneuronal—do not differ greatly in their electrical properties. They have different functions because of the connections they make. These connections, established as the brain develops, determine the behavioral function of individual cells. Although our understanding of how sensory and motor information is processed and represented in the brain is based on the P.34 detailed studies of only a few regions, in those regions in which our understanding is particularly well advanced it is clear that the logical operations of a mental representation can be understood only by defining the flow of information through the connections that make up the various maps. A single component of behavior sometimes recruits a number of groups of neurons that simultaneously provide the same or similar information. The deployment of several neuron groups or several pathways to convey similar information is called parallel processing. Parallel processing also occurs in a single pathway when different neurons in the pathway perform similar computations simultaneously. Parallel processing makes enormous sense as an evolutionary strategy for building a more powerful brain: it increases both the speed and reliability of function within the central nervous system. The importance of abundant, highly specific parallel connections is now also being recognized by scientists attempting to construct computer models of the brain. Scientists working in this field, a branch of computer science known as artificial intelligence, first used serial processing to simulate the brain's higher-level cognitive processes—processes such as pattern recognition, learning, memory, and motor performance. They soon realized that although these serial models solved many problems rather well, including the challenge of playing chess, they performed poorly with other computations that the brain does almost instantaneously, such as recognizing faces or comprehending speech. As a result, most computational neurobiologists have turned to systems with both serial and parallel (distributed) components, which they call connectionist models. In these models elements distributed throughout the system process related information simultaneously. Preliminary insights from this work are often consistent with physiological studies. Connectionist models show that individual elements of a system do not transmit large amounts of information. Thus, what makes the brain a remarkable information processing machine is not the complexity of its neurons, but rather its many elements and, in particular, the complexity of connections between them. Individual stereotyped neurons are able to convey unique information because they are wired together and organized in different ways.

The Modifiability of Specific Connections Contributes to the Adaptability of Behavior That neurons make specific connections with one another simple reflexes can undergo modification that lasts minutes, and much learning results in behavioral change that can endure for years. How can neural activity produce such long-term changes in the function of a set of prewired connections? A number of solutions for these dilemmas have been proposed. The proposal that has proven most farsighted is the plasticity hypothesis, first put forward at the turn of the century by Ramón y Cajal. A modern form of this hypothesis was advanced by the Polish psychologist Jerzy Konorski in 1948: The application of a stimulus leads to changes of a twofold kind in the nervous system. … [T]he first property, by virtue of which the nerve cells react to the incoming impulse … we call excitability, and … changes arising … because of this property we shall call changes due to excitability. The second property, by virtue of which certain permanent functional transformations arise in particular systems of neurons as a result of appropriate stimuli or their combination, we shall call plasticity and the corresponding changes plastic changes.

There is now considerable evidence for plasticity at chemical synapses. Chemical synapses often have a remarkable capacity for short-term physiological changes (lasting hours) that increase or decrease the effectiveness of the synapse. Long-term changes (lasting days) can give rise to further physiological changes that lead to anatomical changes, including pruning of preexisting connections, and even growth of new connections. As we shall see in later chapters, chemical synapses can be modified functionally and anatomically during development and regeneration, and, most importantly, through experience and learning. Functional alterations are typically short term and involve changes in the effectiveness of existing synaptic connections. Anatomical alterations are typically longterm and consist of the growth of new synaptic connections between neurons. It is this potential for plasticity of the relatively stereotyped units of the nervous system that endows each of us with our individuality.

Selected Readings Adrian ED. 1928. The Basis of Sensation: The Action of the Sense Organs. London: Christophers.

Gazzaniga MS (ed). 1995. The Cognitive Neurosciences. Cambridge, MA: MIT Press. P.35

Jones EG. 1988. The nervous tissue. In: LWeiss (ed), Cell and Tissue Biology: A Textbook of Histology, 6th ed., pp. 277–351. Baltimore: Urban and Schwarzenberg.

Newan EA. 1993. Inward-rectifying potassium channels in retinal glial (Muller) cells. J Neurosci 13:3333–3345.

Perry VH. 1996. Microglia in the developing and mature central nervous system. In: KR Jessen, WD Richardson (eds).Glial Cell Development: Basic Principles & Clinical Relevance, pp. 123–140. Oxford: Bios.

Ramón y Cajal S. 1937. 1852–1937. Recollections of My Life. EH Craigie (transl). Philadelphia: American Philosophical Society; 1989. Reprint. Cambridge, MA: MIT Press.

References Adrian ED. 1932. The Mechanism of Nervous Action: Electrical Studies of the Neurone. Philadelphia: Univ. Pennsylvania Press.

Alberts B, Bray D, Lewis J, Raff M, Roberts K, Watson JD. 1994. Molecular Biology of the Cell, 3rd ed. New York: Garland.

Erlanger J, Gasser HS. 1937. Electrical Signs of Nervous Activity. Philadelphia: Univ. Pennsylvania Press.

Hodgkin AL, Huxley AF. 1939. Action potentials recorded from inside a nerve fiber. Nature 144:710–711.

Kandel ER. 1976. The study of behavior: the interface between psychology and biology. In: Cellular Basis of Behavior: An Introduction to Behavioral Neurobiology, pp. 3–27. San Francisco: WH Freeman.

Konorski J. 1948. Conditioned Reflexes and Neuron Organization. Cambridge: Cambridge Univ. Press.

Martinez Martinez PFA. 1982. Neuroanatomy: Development and Structure of the Central Nervous System. Philadelphia: Saunders.

Newman EA. 1986. High potassium conductance in astrocyte endfeet. Science 233:453–454.

Nicholls JG, Martin AR, Wallace BG. 1992. From Neuron to Brain: A Cellular and Molecular Approach to the Function of the Nervous System, 3rd ed. Sunderland, MA: Sinauer.

Penfield W (ed). 1932. Cytology & Cellular Pathology of the Nervous System, Vol. 2. New York: Hoeber.

Ramón y Cajal S. 1933. Histology, 10th ed. Baltimore: Wood.

Sears ES, Franklin GM. 1980. Diseases of the cranial nerves. In: RN Rosenberg (ed). The Science and Practice of Clinical Medicine. Vol. 5, Neurology, pp. 471–494. New York: Grune & Stratton.

Sherrington C. 1947. The Integrative Action of the Nervous System, 2nd ed. Cambridge: Cambridge Univ. Press 1.

Some primary sensory neurons are also commonly called afferent neurons, and we use these two terms interchangeably in the book. The term afferent (carried toward the nervous system) applies to all information reaching the central nervous system from the periphery, whether or not this information leads to sensation. The term sensory should, strictly speaking, be applied only to afferent input that leads to a perception.

Back

3 Genes and Behavior T. Conrad Gilliam Eric R. Kandel Thomas M. Jessell ALL BEHAVIOR IS SHAPED BY the interplay of genes and the environment. Even the most stereotypic behaviors of simple animals can be influenced by the environment, while highly evolved behaviors in humans, such as language, are constrained by hereditary factors. In this chapter we review what is known about the role of genes in organizing behavior. Later in the book we discuss the role of environmental factors. A striking illustration of how genes and environment interact is evident in phenylketonuria. This disease results in a severe impairment of cognitive function and affects 1 child in 15,000. Children who express this disease have two abnormal copies of the gene that codes for phenylalanine hydroxylase, the enzyme that converts the amino acid phenylalanine, a component of dietary proteins, to another amino acid, tyrosine. Many more children carry only one abnormal copy of the gene and have no symptoms. Children who lack both functional copies of the gene build up high blood levels of phenylalanine. High blood levels of phenylalanine in turn lead to the production of a toxic metabolite that interfereswith the normal maturation of the brain.1 Fortunately, the treatment for this disease is remarkably simpleand effective: the mental retardation can be completely prevented by restricting protein intake, thereby reducing phenylalanine in the diet. Phenylketonuria is a particularly clear example of how an individual's phenotype depends on the interaction between genes and environment (Figure 3-1). In phenylketonuria both heredity and environmental factors P.37 in the diet are clearly necessary for the expression ofthis form of mental retardation. A mere change in diet can rescue the genetic defect and the mental functioning.

Figure 3-1 Heredity and environment are both necessary for the expression of phenylketonuria. (From Barondes 1995.)

In considering genetic factors that control behavior we need first to identify the components of behavior that are heritable. Clearly, behavior itself is not inherited; what is inherited is DNA, which encodes proteins. The genes expressed in neurons encode proteins that are important for development, maintenance, and regulation of the neural circuits that underlie all aspects of behavior. In turn, neural circuits are composed of many nerve cells, each of which expresses a special constellation of genes that direct the production of specific proteins. For the development and function of a single neural circuit, a wide variety of structural and regulatory proteins are required. In simple animals a single gene may control a behavioral trait by encoding a protein that affects the function of individual nerve cells in a specific neural circuit. In more complex animals the circuitry is also more complex and behavioral traits are generally shaped by the actions of many genes. Subtle differences in behavior can be achieved not only by the presence or absence of a given gene product or a set of products, but also by the degree to which different gene products are expressed, or by the specific contribution of gene products. The interplay of the genes, proteins, and neural circuits underlying behavior has been studied in various organisms ranging in complexity from worms and flies to mice and humans. Molecular genetics provides the techniques to identify the genes involved in a particular behavior and to determine how the proteins they encode control behavior. In worms, flies, and even in vertebrate organisms such as mice and zebrafish, it is possible to examine directly how genes influence behavior because single-gene mutants of these organisms can be bred and isolated. In this chapter we illustrate how the genetic dissection of behavior in simple animals can provide insight into the mechanisms that regulate human behavioral traits. We then discuss a few important examples of the effects of single-gene defects on human behavior. Finally, we consider complex behavioral traits that typically are determined by the actions of many genes.

Genetic Information Is Stored in Chromosomes Genes contribute to the neural circuitry of behavior in two fundamental ways. First, through their ability to replicate reliably, each gene provides precise copies of itself to all cells in an organism as well as succeeding generations of organisms. Second, each gene that is expressed in a cell directs the manufacture of specific proteins that determine the structure, function, and other biological characteristics of the cell. With rare exceptions, each cell in the human body contains precisely the same complement of genes, thought to be about 80,000. The reason cells differ from one another—why one cell becomes a liver cell and another a brain cell—is that a distinct set of genes is expressed (as messenger RNA) in each cell type. Which genes and proteins become activated in a particular cell depends on interactions between the molecules within the cell, between neighboring cells, and between the cell and the organism's external environment (see Chapter 52). More of the total genetic information encoded in DNA—perhaps 30,000 of the 80,000 genes—is expressed in brain cells than in any other tissue of the body. Genes vary in size from 1 to 200,000 kilobases; the average size is about 10 kilobases. The DNA of each gene that encodes a protein is made up of segments, called exons, which encode parts of the protein and these coding segments are interrupted by noncoding segments called introns. DNA is not distributed randomly within the nucleus but arranged in an orderly way on structures called chromosomes. The number of chromosomes varies among

different organisms. In addition, different types of organisms contain either one or two copies of each chromosome. With some exceptions, unicellular organisms are haploid; they have only a single copy of each chromosome. By contrast, most complex multicellular organisms (worms, fruit flies, mice, and humans) P.38 are diploid; in all their somatic cells they carry two homologous copies of each chromosome and each gene, one from the mother and the other from the father. The number of chromosomes in the germ, or sex, cells (sperm and egg) is half that found in somatic cells. During the nuclear division that accompanies somatic cell division (the process of mitosis) the chromosomes are partitioned equally—each daughter cell receives one copy of each chromosome in the parent cell. However, during the two successive nuclear divisions that accompany division of the germ cells (meiosis), the number of chromosomes is reduced by half. Fertilization of the egg by the sperm restores the diploid number found in somatic cells, with homologous chromosomes contributed by each parent. The 80,000 genes in the human genome are arranged in a precise order along the chromosomes. As a result, each gene is uniquely identifiable by its location at a characteristic position (locus) on a specific chromosome. The two copies of a gene at corresponding loci on a pair of homologous chromosomes commonly harbor sequence variations, or polymorphisms, at multiple sites throughout the gene. At any given site, the alternative gene versions are referred to as alleles. Alleles may be identical or, more commonly, differ to some degree because of polymorphisms or mutations, as discussed below. If two alleles are identical, the organism is said to be homozygous at that locus. If the alleles vary in form (in their nucleotide sequence), the organism is said to be heterozygous at that locus. The recent DNA sequencing of a small number of human genes reveals large variance in the degree of intergenic polymorphism. In general, however, the rate of polymorphic variation between any two individuals is estimated to be 1 per 1000 base pairs in noncoding DNA and 1 per 2000 base pairs in coding DNA. Thus a 10 kilobase gene would harbor, on average, about 10 polymorphisms, including 1 or 2 in the coding sequence DNA. At each of these polymorphic sites, an individual will carry at most two different forms of the same allele, whereas the same allele may exist in many forms within a population. A difference within a population is called allelic polymorphism, or more generally, genetic polymorphism. Prominent examples of allelic polymorphism are the alleles of the genes responsible for hair and eye color. Humans have 46 chromosomes: 22 pairs of autosomes and two sex chromosomes (two X chromosomes in females, one X and one Y chromosome in males). The parents contribute the sex chromosomes to their offspring differently from the manner they supply the autosomes. A spermatozoon carries either an X (femaledetermining) or a Y (male-determining) chromosome, whereas an ovum carries only an X chromosome. As a consequence, males inherit their single X chromosome from their mothers. The 22 autosome pairs and the X and Y sex chromosomes vary in size and cytological banding pattern (Figure 3-2). Chromosome 1 is the largest autosome; it contains 8% of the human genome, or about 6400 genes. Chromosome 22 is the smallest, containing 1% or about 800 genes. Chromosomes also vary in the nucleotide sequence of their DNA, but paired autosomes are usually morphologically (cytogenetically) indistinguishable.

Gregor Mendel's Work Led to the Delineation of the Relationship Between Genotype and Phenotype The existence of alternative allelic forms of genes were discovered in 1866 by Gregor Mendel, who demonstrated the difference between dominant and recessive alleles using garden peas as an experimental system. Mendel started out with self-breeding experiments on peas. These led to the creation of inbred strains of peas that bred true for given characteristics of the pea such as color or the shape of the pod. He then crossed these inbred strains with each other and observed how the various traits were manifested in the progeny of the pea plant. These crosses allowed Mendel to appreciate that the variability in heredity among the progeny lay in differences in discrete factors that are passed unchanged from one plant generation to another, factors we now call genes. Moreover, Mendel found that each pea had two sets of factors, one from the male parent and the other from the female. Mendel carried out his studies before it was known how chromosomes behave during cell division. Forty years later it became clear that the segregation pattern of genes noted by Mendel paralleled, almost exactly, the behavior of chromosomes during meiotic cell division, the division that produces the male and female germ cells. These findings were used by Thomas Hunt Morgan to formulate the chromosomal theory of heredity, according to which each chromosome has a linear array of unique genes running from one end to the other, each gene having a definite location on a particular chromosome. While studying Mendel's results, Wilhelm Johannsen later distinguished between the genotype of an organism (its genetic makeup) and the phenotype of an organism (its appearance). In the broad sense genotype refers to the entire set of alleles forming the genome of an individual; in the narrow sense it refers to the specific alleles of one gene. Phenotype denotes the functional expression or consequences of a gene or set of genes. The phenotype of an individual may change throughout life, whereas the genotype remains constant except for sporadic mutations. Most mutations are simply allelic polymorphisms that are silent; that is, they do not have any effect on the phenotype. Some are not silent but are expressed in ways that nevertheless appear neutral and therefore be-nign P.39 (Box 3-1). Benign mutations are allelic polymorphisms that produce differences in body type, such as eye color or hair color, as well as differences in personality characteristics. The consequence of a mutation is often shaped by the environment. A mutation that favored a hunter-gatherer's survival during periodic food shortages might lead to pathological obesity in a modern-day environment. Many mutations that do not have benign consequences, such as those leading to excessive tallness, dwarfism, or color blindness, do not necessarily impair everyday functions. Some mutations may have significant consequences that are limited to the cell-biological level, without any functional effects. An example would be a mutation that results in the failure of a single type of cell to develop in an animal that can compensate for the loss of that cell type. Only rarely do mutations lead to significant changes in development, cell function, or overt behavior. Some mutations are truly pathogenic, however, and these lead to human disease.

Figure 3-2 Map of normal human chromosomes at metaphase illustrating the distinctive morphology of each chromosome. (Adapted from Watson et al. 1983.)

If a mutant phenotype results from one mutant allele in combination with one wild-type (normal) allele, the mutation or phenotypic trait is said to be dominant. Dominant mutations usually lead to the production of an abnormal protein by the mutant allele or to the expression of the wild-type gene product at an inappropriate time or place. Because they give rise to a new, perhaps toxic, variant of the protein or a new pattern of expression in the body, dominant mutations are often referred to as gain of function mutations. Some dominant mutations produce an inactive protein product that can nevertheless interfere with the function of the wild-type protein, thus leading to a complete loss of function of the gene. Such mutations are termed dominant negative mutations. If a mutant phenotype is expressed only when both alleles of a gene are mutated (that is, only individuals P.40 homozygous for the mutant allele will exhibit the phenotype), the mutation or phenotypic trait is said to be recessive. Recessive mutations usually result from the loss or reduction in amount of a functional protein. As a result, recessive mutations are often loss of function mutations. The reason both alleles need to be defective in a recessive mutation in order for a phenotype to become evident is that a 50% reduction of most proteins (such as most enzymes) usually does not cause serious (or even detectable) problems in cell function.

Box 3-1 The Origins of Genetic Diversity Although DNA replication generally is carried out with high fidelity, spontaneous errors called mutations do occur. Mutations may result from damage to the purine and pyrimidine bases, mistakes during the DNA replication process, and recombinations that occur between two nonhomologous chromosomes as a result of errors in crossing over during meiosis. It is these mutations that give rise to genetic polymorphisms. The rate of spontaneously occurring mutations is low. However, the frequency of mutations greatly increases when the organism is exposed to chemical mutagens or ionizing radiation. Chemical mutagens tend to induce point mutations involving changes in a single DNA base pair or the deletion of a few base pairs. By contrast, ionizing radiation can induce large insertions, deletions, or translocations. Both spontaneous and induced mutations can lead to changes in the structure of the protein encoded by the gene (as in a dominant mutation) or to a partial decrease or absence of gene function or expression (as in recessive mutations). Changes in a single base pair involve one of three types of point mutations: (1) a missense mutation, where the point mutation results in one amino acid in a protein being substituted for another; (2) a nonsense mutation, where a stop codon (triplet) is substituted for a codon within the coding region, thus resulting in a shortened (truncated) protein product; or (3) a frameshift mutation, in which small insertions or deletions change the reading frame, leading to the production of a truncated or abnormal protein. Large-scale mutations involve changes in chromosome structure that can affect the function of many contiguous genes. Such mutations include rearrangement of genes without the addition or deletion of material (inversion), duplication of genes in a chromosome, or the exchange (crossing over) between segments of DNA. Sometimes large deletions of multiple genes occur. While these mutations are usually fatal if present in both copies of a gene (homozygous lethals), they can result in phenotypes in the heterozygous state (such as the mental retardation associated with the Wilms tumor deletion complex). Chromosomal translocation can also cause fusion between different (nonhomologous) chromosomes.

The Genotype Is a Significant Determinant of Human Behavior Independent of Mendel's work, Francis Galton began to apply genetics to human behavior in 1869. In his book Hereditary Genius, Galton proposed that relatives of individuals with extremely high mental ability were more likely to be endowed with similar abilities than would be predicted by chance: the closer the family relationship, the higher the incidence of such gifted individuals. Following Galton's initial insight, genetic studies of human behavior and disease have relied heavily on the analysis of kinship. Relatives share varying degrees of genetic information and are classified as first degree (parents, siblings, and offspring), second degree (grandparents, grandchildren, nephews and nieces, halfsiblings), third degree (first cousins), and so on, depending on the number of steps, more precisely the number of generations (meiotic events), separating the members of the family tree.

Despite the uncontrolled nature of this early study, Galton was among the first to address the interplay of inheritance (nature) and environment (nurture) in the determination of behavior. Galton was well aware that relatives of eminent individuals also share social, educational, and financial advantages, and that these environmental factors might also account for the correlation between eminence and familial relationship. He therefore endeavored to assess more accurately the relative contributions of heritable and environmental factors to behavioral traits. Thus, in 1883 he introduced the idea of the twin study, a method that today remains a primary strategy for evaluating the role of genes and environment in complex behavioral traits. Identical twins are monozygotic; they develop from a single zygote that splits into two soon after fertilization. As a result, identical twins share all genes; they are as alike genetically as is possible for two individuals. In contrast, fraternal twins are dizygotic; they develop from two different fertilized eggs. Thus, dizygotic twins, like normal siblings, share on average half their genetic information. Systematic comparisons of pairs of identical versus fraternal twins can be used to assess the importance of genes in the development of a particular trait. If identical twins tend to be more similar (concordant) than fraternal twins, the trait is attributable, at least in part, to genes. The findings from such twin studies are further supP.41 ported by studies of identical twins that have been separated early in life and raised in different households. Despite sometimes great differences in their environment, such twins share a remarkable number of behavioral traits that we normally consider to be distinctive features of individuality, such as intellectual, religious, and vocational interests (Figures 3-3 and 3-4). Behavioral similarities between identical twins that have been separated at birth are attributable in part to genes, although environmental factors may also play a role. In general, twin studies reinforce the idea that human conduct is shaped by genetic factors but do not refute the role of environmental influences, which clearly exist.

Figure 3-3 Correlations among monozygotic twins reared together (MZT) and those reared apart (MZA) for physiological characteristics, personality traits, interests, and attitudes. A score of zero represents no correlation—the average result for two random members of the population—while a score of 1.0 represents a perfect correlation. Fingerprint ridge count, which is not expected to be subject to significant environmental influence, is virtually identical in MZA and MZT pairs. Other characteristics, expected to be more subject to environmental influences, are not so highly correlated within each class. Although the correlations for these characteristics are low, the results for MZT and MZA are similar. The correlations for the multidimensional personality scale and religious attitudes among MZT and MZA are virtually identical, suggesting a significant, though not necessarily predominant, genetic influence on those traits. Correlations for the occupational interest scale and nonreligious social attitudes among MZA and MZT are more different between the two groups. (Based on Bouchard et al. 1990.)

The environmental contribution to behavioral traits is often divided into shared and nonshared components. Shared environmental influences, such as childrearing practices or income, may underlie observed phenotypic similarities among family members. In contrast, nonP.42 shared influences, such as interactions with peers in school, can create differences among members of the same family. As discussed below, similarities in personality between biological relatives are due primarily to genetic components, with differences arising from genetic factors and nonshared environmental factors.

Figure 3-4 Variation in personality in studies of twins. The units express the degree of variance accounted for by various genetic and environmental influences. (Based on Bouchard 1994.)

Although studies of identical twins and kinships provide strong support for the idea that human behavior has a significant hereditary component, they do not tell us how many genes are important, let alone how specific genes affect behavior. These questions can be addressed by genetic studies in experimental animals in which both the gene and the environment are strictly controlled and by studies of human genetic mutations that give rise to diseases.

Single Gene Alleles Can Encode Normal Behavioral Variations in Worms and Flies A number of studies of natural populations of flies and worms have found that allelic polymorphisms in single genes can contribute to individual differences in naturally occurring behavior, including social behavior. The first example was provided by Ron Kondoka and his colleagues, who found variants in the circadian rhythm of flies as a result of molecular polymorphisms in the period gene. Wild-type flies vary in how well they can maintain their circadian rhythm in the presence of a temperature change, a feature called temperature compensation. As we will discuss below, the protein products of the period and timeless genes are involved in an autoregulatory feedback that is critical for circadian rhythms. The per gene has a repeat region of threonine-glycine that is polymorphic in length. Two of the major variants (with 17 repeats and 20 repeats) are found in Europe along a north-south cline. Flies with long repeats are better able to compensate for temperature shifts than those with short repeats.

A second example of such individual differences was discovered by Marta Sokolowski and her colleagues while examining the natural variation in the foraging behavior of fly larvae. Some larvae are rovers and others are sitters. Rovers follow longer foraging paths, whereas sitters use much smaller paths. The rover larvae also tend to move between patches of food, while the sitters tend to remain feeding within a food pack. This difference between rovers and sitters results from a single gene called forager. The rover allele has complete dominance over the sitter allele. In nature there are 70% rovers and 30% sitters. In fact, sitter larvae can be converted to rover larvae by expressing in them the gene encoding the rover phenotype. The forager gene encodes a cGMP-dependent protein kinase whose activities are higher in rover than in natural sitters, or sitter mutants, which suggests that the protein kinase may be regulated differently in the two natural variants. Single genes can even account for differences in normal social behavior. In the course of studying 22 natural isolates of the nematode worm Caenorhabditis elegans collected from various locations around the world, Jonathan Hodgkin and Tabitha Doniach had found that, when grown on the surface of agar-filled Petri plates seeded with Escherichia coli, these natural isolates distributed themselves on the agar surface in two ways. Half the strains dispersed evenly across the bacterial patch, but the other strains spontaneously formed large, dense aggregates called clumps. This clumping arises, at least in part, from interaction among the worms in the clump. Mario deBono and Cornelia Bargmann realized that this reflected an example of individual differences in social behavior. They called the dispersing strains solitary and the clumping strains social. Bargmann and deBono have identified natural variants in the behavior of worms feeding on E. coli in a Petri dish. Some worms are solitary foragers, moving across the food and feeding alone, while others are social foragers aggregating together on the food while they feed. More than 50 percent of the social foragers are found in groups, whereas less than two percent of the solitary foragers are found in groups. The social worms may aggregate due to the presence of a mutually attractive, as yet unidentified stimulus. DeBono and Bargmann gathered social strains of worms that arose from mutagenesis screens of solitary strains in several laboratories and found that the mutation encodes for a gene that resembles the neuropeptide Y receptor, a G protein-coupled receptor that is ubiquitous and important in mammals for feeding. Genetic analysis of normal, wild-type strains showed that the difference between social and solitary strains was due to the substitution of a single amino acid in a cytoplasmic loop of the neuropeptide Y receptor gene. Neuropeptides are found in the brain along with conventional small molecules and are often involved in regulating responses over long periods of time. Since neuropeptide Y receptors are associated with feeding and appetite in mammals, it raises the intriguing possibility that closely related peptides might control foraging and eating behaviors in a variety of organisms that are evolutionarily divergent.

Mutations in Single Genes Can Affect Certain Behaviors in Flies The influence of genes on behavior can be explored most rigorously in simple animals, such as the fruit fly P.43 P.44 Drosophila. Mutations of single genes in Drosophila can produce abnormalities in learned as well as innate behaviors, such as courtship and circadian rhythms. Moreover, mutations that affect specific aspects of behavior can readily be induced in flies (Box 3-2).

Box 3-2 Introducing Transgenes in Flies and Mice Genes can be manipulated in mice by injecting DNA into the nucleus of newly fertilized eggs (Figure 3-5). In some of the injected eggs the new gene, or transgene, is incorporated into a random site on one of the chromosomes and, since the embryo is at the one-cell stage, the incorporated gene is replicated and ends up in all (or nearly all) of the animal's cells, including the germline. Gene incorporation is most easily detected by coinjecting the marker gene for pigment production into an egg obtained from an albino strain. Mice with patches of pigmented fur indicate successful expression of DNA. The transgene's presence is confirmed by testing a sample of DNA from the injected individuals. A similar approach is used in flies. The DNA need not be injected directly into a nucleus since the vector used, called a P element, is capable of being incorporated into germ cell nuclei at the time the first cells form in the embryo. The development and function of the nervous system of flies can be altered using promoters that are expressed ubiquitously, such as the inducible heat-shock promoter hsp70 in Drosophila. More specific patterns of expression in brain cells can be obtained using promoter and enhancer sequences from genes that are specific to a cell type. Transgenes may be wild-type genes that rescue a mutant phenotype or novel “designer” genes that drive expression of a gene in new locations or produce a specifically altered gene product.

Figure 3-5 Standard procedures for generating transgenic mice and flies. Here the gene injected into the mouse causes a change in coat color, while the gene injected into the fly causes a change in eye color. In some transgenic animals of both species the DNA is inserted at different chromosomal sites in different cells (see illustration at bottom). (From Alberts et al. 1994.)

The genetic analysis of the behavior of flies has its origins in the behavioral screens performed in the 1970s by Seymour Benzer and his colleagues. These screens detected and isolated mutations that affect circadian (daily) rhythms, courtship behavior, movement, visual perception, and memory. The powerful techniques of Drosophila molecular genetics have enabled investigators to identify these genes and characterize how their protein products act. Here we shall focus on one class of genes isolated by Benzer, those that affect circadian rhythms. In Chapter 63 we shall consider genes in Drosophila that influence memory. Many aspects of animal physiology and behavior fluctuate in rhythmic cycles. Most of these rhythms follow a circadian period; others follow shorter-term (ultradian) periods. Circadian clocks are thought to have a significant adaptive advantage. For example, they provide a means of anticipating dawn and thereby coordinate physiological functions with environmental conditions. Circadian rhythms affect everything from locomotor activity to mood and play a major role in the biology of motivation (see Chapter 51). Because of the ubiquity of these clocks among animals (and even fungi), experimental advances in invertebrates should aid in our understanding of human circadian behaviors. Clocks have three basic features. First, the core of the clock is an intrinsic oscillator capable of producing a circadian periodicity of approximately 24 hours. Second, this intrinsic oscillator can adapt its rhythm to changes in the duration of the day-night cycle throughout the year. This regulation is primarily achieved through various light-driven signals that are transmitted by the eye to the brain, where the signals in turn act on the oscillator. Third, there are a set of output pathways from the oscillator that control specific behaviors, such as sleep and wakefulness and locomotor activity. Mutations altering biological rhythms have been isolated in several organisms. The greatest insight into the oscillator has been obtained from studies of two genes in Drosophila, the period (per) gene, identified originally by Benzer and his colleagues, and the timeless (tim) gene identified recently. The period and timeless genes appear to be devoted almost exclusively to the control of rhythms. Even when they are eliminated, the organism has no other major defects. Mutations in either the per or tim gene affect the circadian rhythms of locomotor activity and eclosion (ie, the emergence of the adult from the pupa). Arrhythmic per mutants exhibit no discernible rhythms in either of these behaviors. A long-day per allele produces 28-hour cycles for both locomotor activity and eclosion, whereas two short-day per alleles shorten the cycle (to 19 hours in one case and to 16 hours in the other; see Figure 3-6). How do the per and tim genes keep time? The answer to this question has begun to emerge from genetic and molecular studies of the two genes and their protein products. The protein products of the per and tim genes (PER and TIM) are thought to shuttle between the cytoplasm and nucleus of cells, regulating expression of target genes, including themselves. As a result, the synthesis and accumulation of the messenger RNAs encoding PER and TIM follow a circadian cycle. For the proteins to function, PER has to bind to TIM (Figure 3-7). Both genes are transcribed in the morning and their mRNAs accumulate during the day, during which the protein products appear not to be functional. A key step in the regulation of this cycle is the light-induced degradation of the TIM protein. During the day tim RNA is transcribed but the level of TIM protein remains low because of a high rate of degradation. In the absence of TIM, PER does not function. As a result, TIM and PER complexes are not formed. After dusk, when the levels of TIM and PER increase, the two proteins bind to one another, thus becoming functional, and enter the nucleus where they inhibit the transcription of their own genes as well as other, unidentified target genes. As a consequence, per and tim mRNAlevels decrease and subsequently protein expression decreases. By morning, PER and TIM protein levels have fallen to low enough levels that they no longer repress transcription. The finding that the per and tim transcripts are regulated by negative feedback raises the question of why the PER and TIM proteins do not immediately repress their own expression. The answer lies in a builtin delay in accumulation and translocation of the proteins to the nucleus. The PER protein cannot accumulate until sufficient TIM protein is present to bind to and stabilize it. TIM protein, on the other hand, cannot enter the nucleus unless it is bound to PER protein. Accurate time-keeping therefore depends on an oscillatory cycle in gene expression and inactivation by negative feedback. What does this say for mechanisms in normal and short-cycle flies? In the long-day (28-hour) per mutants the binding affinity of PER proteins for TIM appears to be reduced. Binding thus cannot occur until the two proteins reach higher levels, causing a delay in the entry of the PER-TIM complex into the nucleus and thus extending the period of each cycle. The mechanisms that control circadian rhythms in other organisms are likely to be similar in principle to P.45

the mechanism that controls the rhythmicity of the per and tim genes in Drosophila. In mammals circadian behavioral rhythms are governed by the suprachiasmatic nucleus in the hypothalamus (see Chapter 47). Because circadian behavior in mice is precise, it is easy to set up quantitative genetic screens for mutations that alter the circadian behavior. Joseph Takahashi took advantage of the regularity of this behavior to carry out a chemical mutagenesis screen. By this means he identified a semidominant autosomal mutation named clock. Mice homozygous for the clock mutation show extremely long circadian periods followed by a complete loss of circadian rhythmicity when transferred to constant darkness (Figure 3-8). The clock gene therefore appears to regulate two fundamental properties of the circadian rhythm in mice: the circadian period itself and the persistence of circadian rhythmicity.

Figure 3-6 A single gene, period (per), governs the circadian rhythms of specific behaviors in Drosophila. (From Konopka and Benzer 1971.) A. Locomotor rhythms in normal Drosophila and three per mutant strains: short-day, long-day, and arrhythmic. Flies were exposed to a cycle of 12 hours of light and 12 hours of darkness, and activity was then monitored under infrared light. Heavy lines indicate activity. B. Normal adult fly populations emerge from their pupal cases in cyclic fashion, even in constant darkness. The plots show the number of flies (in each of four populations) emerging per hour over a 4-day period of constant darkness. The arrhythmic per mutant population emerges without any discernible rhythm.

Since no anatomical defects have been observed with the clock mutation, the clock gene appears to encode a protein specific and essential for circadian rhythmicity in the mouse. When the clock gene was cloned it was found to encode a transcription factor, presumably involved in the basic regulation of genes important for the circadian rhythm. Particularly important is the fact that one of the domains of the clock protein (the PAS domain) is also found in PER. This raises the interesting possibility that the clock protein might bind to and interact with a mouse protein homologous to PER. Many mammalian genes related to clock have now been identified and implicated in the control of circadian rhythms.

Figure 3-7 Light-dependent degradation of the TIM protein establishes the circadian control of biological rhythms in Drosophila. The genes that control the circadian clock are regulated by two nuclear proteins, PER and TIM, that slowly accumulate and then bind to one another to form dimers. Dimerization of PER and TIM is necessary for the complex to enter the nucleus and shut off the transcription of target genes, including the genes for PER and TIM themselves. During the hours of daylight TIM protein is degraded by light; thus PER cannot enter the nucleus and the transcription of target genes (including the per and tim genes) continues. After dark, TIM protein is no longer degraded, and the PER-TIM dimers enter the nucleus, where they repress transcription of target genes. In this way the daynight cycle regulates the expression of genes that control biological function. (Adapted from Barinaga 1996.)

P.46 P.47

Defects in Single Genes Can Have Profound Effects on Complex Behaviors in Mice The use of chemical genetic techniques to identify circadian rhythm mutants in mice underscores the importance of this experimental mammal in behavioral genetic studies. Genetic studies of mouse behavior have begun to provide insight into the genetic bases of some human behavioral disorders. Here we discuss the evidence for a genetic basis for three disorders: obesity, impulsivity, and altered motivational state.

Mutations in the Gene Encoding Leptin Affect Feeding Behavior Whether an individual is lean, obese, or of intermediate size is determined in large part by the balance between the amount of food consumed and energy expended, a balance governed by both psychological and physiological factors. Genetics studies of obese mice have provided the best insight into the physiological factors that control ingestive behavior. The physical cloning and characterization of the region around a spontaneous obesity-causing mutation on mouse chromosome 6 led to the identification of the mouse obese (ob) gene and to a highly conserved (homologous) human gene. The mouse ob gene encodes the protein leptin, a small protein of 145 amino acids that is selectively expressed in adipose tissue and released into the bloodstream. Leptin contributes to the homeostatic mechanisms that permit an animal to maintain its weight within 5% of its normal weight for most of its life. Under normal conditions the amount of leptin secreted reflects the total mass of adipose tissue. When adipose tissue decreases, leptin levels decrease and the animal eats more; when adipose tissue increases, leptin levels increase and the animal eats less. Mice with homozygous mutations in the ob gene lack circulating leptin. This lack leads to marked obesity in these mutant animals. When leptin is supplied exogenously, however, food intake and body weight are reduced dramatically. Areceptor for leptin, called OB-R, encodes a protein that is related to a component of certain cytokine receptors that activate specific transcription factors. This leptin receptor is expressed at a high level in the hypothalamus, the part of the brain that controls appetite and feeding (Chapter 32). The gene encoding OB-R is located in the same region of mouse chromosome as the diabetic gene (db). This is interesting because obesity and diabetes are often linked in humans. In fact, db/db mice are also obese and exhibit a phenotype similar to the mice with a mutated ob gene. Moreover, there is good evidence that the db gene encodes the leptin receptor.

Figure 3-8 Locomotor activity records of clock mutant mice. The record shows periods of wheel-running activity by three offspring. All animals were kept on a light-dark cycle (L/D) of 12 hours for the first 7 days, then transferred to constant darkness (D). They later received a 6-hour light pulse (LP) to reset the rhythm. The activity rhythm for the wild-type mouse had a period of 23.1 hours. The period for the heterozygous clock/+ mouse is 24.9 hours. The homozygous clock/clock mice experience a complete loss of circadian rhythmicity upon transfer to constant darkness and transiently express a rhythm of 28.4 hours after the light pulse. (From Takahashi et al. 1994.)

To what extent do these studies of mice provide insight into human disease? Most obese humans are not defective in leptin mRNA or protein levels and indeed produce higher levels than do nonobese individuals. Thus, it is likely that human obesity reflects not a lack of leptin but a failure to respond to normal or even elevated levels of leptin. Failure to respond to leptin could be a result of mutations of the leptin receptor or of molecules that interact with the receptor. Leptin may affect feeding behavior by regulating neuropeptide and neurotransmitter expression in hypothalamic cells. Lesions of the hypothalamus affect body weight. For example, ablation of the ventromedial hypothalamus or the arcuate nucleus results in obesity. Leptin administration markedly inhibits the biosynthesis and release of neuropeptide Y, a peptide that stimulates food P.48 P.49 P.50 intake when administered to rodents. Remarkably, as we have discussed earlier, the link between neuropeptide Y and food intake appears to have been conserved, in a general sense, between C. elegans and man.

Box 3-3 Generating Mutations in Flies and Mice Flies Genetic analysis of behavior in Drosophila relies on behavioral assays of animals in which individual genes have been mutated. Experimental mutations in Drosophila were originally produced through radiation-induced mutagenesis. This method, however, results in large-scale deletions or rearrangements in chromosomes; several genes are often affected, even when small deletions are the target, and molecular characterization of relevant genes is difficult. In contrast, the chemical ethyl methanesulfonate (EMS) induces point mutations and thus facilitates the characterization of mutations at specific loci. Many spontaneous mutations and chromosomal rearrangements are produced by transposable elements. The most useful class of transposable elements in Drosophila is the P element. P elements encode a transposase enzyme that mediates the mobilization of the element and a repressor product that blocks transposition. P elements have become major tools of the modern Drosophila geneticist. In one technique, P elements are used to isolate mutations in any Drosophila gene of interest. The investigator screens for mutants of the gene in progeny of crosses between Drosophila strains that carry P elements and those in which they are absent. New mutations result from the transposition of a P element into a gene. A vector is then constructed in which a P element is inserted. This vector is used as a probe to identify and isolate DNA segments that contain P elements; elements inserted into the gene of interest are found within a subset of these segments. The gene can then be cloned and studied.

Mice Recent advances in molecular manipulation of mammalian genes have permitted in situ replacement of a known, normal gene with a mutant version. The process of generating a strain of mutant mice involves two separate manipulations: the replacement of a gene on a chromosome by homologous recombination in a special cell line known as embryonic stem cells (Figure 3-9), and the subsequent incorporation of this modified cell line into the germ cell

population of the embryo (Figure 3-10). The gene of interest must first be cloned. The gene is mutated, and a selectable marker, usually a drug-resistance gene, is then introduced into the mutated fragment. The altered gene is then transfected into embryonic stem cells, and clones of cells that incorporate the altered gene are isolated. To identify a clone in which the mutated gene has been integrated into the homologous (normal) site, rather than some other random site, DNA samples of each clone are tested.

Figure 3-9. Experimentally controlled homologous recombination is the first step in creating mutant mice. Cloned DNA from the mouse gene to be mutated is modified by genetic engineering so that it contains a bacterial gene, neo. Integration of neo into a mouse chromosome makes the mouse cells resistant to drugs that otherwise would be lethal to the cells (drug X). A viral gene, tk, is also added, attached to one end of the mouse DNA. Integration of tk into a mouse chromosome makes the cells sensitive to a different drug (drug Y). (Adapted from Albertset al. 1994.) A. Most insertions occur at random sites in the mouse chromosome, and these nearly always include both ends of the engineered DNA fragment. Colonies of cells in which homologous recombination has incorporated the center of the engineered DNA fragment without the ends are obtained by selecting for those rare mouse cells that grow in the presence of both drugs. B. Most of the cells that grow in the presence of both drugs will carry the targeted gene replacement.

When a suitable clone has been obtained, cells are injected into a mouse embryo at the blastocyst stage (3–4 days after fertilization), when the embryo consists of approximately 100 cells. These embryos are then reintroduced into a female that has been hormonally prepared for implantation and allowed to come to term. Embryonic stem cells in the mouse have the capability of participating in all aspects of development, including the germline. Thus, injected cells can become germ cells and pass on the altered gene. Since incorporated stem cells generally mix into other tissues besides the germline, their presence can be tested when the injected embryo is born. Initially, this can be done by using a stem cell line from a mouse strain with a fur color different from that of the strain used to obtain the embryo. The mixed (chimeric) offspring appear to have a patchy colored coat. These progeny are then mated to determine if any stem cells have become germ cells. If so, their progeny will carry the altered gene on one of their chromosomes, detectable by analyzing DNA samples from each of the offspring. When the heterozygous individuals are mated together, one-fourth of the progeny will be homozygous mutant. This technique has been used to generate mutations in various genes crucial to development or function in the nervous system.

Figure 3-10. Altered embryonic stem cells derived from mouse blastocysts are used to create transgenic mice. Embryonic stem (ES) cells are transfected with altered DNA. ES cells that have integrated a transgene for a particular trait can be selected by using a donor that carries an additional sequence, such as a drug-resistance gene (see Figure 3-9). An alternative is to assay the transfected ES cells for successful integration of the donor DNA using polymerase chain reaction (PCR) technology. After obtaining a population of ES cells with a high proportion carrying the marker, the cells are then injected into a recipient blastocyst. This blastocyst is implanted into a foster mother to generate a chimeric mouse. Some of the tissues of the chimeric mice will be derived from the cells of the recipient blastocyst; other tissues will be derived from the injected ES cells. To determine whether ES cells have contributed to the germline, the chimeric mouse is crossed with a mouse that lacks the donor trait. Any progeny that have the trait must be derived from germ cells that have descended from the injected ES cells. By this means, an entire mouse is generated from the altered ES cell. (Adapted from Lewin 1994.)

Mutations in the Gene Encoding a Serotonergic Receptor Intensify Impulsive Behavior Serotonin (5-hydroxytryptamine) is a monoamine that serves as a neurotransmitter in the brain. The level of serotonin is thought to be reduced in depressive illness. As we shall learn later (Chapter 44), neurons that synthesize serotonin are clustered in several nuclei in the brain stem, the most prominent of which are the raphe nuclei. Their axons project to many regions of the brain, notably the cerebral cortex. Neurons that synthesize serotonin modulate the activity of cortical and subcortical neurons in several ways by activating different receptor subtypes: some excitatory, some inhibitory, some both. Because of its action on different receptors, serotonin has been implicated in the regulation of mood states, including depression, anxiety, food intake, and impulsive violence (see Chapter 61). Several animal studies have shown that aggressive behavior is often associated with decreased activity of serotonergic neurons. These studies are of particular interest because they provide a glimpse of how social and genetic factors interact to modify behavior. Most animals, including humans, become aggressive when threatened, such as when their territory is invaded, their offspring are attacked, or sexual interactions are prevented. The importance of serotonergic transmission in aggressive behavior is clearly evident in studies of mice in which the gene for the serotonin 1B

receptor has been ablated by targeted deletion (Box 3-3). When mice lacking the serotonin 1B receptor are isolated for four weeks and then exposed to a wildtype mouse, they are much more aggressive than wildtype animals under similar conditions. The mutant mice attack intruders faster than wild-type mice or mice lacking only one copy of the serotonin 1B receptor gene, and the number and intensity of attacks is significantly greater than that of wild-type mice. Thus, the serotonin 1B receptor plays a role in mediating aggressive behavior in mice. Serotonin activity has been implicated as one of several important biological factors in determining the threshold for violence. People with a history of impulsive aggressive behavior (and of suicide)—and mouse strains that display increased aggressiveness—have low concentrations of serotonin in the brain. Inhibition of serotonin synthesis or destruction of serotonergic neurons increases aggressiveness in mice and monkeys. Finally, certain serotonin agonists that act on the serotonin 1B receptor inhibit aggression. In humans a variety of social stressors, such as social or sexual abuse during childhood, are thought to lower the biological thresholds for violence, including the level of serotonin in the brain. Indeed, male monkeys raised in isolation have reduced levels of serotonin in their brains, illustrating that both environmental and genetic factors can converge to influence the metabolism of serotonin. The relationship of serotonin levels to aggression in humans is not simple, however. This complexity is evident in studies of a Dutch family that transmits an Xlinked form of mental retardation. Fourteen of the affected males have a history of impulsive behavior that includes arson, rape, and attempted murder. Each of these men carries a point mutation in the gene that encodes the enzyme monoamine oxidase A, one of the two major enzymes that metabolizes monoamines. This class of neurotransmitter includes serotonin, norepinephrine, and dopamine (see Chapters 60 and 61). The mutation apparently leads to increased levels of serotonin, yet the affected people show enhanced impulsiveness. Thus, the relationship between serotonin and aggression is not simply that reduced serotonin causes aggression and enhanced serotonin causes placidity. Both increases and decreases in serotonin levels may enhance aggression. These findings suggest, not surprisingly, that in humans the relationship between serotonin and a complex trait such as aggression is not direct and may be quite subtle. Finally, although monoamines, in particular serotonin, are important in aggressive behavior, other transmitter systems also affect this behavior, as would be expected for a complex behavioral trait.

Deletion of a Gene That Encodes an Enzyme Important for Dopamine Production Disrupts Locomotor Behavior and Motivation Dopamine, like serotonin, is a major monoaminergic transmitter in the central nervous system. The majority of dopaminergic neurons have their cell bodies in the substantia nigra while their axons project to the corpus striatum. Dopaminergic neurons have been implicated in the regulation of motor behavior—the degeneration of dopaminergic neurons underlies Parkinson's disease, a debilitating disorder of movement. Other dopaminergic pathways are thought to regulate motivated behaviors. Dysfunction of these pathways may contribute to schizophrenia (see Chapter 60). The role of the dopaminergic system in mammalian P.51 behavior has traditionally been studied through pharmacological techniques. Recently, however, gene knockout techniques have been applied to this system. In one set of experiments the ability of neurons to synthesize dopamine was blocked by selectively inactivating the gene that encodes tyrosine hydroxylase, one of the enzymes important in dopamine synthesis. The dopamine-deficient mice were born, began to nurse, and grew normally for about two weeks and then became inactive, failed to eat or drink, and died shortly thereafter. However, daily administration of L-DOPA, the product of tyrosine hydroxylase, restored normal feeding and produced increased activity. Dopamine is cleared from the synapse by a highaffinity dopamine transporter. In mutant mice with a deficiency in this transporter the amount of extracellular dopamine is 100-fold greater than normal. The mutant mice exhibit spontaneous and excessive locomotion similar to that obtained in normal mice when the dopamine transporter is blocked pharmacologically (as with a psychostimulant such as cocaine).

Single Genes Are Critical Factors in Certain Human Behavioral Traits Mutations in a Dopamine Receptor May Influence Novelty-Seeking Behavior As we have seen, studies of identical twins suggest that a number of personality characteristics have a significant heritable component, but in no case has this finding been rigorously demonstrated by identifying a specific gene. One fascinating candidate is novelty-seeking behavior, a behavior characterized by exhilaration or excitement in response to stimuli that are novel. People who score high on tests of novelty seeking tend to be impulsive, exploratory, fickle, excitable, quick-tempered, and extravagant. They often do things for thrills, as opposed to thinking things through before coming to a decision. Twin studies suggest that novelty-seeking behavior has a heritability of about 40%. Asignificant component (10% of the genetic component) seems to be due to a polymorphism in a single gene, the gene that encodes the D4 dopamine receptor. Dopamine is involved in exploratory and pleasure-seeking behavior. There are at least five known receptors for dopamine, called D1 to D5 (Chapter 60). The D4 receptor is expressed in the hypothalamus and the limbic areas of the brain concerned with emotion. In general, the coding sequence of the receptors for dopamine are highly conserved (as are the coding sequence for other receptors to chemical transmitters), and polymorphisms are very rare. Nevertheless, an interesting polymorphism has been found in the D4 receptor. One form of the gene, called the short form, has a 48-base pair DNA sequence in one of its cytoplasmic domains. By contrast, the long form of the D4 receptor gene has seven repeats of this domain. Additionally, the long and short forms of the receptor appear to have slightly different signaling properties in response to dopamine. It appears that these slight differences in the long form of the receptor correlate with novelty seeking.

Mutations in Opsin Genes Influence Color Perception Color vision is one of the few cases in which variation in normal human perception can be explained at a molecular level. Molecular cloning techniques have been used to identify and clone the genes encoding the proteins for the red, green, and blue pigments that transduce different wavelengths of light (see Chapter 29). Defects in one or more of the genes encoding red and green pigments lead to varying degrees of color blindness. The genes for red and green pigments are arrayed head-to-tail, close to one another on the X chromosome and differ in only about 1 in 20 of their amino acid residues. Because of this tandem organization and similarity of sequence, crossing over between the red and green pigment genes occurs frequently, leading to gene rearrangement.2 The resulting abnormality in both genes explains the origin of many cases of red-green color blindness. Subtle variations in color perception occur even among individuals with normal color vision. This is attributable to polymorphism in the red pigment gene in humans. In 62% of the male population with normal color vision, amino acid 180 is a serine residue while in the remaining 38% it is an alanine residue. The effects of this sequence difference can be revealed in psychophysical tests in which subjects are asked to match the intensity of a mixture of red and green light. The intensity of red light needed to match a standard depends on the amino acid at position 180. Because females have two X chromosomes, they fall into three groups: homozygotes for Ser180, homozygotes for Ala180, and heterozygotes who display an intermediate phenotype. Thus, a major variation in human color perception can be explained by a small change in the coding sequence of a single gene.

Box 3-4 Genetic Polymorphisms If two genes are located very near one another they are likely to be inherited together. Thus, if an abnormality of one gene produces a disease and a nearby marker gene encodes a readily recognized phenotypic trait (such as hair or eye color) or a readily detectable gene product (such as a protein present in the blood), people who express the marker will likely also express the disease—even though the marker may have nothing to do with the disease. Both the phenotypic trait and the DNA sequence of the gene vary in the normal population. In the past, genetic markers were used to distinguish variations in the protein coding regions of genes, such as blood group antigens, enzymes, and antigens of the histocompatibility complex. However, coding sequences represent only 5–10% of the total human genome; 90 or 95% of the genome contains noncoding regions. It is now possible to saturate the human genome with markers that distinguish variations that occur in otherwise homologous DNA sequences throughout the whole genome (including noncoding as well as coding sequences). This broad coverage has made it much easier to trace the inheritance of a disease to a specific region of a particular chromosome.

Figure 3-11A. The presence of a restriction fragment length polymorphism (RFLP) can be detected by analyzing DNA fragments cleaved by restriction endonucleases, enzymes that cut at specific restriction sites in nucleotide sequences. In this example chromosome b is missing a restriction site that is present on chromosome a. As a result, cutting chromosome b produces a larger than normal DNA fragment in this region. After cutting, the DNA from both chromosomes is separated according to size by means of gel electrophoresis and transferred to nylon filters (in a procedure called Southern blotting). Autoradiography is then used to reveal the polymorphism. Because the b fragment is larger, it is distinguishable from the a fragment. (Adapted from Alberts et al. 1994.)

One type of DNA marker, a restriction fragment length polymorphism (RFLP), is created by differences in DNA sequence in paired alleles. At one allele a cutting site for a particular restriction enzyme (an enzyme that cuts DNA only at a specific nucleotide sequence) is eliminated or an extra site added, while the other allele remains normal. As a result, the restriction enzyme produces DNA fragments of different lengths from the two alleles. These so-called restriction fragments can be separated by electrophoresis in agarose gels and distinguished by specific DNA probes (Figure 3-11A,3-11B,3-11C). When such a polymorphic region of the DNA is closely linked to a particular gene, inheritance of the gene can be traced by following the inheritance of a particular pattern of restriction fragments. The method can be used to trace pathogenic genes (Figure 3-11B,C).

Figure 3-11B. Genetic linkage analysis detects the coinheritance of a mutated gene responsible for a human disease and a nearby restriction fragment length polymorphism (RFLP) marker. In this example the gene responsible for the disease is inherited in four offspring, three of which coinherit the marker. Thus, the gene responsible for the disease is located close to the RFLP marker on this chromosome. (Adapted from Alberts et al. 1994.)

Figure 3-11C. Inheritance of the gene responsible for Huntington disease can be traced by following the inheritance of a particular restriction fragment length on chromosome 4.

P.52 Novelty seeking is a natural variation in human behavior. Color blindness is a similar variation in perception. It may be annoying to those who have it, but it interferes only marginally with life's function and not at all with longevity. These relatively neutral mutations differ importantly from mutations that produce serious disease.

Mutations in the Huntingtin Gene Result in Huntington Disease One of the first complex human behavioral abnormalities to be traced to a single gene is Huntington disease, a degenerative disorder of the nervous system. Huntington disease affects both men and women with a frequency of about 5 per 100,000. It is characterized by four features: heritability, chorea (incessant, rapid, jerky movements), cognitive impairment (dementia), and death 15 to 20 years after the onset of symptoms. In most patients the onset of the disease occurs in the fourth to fifth decade of life. Thus, the disease often strikes after individuals have married and had children. Huntington disease involves the death of neurons in the caudate nucleus, a part of the basal ganglia involved in regulating voluntary movement. The death of P.53 nerve cells in the caudate nucleus is thought to cause the chorea. The basis for the impaired cognitive functions and eventual dementia is less clear and is due either to a loss of cortical neurons or to the disruption of normal activity in the cognitive portion of the basal ganglia (see Chapter 43). The selective loss of neurons in the caudate nucleus can be demonstrated in living patients using imaging techniques. Huntington disease is inherited as an autosomal dominant disorder and the mutation is highly penetrant. 3 The Huntington disease gene was identified on

chromosome 4 using a technique based on DNA markers to map heritable disease mutations relative to genetic polymorphisms (Box 3-4). This gene encodes a large protein called Huntingtin, the function of which is as yet unknown.

Figure 3-12. The DNA mutation in Huntington disease is an unstable CAG repeat. A. The nucleotide sequence in the region of the unstable CAG repeat in the Huntingtin gene. B. Distribution of CAG repeat lengths on normal and Huntington disease (HD) chromosomes. The percentages of normal and HD chromosomes containing different CAG repeat lengths (from 6 to 125) are compiled from several published studies. C. A highly significant inverse correlation between age of onset of Huntington disease movements and CAG repeat length occurs across all HD alleles. (Modified from Gusella and MacDonald 1995.)

P.54 The mutated form of the Huntingtin protein contains a stretch of glutamine residues that is much longer than in the normal protein. The codon (CAG) that encodes glutamine is repeated 19–22 times in the normal gene but 48 or more times in the mutated gene (Figure 3-12A). This expansion results in abnormally long stretches of polyglutamine in the protein. The number of ways in which the abnormal stretch of glutamines affect protein function is not known. Diseases that involve trinucleotide expansion have an additional feature: each successive generation of a family that harbors the mutant gene manifests the disease with greater severity at an earlier age (genetic anticipation). Thus, an individual may have a mild case of Huntington disease that was not manifested until age 60, whereas his great grandchild may develop more serious symptoms by age 40 (Figure 3-12B, C). This trend is due to the instability of the expanded trinucleotide repeat. As the repeat passes through the germline, the number of repeats tends to increase, particularly in the paternal line. These repeats are thought to create hairpin-like structures in DNA that interfere with its replication. As the repeats attain a certain length, the hairpin-like structures stabilize, leading to persistent mistakes in replication and consequently further expansion of the trinucleotide repeat. The polyglutamine structures appear to affect the protein in one of two ways: they may make the altered protein destructive to the cell, producing a gain-of-function mutation; or they may bind other proteins required for normal cellular function. Expanded tri-nucleotide repeat diseases are usually genetically dominant. Table 3-1 Neurological Diseases Involving Trinucleotide Repeats1

Disease X-linked spinal and bulbar muscular atrophy

Repeat length2

Repeat

Gene product

Fragile X mental retardation3

CAG CGG

Normal: 11–34Disease: 40–62 Normal: 6 to ~50Premutation: 52–200Disease: 200 to>1000

Androgen receptor FMR-1 protein

Myotonic dystrophy3

CTG

Normal: 5–30Premutation: 42–180Disease: 200 to >1000

Myotonin protein kinase

Huntington disease

CAG

Normal: 11–34Disease: 37–121

Huntingtin

Spinocerebellar ataxia type 1

CAG

Normal: 19–36Disease: 43–81

Ataxin-1

FRAXE mental retardation3 Dentatorubral-pallidoluysian atrophy

GCC

Normal: 6–25Disease: >200

?

CAG

Normal: 7–23Disease: 49–75

?

1Eight

diseases are now associated with the expansion of a trinucleotide CAG repeat in the coding region of the responsible gene: spinal and bulbarmuscular atrophy (SBMA); Huntington disease (HD); dentatorubralpallidoluysian atrophy (DRPLA); spinocerebellar ataxia type 1 (SCA1); and SCA2,3, 6, and 7. In addition, three congenital fragile X syndromes, each associated with hypermethylation and unstable trinucleotide repeats, have been identified: FRAXA(CGG); FRAXE (GCC), and FRAXF (GCC). For each of the FRA genes, expression is extinguished by expansion and methylation.

2

Although individuals with repeat length in the “premutation” size range are phenotypically normal, the corresponding chromosomes are very likely to expand to the “disease-length” category in

the next meiosis.3 CGG, CTG, and CGG expansions are transcribed into the noncoding region of the mRNAs, whereas the GAG expansions associated with neuro-degenerative disorders are translated into glutamine tracts. (Adapted from Warren 1996.)

P.55 Strikingly, many other hereditary diseases of the nervous system involve similar expansions in trinucleotide repeats within the coding region of the gene responsible for the disease. These diseases include Friedreich's ataxia type 1, spinocerebellar ataxia, and certain spinal and bulbar muscular dystrophies (Table 31 Figure 3-13). By contrast, fragile X mental retardation is an X-linked recessive disease that involves a trinucleotide repeat in the control region near the coding region of the gene, leading to the inactivation of the FMR (fragile X mental retardation) gene. As in Huntington disease, progressive death of specific subpopulations of neurons or muscle cells occurs in many of these diseases.

Most Complex Behavioral Traits in Humans Are Multigenic So far we have considered examples of the effects of single genes on behavior. Classic genetic analysis focuses on Mendelian traits, which, as we have seen, are normally determined by allelic variation within a single gene. However, most behavioral traits as well as most common genetic disorders are multigenic; they are determined by several genes interacting with environmental factors.4 In contrast to single-locus Mendelian traits, multigenic traits do not have a simple recognizable pattern of inheritance (autosomal dominant, recessive, or Xlinked), and thus the relative contributions of several genes to one trait is difficult to analyze. Nevertheless, determining which genes contribute to complex human traits has profound implications for the care and treatment of human disease. Most common multigenic diseases, such as diabetes, coronary artery disease, asthma, schizophrenia, P.56 and manic-depressive disorder, are thought to represent a variety of disorders both etiologically and genetically. Thus, different mutant alleles and environmental factors are thought to produce indistinguishable phenotypes. In a typical multigenic disease, such as diabetes, there are scores of different alleles (among 10–12 different loci; see below) distributed throughout the human population of the world that are capable of contributing to the disease. In any one family three or four of these mutant alleles are likely to be sufficient to gives rise to the disease. In fact, it is possible that each of the alleles that contributes to a multigenic disease functions as a normal polymorphism when expressed by itself but gives rise to disease if expressed together with other alleles in a certain genetic background. Moreover, because mono-zygotic twins with identical genetic endowment are often discordant for multigenic traits, the role of nongenetic factors must be important.

Figure 3-13 This model of a gene containing three exons and two introns (intervening blue line) depicts the location and type of expanded triplets involved in certain neurological diseases. CGG repeats are found within the 5′ untranslated region of the first exons of the genes for fragile X syndrome, fragile XE mental retardation (MR), and fragile site 11B. CGG repeats are also found at two fragile sites, XF and 16A, which are not known to be in the vicinity of any genes and, like fragile site 11B, are not known to result in any disease phenotype. GAA repeats are found within the first exon of the X25 gene for Friedrich's ataxia. CAG repeats occur at five loci responsible for neurological diseases. These repeats are coding regions and thus result in the lengthening of a normal polyglutamine tract in their respective gene products. The repeats for Haw River syndrome are at the same locus as those for dentatorubral-pallidoluysian atrophy and similarly involve expansion of the same CAG repeat. A CTG repeat (CAG on the other strand) occurs in the 3′ untranslated region of the final exon of the protein kinase gene for myotonic dystrophy. (Adapted from Warren 1996.)

Several techniques have facilitated the genomewide search for multigenic disorders in humans. The most common genetic mapping strategy is linkage analysis, in which a gene's locus is determined by comparing the inheritance of the mutant gene with a precisely mapped polymorphic DNA marker in a family afflicted with the particular disease. ADNAmarker is useful if it maps to a unique locus within the human genome and it identifies frequent polymorphic variations between individuals at this locus. Coinheritance of a particular DNAmarker with a mutant phenotype (or disease state) suggests that the marker and the mutant gene are physically close together on the chromosome. Until 1980 polymorphisms could only be detected by differences in the behavior of the protein, for example, by differences in enzyme activity or electrophoretic mobility. In the early 1980s it was appreciated that the noncoding regions, which make up 90-95% of the DNA, are the sites of frequent DNA polymorphisms. Indeed, single base pair changes that give rise to variants are relatively frequent in the human genome, with rates perhaps as high as 1 in 500 base pairs, and

most of these changes occur in noncoding regions. The method of restriction fragment length polymorphisms (see Box 3-4) is used to detect polymorphisms throughout the genome. The coinheritance of a DNA marker and mutant gene can occur by chance, or it can occur because the two loci recombine infrequently during meiosis, a direct result of their physical proximity. The chance that any two unlinked loci—for example, loci from different chromosomes—will be inherited together is 1/2, and the chance that they will be coinherited in n siblings is (1/2)n. Thus, if two loci are coinherited in all eight affected siblings from a single family, the odds against this being a random event would be (1/2)8 = 256:1. In practice this is a more complicated event, one that is better analyzed by computer programs that calculate the ratio of the odds for and against linkage, while considering various statistical issues, and generate a value known as the lod (log of the odds) score. (For practical purposes a lod score equal to or greater than 3 indicates that evidence for linkage between a gene marker is significant. This represents odds of 20:1 in favor of linkage between the two loci.) A related method of identifying polymorphisms is the characterization of simple sequence repeats by the polymerase chain reaction (PCR). The construction of high-resolution human genetic maps composed of these markers and the application of semi-automated screening technologies have facilitated linkage analysis. A P.57 gene that contributes to a multigenic trait is often called a quantitative trait locus (QTL) to indicate that it contributes to the genetic variance of a particular trait. QTL analysis is currently being used with mice and rats to track the genes that contribute to a number of behaviors (Box 3-5).

Box 3-5 Analysis of Multigenic Traits Quantitative trait locus (QTL) analysis is a method for identifying the multiple genes that condition a single behavioral trait. QTL analysis requires at least two strains of a species, each of which has been inbred until all members of the group are genetically identical and have two uniform sets of chromosomes. In the hypothetical example described here (Figure 3-14), two strains of mice have been selectively bred for aggressiveness (A) and docility (D).

●

Aggressive A-type mice are bred with docile D-type mice, producing a first generation (F1) hybrid offspring in which every mouse has one set of chromosomes from each parent. In the F1 generation the chromosomes in the cells that produce eggs and sperm exchange material. Segments of the mother's and father's DNA are recombined on individual chromosomes. ●

The F1 generation is bred back to D-type mice, producing offspring with one recombinant set of chromosomes and one set that is pure D. In each offspring the recombinant chromosome will carry a unique mix of genes from both original strains. ●

Second-generation mice will show a range of aggressiveness because more than one gene determines aggressiveness and the mix of genes in the recombinant chromosome set varies. In Figure 3-14 the levels of aggressiveness in the second-generation mice are indicated by the different colors. ●

Sites in the genome that contain genes that contribute to aggression are identified by searching each mouse's DNA for genetic markers, landmarks scattered throughout the genome that are known to differ between the aggressive and docile strains. Each marker is examined to determine whether a mouse has inherited the A-type or D-type. ●

For each marker, the mice are sorted into those that have A-type DNA at that locus and those that have D-type DNA. The aggressiveness scores for the mice in the two groups are then compared. If the A-type group is significantly more aggressive than the D-type group, that marker represents a QTL that may contain a gene contributing to aggressiveness. Since each QTL interval contains many genes, additional methods must be used to find the one conditioning aggression.

(Modified from Barinaga 1994.)

Figure 3-14.

Linkage analysis is very sensitive to the model of transmission—dominant, recessive, X-linked, and others —and loses power when applied to multigenic traits where the mode of transmission is not known a priori. In the study of multigenic traits, therefore, researchers will often analyze the DNA marker data by linkage analysis (where genetic parameters must be specified prior to analysis) and by various nonparametric analyses that are much less dependent upon underlying genetic parameters. An example is sib-pair analysis where P.58 one evaluates whether particular alleles (or chromosomal segments) are shared among affected siblings more often than would be predicted by chance alone. When the degree of allele-sharing reaches statistical significance, one concludes that the causal or predisposing mutation is contained within the shared region.

Figure 3-15. Many complex human behavioral disorders have a genetic component. A. Concordance for disease phenotypes among monozygotic twins (MZ) and dizygotic twins (DZ) for some behavioral disorders. The proband is the family member through which the family was initially discovered and explored. (Modified from Plomin et al. 1994.) B. The risk of developing schizophrenia is a function of pedigree. (Modified from Gottesman 1991.)

Family, twin, and adoption studies indicate not only that patients who suffer from the major psychiatric disorders have a genetic predisposition to those disorders but also that in the normal population at large components of character and general cognitive abilities have important genetic components. In the past it was generally assumed that these genetic contributions to character and cognitive functioning decline over the course of one's lifetime because of the accumulation over the years of social and environmental experience. However, a study of the cognitive capabilities of 240 pairs of twins in the ninth decade of their life showed that genes continue to account for 50% of the variance in later life, much as they do earlier in life. Thus, while environmental factors are important, genes clearly contribute to a variety of normal higher mental functions. Similarly, bipolar affective disorder (manic-depressive illness) frequently occurs in both siblings if they are monozygotic twins, but it occurs less frequently in both siblings if they are dizygotic twins. The heritability of P.59

bipolar affective disorder, as well as that of schizophrenia, has been estimated to be about 50-60% (Figure 3-15). Thus, factors other than genes must play a critical role in determining the onset of disease in these multifactorial disorders. Like other complex traits, schizophrenia and depression are most likely multigenic and multifactorial. It will be important to distinguish between various models of transmission. According to one (monogenic) model, many genes in the population can contribute to schizophrenia but each gene is rare and has a strong effect. Genetic linkage studies now indicate that such a monogenic model is likely to account for only a small fraction of schizophrenia patients. Asecond (oligogenic) model assumes that a small number of genes interact together to create a threshold of vulnerability for the disorder. Yet another (polygenic) model assumes that these disorders result from the cumulative effect of many genes, each with a minute effect. Several genetic forms of epilepsy most likely fit the monogenic model, whereas the major psychotic illnesses are thought to fit the oligogenic model. There may, however, be a subpopulation of people with major mental illness who suffer from the consequence of a powerful gene. Schizophrenia and bipolar affective disorder were among the first multigenic traits to be analyzed by genetic linkage analysis. In fact, many of the early lessons learned from multigenic gene mapping came from mistakes made in these pioneering studies. Segregation analysis and genetic modeling studies indicate that both schizophrenia and bipolar disorder result from the effects of a small number of mutant genes. Thus, although mutations in a set of 10 or more genes may contribute to schizophrenia on a population basis (due to genetic heterogeneity), the combined effects of even a subset of these mutants would presumably be sufficient to place an individual at high risk for the disorder. Furthermore, we know from twin studies that environmental and genetic factors together determine the overall likelihood of manifesting these disorders. According to this multifactorial model, a single mutation would produce a relatively small contribution to the overall predisposition to illness in the population and thus would be difficult to detect by genetic-linkage strategies. In any individual, however, one gene could actually be a quite strong contributor. For this reason, current psychiatric genetic studies usually involve international consortia cooperating in the systematic ascertainment and diagnosis of very large clinical samples, which lend sufficient power for the detection of small genetic contributions to illness. We shall see in Chapter 60 that the genotyping of several pedigrees has provided a possible genetic locus for susceptability to schizophrenia.

An Overall View Most aspects of behavior are under genetic control. Evidence for this can be seen in the striking biological similarities of human twins and in our ability to select and breed domestic and laboratory animals for particular behavioral traits. Such breeding experiments generally indicate that behavioral traits are multigenic in origin. Only in rare instances has the source of natural variation been traceable to a single predominant genetic factor, as in the development of certain forms of obesity in mice. Now, however, we are entering a new era in which it will be much easier to trace genes that control behavior. The availability of the complete genome for an organism will facilitate our understanding of how genes control genetic pathways important for cellular function, and this advance will allow much more effective and meaningful correlations with behavior. Several genomes are already completed: those of Escherichia coli and several other prokaryotic micro-organisms (5,000 genes, about 5 megabase (Mb) pairs), that of the yeast Saccharomyces cervisiae (6,000 genes, 12 Mb), and that of the worm Caenorhabditis elegans (20,000 genes, 97 Mb). The human genome—all 80,000 genes—is likely to be completed by the year 2003, and work on the genomes of Drosophila and mouse are well underway. From the several genomes that have been completed we have already learned a number of surprising facts. First, the human genome seems to have undergone two major replications from the primitive genome of single-celled organisms. Second, fully 40% of the genes in yeast and C. elegans are novel; their function is completely unknown. Third, from C. elegans we have learned that genes fall into two large classes that perform different functions and have different positions on the chromosomes. One set of 5,000 genes performs the core or housekeeping functions of the cell, the genes encode the proteins for intermediary metabolism for the metabolism of DNA, RNA and protein, for cytoskeletal structures, transport and secretion. The housekeeping genes are highly conserved, in both number and structure, and their ancestors have been found in yeast. Most likely they occur in comparable number in all organisms. In C. elegans these core function genes are clustered together in the central region of the chromosomes where they appear to be protected from evolutionary change. The second set of about 15,000 genes are more specialized, and newer from an evolutionary perspective; they are not found in yeast. These specialized genes are mostly concerned with intercellular signaling, transcription, and other forms of regulatory control unique to multicellular organisms. These newer genes are positioned P.60 at the two ends of the chromosomes, where they appear to be more susceptible to evolutionary pressures. They include genes for 400 protein kinases, 480 zinc finger proteins that appear to be transcription factors, and 790 membrane-spanning receptors. Genes have been identified in C. elegans for most classes of human transcription factors and signaling proteins. In fact, many genes in C. elegans are similar to human genes involved in disease. Indeed, 70% of human proteins so far identified can be related to orthologs—similar proteins with a presumed common ancestor—in C. elegans. Finally, simple perturbations of a yeast cell, such as the action of a mating factor, affects not a few but a large number of genes. Thus, in the future the perspective of genetic analysis will change from examining how single genes and proteins work to examining how many genes and proteins interact to produce a patterned response. It is expected that the complete human genome, and the genomes of still other key organisms, will be to biology what the periodic table of elements has been to chemistry. For any species the genome will define all the genetic elements on which life's processes depend. The ability to analyze entire genomes promises to provide us with new insights that should dramatically change our ability to analyze behavioral processes, thereby altering dramatically the theory and practice of all areas of medicine, including neurology and psychiatry. For example, what we already know about the human genome has brought molecular geneticists to the brink of identifying the combinations of genes contributing to certain multigenic disorders. The wealth of genetic information derived from such genetic linkage studies has enormous practical benefits. Researchers recently identified 10 to 12 different genes that predispose individuals to insulin-dependent diabetes mellitus. In addition, a variation in the number of repeating sequences within the gene encoding the dopamine D4 receptor is thought to make an important contribution to the overall genetic variance that characterizes noveltyseeking behavior. In the future the detection of genes that produce only a small effect on phenotype is likely to have a major impact on the study of behavioral disorders. These findings raise fascinating issues about natural genetic variations in humans that we should be able to confront soon. To what degree do genetically transmitted differences in behavioral traits reflect quantitative variation in the expression of benign alleles and therefore natural variations of a normal behavior, as opposed to mutations of the same gene that produce a disease state? To what degree do the genetic contributions to natural variations in behavior reflect variations in the level of expression of the same protein? The answers to such questions will be essential for developing rational therapeutic strategies for treating psychiatric disorders. Variations in genes—in DNA sequences—represent the basic material for evolutionary change. These variations also form the basis for individual differences in risk for the many genetically complex diseases that confront neurology and psychiatry.

Selected Readings Auwerx J, Staels B. 1998. Leptin. Lancet 351:737–742.

Bargmann CI. 1998. Neurobiology of the Caenorhabditis elegans genome. Science: 2028–2033.

Bouchard TJ, Jr. 1994. Genes, environment, and personality. Science 264:1700–1701.

Collins FS, Patrinos A, Jordan E, Chakravati A, Gesteland R, Walters L, and the members of the DOE and NIH planning groups. 1998. New goals for the U.S. human genome project: 1998–2003. Science 282:682–689.

Dunlap JC. 1998. Common threads in eukaryotic circadian systems. Curr Opin Genet Dev 8:400–406.

Hall JC. 1994. The mating of a fly. Science 264:1702–1714.

Hardin PE. 1998. Activating inhibitors and inhibiting activators: A day in the life of a fly. Curr Opin Neurobiol 8:642–647.

Houseknecht KL, Baile CA, Matteri RL, Spurlock ME. 1998. The biology of leptin: a review. J Anim Sci 76:1405–1420.

Jennings C. 1995. How trinucleotide repeats may function. Nature 378:127.

Mendel G. 1866. Versuche über Pflanzen-Hybriden. Verh Naturforsch 4:3–47; 1966. Translated in: C Stern, ER Sherwood (eds). The Origin of Genetics: A Mendel Source Book. San Francisco: WH Freeman.

Palmiter RD, Erickson JC, Hollopeter G, Baraban SC, Schwartz MW. 1998. Life without neuropeptide Y. Recent Prog Horm Res 53:163–199.

Plomin R, DeFries JC. 1998. The genetics of cognitive abilities and disabilities. Sci Am 278:62–69.

Plomin R, Owen MJ, McGuffin P. 1994. The genetic basis of complex human behaviors. Science 264:1733–1739.

Plomin R, Rutter M. 1998. Child development, molecular genetics, and what to do with genes once thay are found. Child Dev 69:1223–1242.

Suzuki DT, Griffiths AJF, Miller JH, Lewontin RC. 1989. An Introduction to Genetic Analysis, 4th ed. New York: WH Freeman. P.61

Takahashi JS, Pinto LH, Vitaterna MH. 1994. Forward and reverse genetic approaches to behavior in the mouse. Science 264:1724–1733.

Wilsbacher LD, Takahashi JS. 1998. Circadian rhythms: molecular basis of the clock. Curr Opin Genet Dev 8:595–602.

Young MW. 1998. The molecular control of circadian behavioral rhythms and their entrainment in Drosophila. Annu Rev Biochem 67:135–152.

References Alberts B, Bray D, Lewis J, Raff M, Roberts K, Watson JD. 1994. Molecular Biology of the Cell, 3rd ed. New York: Garland.

Baily DW. 1981. Recombinant inbred strains and bilineal congenic strains. In: HL Foster, JD Small, JG Fox (eds). The Mouse in Biomedical Research. Vol. 1, Recombinant Inbred Strains and Bilineal Congenic Strains, pp. 223–239. New York: Academic.

Barinaga M. 1994. Genes and behavior news report. Fruit flies, rats, mice: evidence of genetic influence. A new tool for examining multigenic traits. Science 264:1690–1693.

Barinaga M. 1995. New clock gene cloned. Science 270:732–733.

Barinaga M. 1996. Researchers find the reset button for the fruit fly clock. Science 271:1671–1672.

Benjamin J, Li L, Patterson C, Greenberg BD, Murphy DL, Hamer DH. 1996. Population and familial association between the D4 dopamine receptor gene and measures of novelty seeking. Nat Genet 12:81–84.

Bouchard TJ Jr., Lykken DT, McGue M, Segal NL, Tellegen A. 1990. Sources of human psychological differences: the Minnesota study of twins reared apart. Science 250:223–228.

Chakravarti A, 1999. Population genetics–making sense out of sequence. Nat Genet Suppl 21:56–60.

Chen H, Charlat O, Tartaglia LA, Woolf EA, Weng X, Ellis SJ, Lakey ND, Culpepper J, Moore KJ, Breitbart RE, Duyk GM, Tepper RI, Morgenstern JP. 1996. Evidence that the diabetes gene encodes the leptin receptor: identification of a mutation in the leptin receptor gene in db/db mice. Cell 84:491–495.

Cordell HJ, Todd JA. 1995. Multifactorial inheritance in type 1 diabetes. Trends Genet 11:499–504.

Cloninger CR, Adolfsson R, Svrakic NM. 1996. Mapping genes for human personality. Nat Genet 12:3–4.

Davies JL, Kawaguchi Y, Bennett ST, Copeman JB, Cordell HJ, Pritchard LE, Reed PW, Gough SC, Jenkins SC, Palmer SM, et al. 1994. A genome-wide search for human type 1 diabetes susceptibility genes. Nature 371:130–136.

de Bono M, Bargmann CI. 1998. Natural variation in a neuropeptide Y receptor homolog modifies social behavior and food response in C. elegans. Cell 94:679–689.

Ebstein RP, Novick O, Umansky R, Priel B, Osher Y, Blaine D, Bennett L, Nemanov M, Katz M, Belmaker RH. 1996. Dopamine D4 receptor (D4DR) exon III polymorphism associated with the human personality trait of novelty seeking. Nat Genet 12:78–80.

Galton F. 1869. Hereditary Genius: An Inquiry into Its Laws and Consequences. London: Macmillan; 1962. Reprint. Cleveland: Meridian Books.

Giros B, Jaber M, Jones SR, Wightman RM, Caron MG. 1996. Hyperlocomotion and indifference to cocaine and amphetamine in mice lacking the dopamine transporter. Nature 379:606–611.

Gottesman II 1991. Schizophrenia Genesis. The Origins of Madness. New York: WH Freeman.

Gusella JF, MacDonald ME. 1995. Huntington's disease. Semin Cell Biol 6:21–28.

Heath MJ, Hen R. 1995. Serotonin receptors. Genetic insights into serotonin function. Curr Biol 5:997–999.

The Huntington's Disease Collaborative Research Group. 1993. A novel gene containing a trinucleotide repeat that is expanded and unstable on Huntington's disease chromosomes. Cell 72:971–983.

King DP, Zhao Y, Sangoram AM, Wilshacher LD, Tanka M, Antoch MP, Steeves TDL, Vitaterna MH, Kornhauser JM, Lowry PL, Turek FW, Takahashi JS. 1997. Positional cloning of the mouse circadian clock gene. Cell 69:641–653.

Konopka RJ, Benzer S. 1971. Clock mutants of Drosophila melangaster. Proc Natl Acad Sci U S A 68:2112–2116.

Lee C, Parikh V, Itsukaichi T, Bae K, Edery I. 1996. Resetting the Drosophila clock by photic regulation of PER and a PER-TIM complex. Science 271:1740–1744.

Lee GH, Proenca R, Montez JM, Carroll KM, Darvishzadeh JG, Lee JI, Friedman JM. 1996. Abnormal splicing of the leptin receptor in diabetic mice. Nature 379:632–635.

Lewin B. 1994. Genes, Vol. 5. Oxford: Oxford Univ. Press.

McClearn GE, Johansson B, Berg S, Pedersen NL, Ahern F, Petrill SA, Plonim R. 1997. Substantial genetic influence on cognitive abilities in twins 80 or more years old. Science 276:1560–1564.

Myers MP, Wager-Smith K, Rothenfluh-Hilfiker A, Young MW. 1996. Light-induced degradation of TIMELESS and entrainment of the Drosophila circadian clock. Science 271:1736–1740.

Nickelson DA, Taylor SL, Weiss KM, Clark AG, Hutchinson RG, Stengard J, Salomaa V, Vartiainen E, Boerwinkle E, Sing CF. 1998. DNA sequence diversity in a 9.7Kb region of the human lipoprotein lipase gene. Nat Genet 19:233–240.

Qu D, Ludwig DS, Gammeltoft S, Piper M, Pelleymounter MA, Cullen MJ, Mathes WF, Przypek R, Kanarek R, Maratos-Flier E. 1996. A role for melaninconcentrating hormone in the central regulation of feeding behaviour. Nature 380:243–247.

Risch N. 1990. Linkage strategies for genetically complex traits. I. Multilocus models. Am J Hum Genet 46:222–228.

Saudou F, Amara DA, Dierich A, LeMeur M, Ramboz S, Segu L, Buhot MC, Hen R. 1994. Enhanced aggressive behavior in mice lacking 5-HT1B receptor. Science 265:1875–1878.

Tecott LH, Barondes SH. 1996. Genes and aggressiveness. Behavioral genetics. Curr Biol 6:238–240.

Thomas SA, Matsumoto AM, Palmiter RD. 1995. Noradrenaline is essential for mouse fetal development. Nature 374:643–646. P.62

Vosshall LB, Price JL, Sehgal A, Saez L, Young MW. 1994. Block in nuclear localization of period protein by a second clock mutation, timeless. Science 263:1606–1609.

Warren ST. 1996. The expanding world of trinucleotide repeats. Science 271:1374–1375.

Watson JD. 1997. Genes and Politics. Keynote Address. Congress of Molecular Medicine. Berlin, Germany. Annual Report. Cold Spring Harbor, NY: Cold Spring Harbor Laboratories.

Watson JD, Tooze J, Kurtz DT (eds). 1983. Recombinant DNA: A Short Course. New York: Scientific American; distr. by WH Freeman.

Zhang Y, Proenca R, Muffei M, Barone M, Leopold L, Friedman, JM. 1994. Positional cloning of the mouse obese gene and its human homologue. Nature 372:425–432.

Zhou QY, Palmiter RD. 1995. Dopamine-deficient mice are severely hypoactive, adipsic, and aphagic. Cell 83:1197–1209.

Zhou QY, Quaife CJ, Palmiter RD. 1995. Targeted disruption of the tyrosine hydroxylase gene reveals that catecholamines are required for mouse fetal development. Nature 374:640–643. 1The

specific biochemical processes by which high levels of phenylalanine adversely affect maturation of the brain are still not understood.

2This

gene rearrangement is the result of unequal crossing over between the X chromosomes in a female. This unequal crossover appears as a hemizygous condition in male offspring (genes on the male's X chromosome are called hemizygous because they exist only in one copy).

3Penetrance

refers to the frequency with which a heritable trait is manifested phenotypically by individuals carrying the mutant gene(s). Thus the Huntington disease gene is 100% penetrant.

4The

term multigenic includes both oligogenic and polygenic traits. An oligogenic trait or disorder is determined by a small number of genes, each contributing to the phenotype in a significant way. In contrast, a polygenic trait is the result of many genes, each with a small effect on the phenotype.

Back

I The Neurobilogy of Behavior

Cave Paintings Contain the First Human Signatures. A paleolithic cave painting from the Chauvet cave in the Ardèche region of France showing a negative image of a right human hand. Cave paintings, found in France and Spain in the regions at the borders of the two countries, primarily show game animals—bison, reindeer, horses, deer, oxen, rhinoceros, and mammoths. Although the purpose of the paintings cannot be known for certain, it is believed that they were used in magical or religious rituals to ensure a good hunt. Images of hands occur either in the negative, as shown here, or in the positive, and always in red. While their meaning is uncertain, it is tempting to think that this hand, which is over 30,000 years old, is early evidence of human cognition. (Reproduced with permission from Chauvet J-M, Deschamps EB, Hillare C. 1996. Dawn of Art: The Chauvet Cave, p. 120. New York: Harry N. Abrams, Incorporated.).

P.2 THE TASK OF NEURAL SCIENCE is to understand the mental processes by which we perceive, act, learn, and remember. How does the brain produce the remarkable individuality of human action? Are mental processes localized to specific regions of the brain, or do they represent emergent properties of the brain as an organ? If specific mental processes are represented locally in different brain regions, what rules relate the anatomy and physiology of a region to its specific role in mentation? Can these rules be understood better by examining the region as a whole or by studying its individual nerve cells? To what extent are mental processes hard-wired into the neural architecture of the brain? What do genes contribute to behavior, and how is gene expression in nerve cells regulated by developmental and learning processes? How does experience alter the way the brain processes subsequent events? This book attempts to address these questions. In so doing it describes how neural science is attempting to link molecules to mind—how proteins responsible for the ctivities of individual nerve cells are related to the complexity of mental processes. Today, it is possible to link the molecular dynamics of individual nerve cells to representations of perceptual and motor acts in the brain and to relate these internal mechanisms to observable behavior. New imaging techniques permit us to see the human brain in action—to identify specific regions of the brain associated with particular modes of thinking and feeling. In the first part of this book we consider the degree to which mental functions can be located in specific regions of the brain. We also examine the extent to which a behavior can be understood in terms of the properties of specific nerve cells and their interconnections in one region of the brain. The human brain is a network of more than 100 billion individual nerve cells interconnected in systems that construct our perceptions of the external world, fix our attention, and control the machinery of our actions. A first step toward understanding the mind, therefore, is to learn how neurons are organized into signaling pathways and how they communicate by means of synaptictransmission. One of the P.3 chief ideas we shall develop in this book is that the specificity of the synaptic connections established during development underlie perception, action, emotion, and learning. We must also understand both the innate (genetic) and environmental determinants of behavior. Specifically, we want to know how genes contribute to behavior. Of course, behavior itself is not inherited—what is inherited is DNA. Genes encode proteins that are important for the

development and regulation of the neural circuits that underlie behavior. The environment, which begins to exert its influence in utero, becomes of prime importance after birth. Modern neural science represents a merger of molecular biology, neurophysiology, anatomy, embryology, cell biology, and psychology. Along with astute clinical observation, neural science has reinforced the idea first proposed by Hippocrates over two millennia ago that the proper study of mind begins with the study of the brain. Cognitive psychology and psychoanalytic theory have emphasized the diversity and complexity of human mental experience. Both disciplines recognize the importance of genetic as well as learned factors in determining behavior. By emphasizing functional mental structure and internal representation, psychoanalysis served as a source of modern cognitive psychology, a psychology that has stressed the logic of mental operations and of internal representations. Experimental cognitive psychology and clinical psychotherapy can now be strengthened by insights into the cellular neurobiology of behavior. The task for the years ahead is to produce a psychology that—though still concerned with problems of how internal representations are generated, with psychodynamics, and with subjective states of mind—is firmly grounded in empirical neural science.

Back

4 The Cytology of Neurons James H. Schwartz Gary L. Westbrook THE CELLS OF THE NERVOUS system vary more than those in any other part of the body. Nevertheless, all neurons have common features that distinguish them from cells in other tissues. For example, they typically are highly polarized. Furthermore, cell functions are compartmentalized, an arrangement that contributes significantly to the processing of electrical signals. The chief functional compartments of neurons—the cell body, dendrites, axons, and terminals—are usually separated by considerable distances, a feature that accounts for the functional polarization discussed in Chapter 2. In most neurons the cell body, which contains the nucleus and the organelles for making RNA and protein, contains less than a tenth of the cell's total volume. The dendrites and axon that originate from the cell body make up the remainder. As discussed in Chapter 2, dendrites are thin processes that branch several times and are specially shaped to receive synaptic input from other neurons. The cell body usually gives off a single axon, another thin process that propagates electrical impulses, often over considerable distances, to the neuron's synaptic terminals on other nerve cells or on target organs. Neurons also differ from most other cells in being excitable. Rapid shifts in electrical potential are made possible by specialized protein structures (ion channels and pumps) in the cell membrane that control the instantaneous flow of ions into and out of the cells. Polarization and electrical excitability are not unique to neurons, however. Epithelial cells and other nonneuronal secretory cells also are polarized, with basolateral and apical surfaces that differ in structure and function. Some nonneural cells, notably muscle, are excitable, and like nerve cells their excitability depends on special protein molecules that allow ions to pass across the plasma membrane. In neurons, however, polarity and excitability are developed to a higher degree, permitting signals to be received, processed, and conducted over long distances. Although built on a common plan, neurons are quite diverse—over 50 distinct types have been described. This cytological diversity, which results from developmental differentiation, is also apparent on a molecular level. Each neuron expresses a combination of general and specific molecules. The kinds of proteins a cell synthesizes depends on the genes expressed in the cell; each type of cell synthesizes certain macromolecules (enzymes, struc P.68 tural proteins, membrane constituents, and secretory products) and not others. In essence each cell is the macromolecules that it makes. Many of these molecules are common to all cells in the body; some are characteristic of all neurons, others of large classes of neurons, and still others are restricted to only a few nerve cells.

Figure 4-1 The epithelial blueprint of a neuron. A. This diagram of a spinal motor neuron shows the cell body and the nucleus surrounded by the nuclear envelope, which is continuous with the rough and smooth endoplasmic reticulum. The space between the two membranes that constitute the nuclear envelope is continuous with the extracellular space. Dendrites emerge from the basal aspect of the neuron, the axon from the apical aspect. (Adapted from Williams et al. 1989.) B. This diagram of an epithelial cell shows a membrane system called the vacuolar apparatus, which includes all the major or- ganelles found in the neuron. Vesicles, which bud off the endoplasmic reticulum, shuttle to the cis face of the Golgi complex.

This chapter begins with an overview of the neuron, describing traits common to all neuronal types. We then discuss the differences among nerve cells. We have chosen to illustrate neuronal diversity with a detailed description of only three types of neurons: the sensory neurons of the dorsal root ganglion, the motor neurons of the spinal cord, and the pyramidal cells of the hippocampus. Neuronal structure can be readily illustrated by comparing the sensory and motor neurons in the spinal cord that mediate the stretch reflex, responsible for the classic kneejerk reflex. The distinctive features of the two neurons in this simple reflex circuit nicely illustrate the relationship between anatomy and function. The specialized features of nerve cells in complex neuronal circuits in the brain are illustrated by examining the pyramidal neurons of the CA3 and CA1 regions of the hippocampus. These cortical neurons belong to circuits thought to be responsible for memory storage (Chapters 62 and 63) and to be affected in certain forms of epilepsy (Chapter 46). P.69

The Structural and Functional Blueprint of Neurons Is Similar to Epithelial Cells Neurons develop from epithelial cells and retain fundamental epithelial features. For example, both cell types have distinctive poles: the epithelial cell's basolateral surface corresponds to the aspect of the neuron's cell body from which dendrites arise, while the apical surface corresponds to the aspect of the neuron from which the axon arises (Figure 4-1A). The boundaries of the neuron are defined by the external cell membrane, or plasmalemma. Nerve cell membranes have the general asymmetric bilayer structure of all biological membranes and represent a hydrophobic barrier impermeable to most water-soluble substances. The cytoplasm has two main components: the cytosol (including the cytoskeletal matrix) and the membranous organelles. The cytosol is the aqueous phase of the cytoplasm. In this phase only a very few proteins are freely soluble, mostly enzymes that catalyze various metabolic reactions. Many cytosolic proteins have general housekeeping functions and are common to all neurons. Others have specific roles in particular types of neurons; for example, the enzymes involved in the synthesis and degradation of the particular substance used as a neuro-transmitter. Moreover, some cytosolic proteins are distributed unevenly in the cell because they interact to form aggregates, particles, or matrices. Many cytosolic proteins involved in signaling are concentrated at the cell's periphery in the cytoskeletal matrix immediately adjacent to the plasmalemma.

Membranous Organelles Are Selectively Distributed Throughout the Neuron The membranous organelles of the cytoplasm include the mitochondria and peroxisomes as well as a complex system of tubules, vesicles, and cisternae (the vacuolar apparatus) that consists of the rough endoplasmic reticulum, the smooth endoplasmic reticulum, the Golgi complex, secretory vesicles, endosomes, lysosomes, and a multiplicity of transport vesicles that functionally interconnect these various compartments (Figures 4-1B and 4-2). Membranes of the vacuolar apparatus are thought to be derived from deep invaginations of the cell's external membrane that become discrete organelles. Their lumen corresponds topologically to the outside of the cell; consequently the inner leaflet of their lipid bilayer corresponds to the outer leaflet of the plasmalemma (Figure 4-1B). Even though the major subcompartments of this system are anatomically discontinuous, membranous and lumenal material are moved from one compartment to another with great efficiency and specificity by means of transport vesicles. For example, proteins and phospholipids synthesized in the rough endoplasmic reticulum are transported to the Golgi complex and then to secretory vesicles destined to fuse with the plasmalemma by exocytosis (the secretory pathway). Conversely, membrane taken into the cell in the form of en-docytic vesicles is incorporated into early endosomes, which are sorting compartments concentrated at the cell's periphery; the membrane is then either shuttled P.70 back to the plasmalemma by vesicle recycling or directed to late endosomes and eventually to lysosomes for degradation (the endocytic pathway).

Figure 4-2 Endoplasmic reticulum in a pyramidal cell. This micrograph of the basal pole of a pyramidal neuron's cell body, from which a single dendrite emerges, reveals therough and smooth endoplasmic reticulum (ER) above the nucleus (N). A portion of the Golgi complex (G) appears at the base of the dendrite (Den); some Golgi cisternae have entered the dendrite, as have mitochondria (Mit), lysosomes (Ly), and ribo-somes (R). Microtubules (Mt) are the prominent cytoskeletal filaments seen in the cytosol. Axon terminals (AT) are seen synapsing on the neuron. (From Peters et al. 1991.)

Figure 4-3 Under the light microscope the Golgi complex appears as a network of filaments that extend into dendrites (arrows), but not into the axon. The arrowheads at the bottom indicate the axon hillock. The Golgi complex in this micrograph is in a large neuron of the brain stem immuno-stained with antibodies specifically directed against this or- ganelle. (From De Camilli et al. 1986.)

A specialized portion of the rough endoplasmic reticulum forms a spherical flattened cisterna called the nuclear envelope, which surrounds the chromosomal DNAand its associated proteins and defines the nucleus (see Figure 4-1). This cisterna is continuous with other portions of the rough endoplasmic reticulum. Because of this continuity, the nuclear envelope is presumed to have evolved to ensheathe the chromosomes by an in-vagination of the plasmalemma. The nuclear envelope is interrupted by the nuclear pores, where fusion of the inner and outer membrane of the nuclear envelope results in the formation of hydrophilic channels through which proteins and RNA are exchanged between the cytoplasm proper and the nuclear cytoplasm. Thus the nucleoplasm and cytoplasm can be considered functionally continuous domains of the cytosol.

Figure 4-4 Neurons develop two distinct types of processes, dendrites and axons, even when grown in isolation. The figure shows a hippocampal neuron grown in isolation in primary culture and stained by double immunofluorescence for the synaptic vesicle protein synaptophysin and the transferrin receptor, a protein involved in iron uptake. When photographed through an appropriate filter, immunofluorescence corresponding to the transferrin receptor is seen only in dendrites (A). When photographed for synapsin, synaptic vesicles are selectively concentrated in the axon (arrow) as revealed by synapsin immunofluorescence (B). (From Cameron et al. 1991.)

Mitochondria and peroxisomes make use of molecular oxygen. Mitochondria generate ATP, the major molecule by which cellular energy is transferred or spent. Peroxisomes engage in detoxification through peroxidation reactions and also prevent the accumulation of the strong oxidizing agent hydrogen peroxide. These two organelles, which are thought to be derived from symbi P.71 otic organisms that invaded eukaryotic cells early in evolution, are not functionally continuous with the vacuolar apparatus of the cell.

Figure 4-5 Atlas of fibrillary structures. A. Microtubules, the largest-diameter fibers (25 nm), are helical cylinders composed of 13 protofilaments each 5 nm in width. Protofilaments are linearly arranged pairs of alternating α- and β-tubulin subunits (each subunit has a molecular weight of about 50,000). A tubulin molecule is a heterodimer consisting of one α- and one β-tubulin subunit. 1. In this exploded view up a microtubule the arrows indicate the direction of the right-handed helix. 2. A side-view of a microtubule shows the alternating α- and β-subunits. B. Neurofilaments are built with fibers that twist around each other to produce coils of increasing thickness. The thinnest units are monomers that form coiledcoil heterodimers. These dimers form a tetrameric complex that becomes the protofilament. Two protofilaments become a protofibril, and three protofibrils are helically twisted to form the 10 nm neurofilament. (Adapted from Bershadsky and Vasiliev 1988.) C. Microfilaments, the smallest-diameter fibers (about 7 nm), are composed of two strands of polymerized globular (G) actin monomers arranged in a helix. Several isoforms of G-actin are encoded by families of actin genes. In mammals there are at least six different (but closely related) actins. Each variant is encoded by a separate gene. Microfilaments are polar structures; the globular monomers actually are asymmetric. The monomers look like arrowheads, with a pointed tip and chevron-shaped (barbed) end, and polymerize tip to tail.

The cytoplasm of the cell body extends into the den-dritic tree without any functional boundary. Generally, all organelles present in the cytoplasm of the cell body are also present in dendrites, although the concentrations of some organelles, such as the rough endoplasmic reticulum, the Golgi complex, and lysosomes, progressively diminish with distance from the cell body. In contrast, a sharp functional boundary exists at the axon hillock, the point of emergence of the axon. For example, ribosomes, the rough endoplasmic reticulum, and the Golgi complex—the organelles that represent the main protein biosynthetic machinery of the neuron—for the most part are excluded from axons (Figure 4-3). Lysosomes and certain proteins, which in epithelial cells are selectively targeted to the basolateral surface of the cell, also are excluded from axons. Axons are, however, rich in synaptic vesicles, synaptic vesicle precursor membranes, and endocytic intermediates involved in synaptic vesicle traffic (Figures 4-1 and 4-4). Mitochondria and the smooth endoplasmic reticulum are present in all neuronal compartments, including the axon. The smooth endoplasmic reticulum is anatomically continuous with the rough endoplasmic reticulum. One of its functions is to act as a regulated Ca2store throughout the neuronal cytoplasm. It also performs a variety of enzymatic reactions and is involved in lipid metabolism.

Figure 4-6 The cytoskeletal structure of an axon is visualized here by means of quick freezing and deep etching. The figure shows the dense packing of microtubules and neurofilaments linked by cross-bridges. Microtubules are indicated by stars. The arrows bracket the microtubule-rich domain of the axon through which organelles are transported both in the an-terograde and the retrograde direction. M = myelin sheath. × 105,000. (Courtesy of B. Schnapp and T. Reese.)

P.72

The Cytoskeleton Determines the Shape of the Neuron The cytoskeleton is the major intrinsic determinant of the shape of a neuron and is responsible for the asymmetric distribution of organelles within the cytoplasm. It contains three main filamentous structures: micro-tubules, neurofilaments (called intermediate filaments in nonneuronal cells), and actin microfilaments (Figures 4-5 and 4-6). These filaments and their associated proteins account for about 25% of the total protein of the neuron. Microtubules form long scaffolds that extend the full length of the neuron and play a key role in developing and maintaining the neuron's processes. Asingle micro-tubule can be as long as 0.1 mm. Microtubules are constructed of 13 protofilaments in a tubular array with an outside diameter of 25–28 nm (Figure 45A). Each protofilament consists of several pairs of α- and β-tubulin subunits arranged linearly. The polar structure of the tubulin dimer creates a plus and a minus end of the polymer. The tubulins are encoded by a multigene family; at least six genes code for both the - and -subunits. More than 20 isoforms of tubulin are present in the brain because of the expression of different genes as well as post-translational modifications.

Figure 4-7 The dendritic architecture in the cerebellar cortex is visualized here by immunoperoxidase staining for the microtubule-associated protein MAP2, a dendrite-specific MAP. Dendrites of all classes of neurons are stained. The field is dominated by the dendrites of Purkinje cells. (Courtesy of P. De Camilli.)

Tubulin is a GTPase and microtubules grow by the addition of GTP-bound tubulin dimers at their plus end. Shortly after polymerization GTPis hydrolyzed to GDP. When a microtubule stops growing its plus end becomes capped by GDP-bound tubulin. Given the low affinity of the GDP-bound tubulin for the polymer, this would lead to rapid catastrophic depolymerization unless the microtubule were stabilized by interaction with other proteins. In fact, microtubules undergo rapid cycles of polymerization and depolymerization in dividing cells, but they are much more stable in mature dendrites and axons. This stability is due to microtubuleassociated proteins (MAPs), which promote the oriented polymerization and assembly of the microtubules. The MAPs in the axons differ from those in the dendrites. For example, MAP2 is present in dendrites but P.73 absent from axons (Figure 4-7), while tau and MAP3 are present in the axon.

Figure 4-8 A sensory (dorsal root ganglion) cell and a spinal motor neuron form a monosynaptic circuit that controls the knee-jerk stretch reflex. A. Sensory neuron. Left: The axon of the primary sensory neuron is typically quite convoluted before it bifurcates into a central and a peripheral branch. The cell body contains a prominent nucleus. (From Dogiel 1908.) Right: Low-power electron micrograph shows the cell body of a large dorsal root ganglion cell. A prominent nucleolus (Nuc) can be seen within the nucleus (N). The cell body of the neuron is surrounded by Schwann cells (Sc), the type of glial cells found in the peripheral nervous system. (Courtesy of R. E. Coggeshall and F. Mandriota.) B. Motor neuron. Left: Many dendrites typically branch from the cell bodies of spinal motor neurons, as shown by five spinal motor neurons in the ventral horn of a kitten. (From Ramón y Cajal 1909.) Right: Detail of the cell body of a motor neuron is shown in this photomicrograph. An enormous number of nerve endings from presynaptic neurons (arrows) are visible. These terminals, called synaptic boutons, appear as knob-like enlargements on the cell membrane. The synaptic boutons are prominent in this micrograph because the tissue is specially impregnated with silver. Three dendrites (Den) are also shown. The nucleus and its nucleolus are surrounded by Nissl substance (Ns), clumps of ribosomes associated with the membrane of the endoplasmic reticulum. (Courtesy of G. L. Rasmussen.)

Neurofilaments, 10 nm in diameter, are the bones of the cytoskeleton (see Figure 4-5B). They are the most abundant fibrillar components of the axon. (On average, there are 3-10 times more neurofilaments than microtubules in an axon.) Neurofilaments are related to the intermediate filaments of other cell types, all of which belong to a family of proteins called cytokeratins. (Other cytokeratins include vimentin, glial fibrillary acidic protein, desmin, and keratin.) Unlike microtubules, neuro-filaments are very stable and almost totally polymerized P.74 in the cell. In Alzheimer's disease and some other degenerative disorders they become modified and form a characteristic lesion called the neurofibrillary tangle (see Chapter 58).

Figure 4-9 Connections between sensory neurons and motor neurons in the spinal cord of an embryonic rat are shown in this micrograph. The sensory axons (orange) enter the spinal cord through the dorsal root and then run longitudinally in the dorsal column. Collaterals descend from the dorsal column to the spinal gray matter, where they arborize and make synaptic contact with the dendrites of motor neurons (green). (Courtesy of W. Snider.)

Microfilaments, 3-5 nm in diameter, are the thinnest of the three main types of fibers that make up the cy-toskeleton (see Figure 4-5C). Like the thin filaments of muscle, microfilaments are polar polymers of globular actin monomers (each bearing an ATP or ADP) wound into a double-stranded helix. Actin is a major constituent of all cells, perhaps the most abundant animal protein in nature. Several closely related molecular forms of actin, each encoded by a different gene, have been identified: the actin of skeletal muscle, and at least two other molecular forms, β and γ. Neural actin is a mixture of the β and γ species, which differ from muscle actin at a few amino acid residues. Most of the actin molecule is highly conserved, not only in different cells of an animal but also in organisms as distantly related as humans and protozoa.

Figure 4-10 The ending of a sensory nerve in the muscle is shown in this photomicrograph of a cat soleus muscle. Numerous fibers of a single primary afferent axon (Ia) coil around specialized muscle fibers within the muscle spindle, the sensory organ for stretch. Specialized intrafusal fibers innervated by the IA afferent fibers include the bag fibers (B) and chain fibers (Ch). (From Boyd and Smith 1984.)

Unlike the microtubules and neurofilaments, actin filaments form short polymers: they are concentrated at the cell's periphery in the cortical cytoplasm lying just underneath the plasmalemma, where, together with a very large number of actin-binding proteins (for example, spectrin-fodrin, ankyrin, talin, and actinin), they form a dense network. This matrix plays a key role in the dynamic function of the cell's periphery, such as the motility of growth cones during development, generation of specialized microdomains on the cell surface, and the formation of pre- and postsynaptic morphologic specializations. Like microtubules, microfilaments are in a dynamic P.75 state and undergo cycles of polymerization and depoly-merization. At any one time about half the total actin in neurons can exist as unpolymerized monomers. The state of actin within the cell is controlled by binding proteins. These proteins facilitate assembly and block changes in polymer length by capping the rapidly growing end of the filament or by severing it. Other binding proteins cross-link or bundle microfilaments. The dynamic state of microtubules and microfilaments permit the mature neuron to retract old processes and extend new ones.

Figure 4-11 The insulating myelin sheath of the axon has regularly spaced gaps called the nodes of Ranvier. Electron micrographs show the region of nodes in axons from the peripheral nervous system, spinal cord, and cerebral cortex. The axon (Ax) runs from the top to the bottom in all three micrographs. The axon is coated with many layers of myelin (M), which is lacking at the nodes (Nd), where the axolemma (Al) is exposed. (In the peripheral nervous system the support cell responsible for myelination is called a Schwann cell (Sc), and in the central nervous system it is an oligodendrocyte.) The elements of the cytoskeleton that can be seen within the axon are microtubules (Mt) and neurofilaments (Nf). Mitochondria (Mit) are also seen. (From Peters et al. 1991.)

In addition to serving as cytoskeleton, microtubules and actin filaments act as tracks along which other or-ganelles and proteins are driven by molecular motors. Since these filamentous polymers are polar, each motor drives its organelle cargo in one direction only. In the axon all microtubules are arranged in parallel, with the plus end pointing away from the cell body and the minus end facing the cell body. This regular orientation permits the orderly movement of distinct classes of or-ganelles along the axon, thus maintaining the special distribution of organelles throughout the cell. In dendrites, however, microtubules with opposite polarities are mixed, and this explains why the organelles of the cell body and dendrites are similar. Actin motors, called myosins, mediate other types of cell motility, including extension of the cell's processes. Myosin is also thought to translocate membranous organelles within the cortical cytoplasm. Actomyosin in muscle is responsible for contraction (Chapter 34).

Figure 4-12 The dendritic structure of a spinal motor neuron. A. Light micrograph of a motor neuron in the lumbosacral region of a cat's spinal cord. The cell body is shown in the lower left of the picture. The boxed area shows distal dendritic branches receiving contacts (arrows) from sensory (Ia afferent) neurons. Both sensory and motor neurons were identified by injection of the enzyme horseradish peroxidase, which serves as an intracellular marker. Because this is one of a set of serial sections, the complete dendritic branching pattern of this motor neuron can be reconstructed. The upper arrowhead identifies a presynaptic contact on a fifth-order dendritic branch, and the lower arrowhead points to a contact on a third-order branch. (From Brown and Fyffe 1981.) B. Presynaptic contacts (arrows) on primary dendrites within 45 m of the cell body of the motor neuron shown in A. (From Brown and Fyffe 1984.)

P.76

The Neurons That Mediate the Stretch Reflex Differ in Morphology and Transmitter Substance The relationship between neuronal structure and functions can be seen by comparing the sensory and motor neurons that mediate the stretch reflex. As described in Chapter 2, the monosynaptic component of the stretch reflex is a simple two-neuron circuit consisting of large sensory neurons that receive information from muscle cells and motor neurons that cause the skeletal muscles of the limb to contract (see Figure 2-5).

The Sensory Neuron Conducts Information From the Periphery to the Central Nervous System Sensory neurons for the stretch reflex convey information about the state of muscle contraction. Their cell bodies are round with large diameters (60-120 µm) and are located in dorsal root ganglia situated immediately adjacent to the spinal cord. At maturity these neurons possess a single axonal process that bifurcates into two branches a short distance from the cell body (Figure 4-8). The peripheral branch projects to muscle and the central branch to the spinal cord, where it forms synapses on the cell bodies and dendrites of motor neurons (Figure 4-9). The peripheral branch of the sensory axon coils around a fine, specialized muscle fiber within the muscle spindle, a sensory receptor sensitive to stretch (Figure 410). The peripheral branch is 14-18 µm in diameter and is coated with an insulating sheath of myelin 8-10 µm thick. (Myelination is discussed in some detail later in the chapter.) The myelin sheath is regularly interrupted along the length of the axon. At these gaps, P.77 called nodes of Ranvier, the plasma membrane of the axon (the axolemma) is exposed to the extracellular space for about 0.5 µm (Figure 4-11). This arrangement greatly increases the speed at which the nerve impulse is conducted along the axon (in humans, 80 m/s) because the signal jumps from one unmyelinated node to the next by saltatory conduction (see Chapters 8 and 9). The central branch of the sensory axon enters the spinal cord in the dorsal horn, where it bifurcates into branches that ascend and descend in the spinal cord. Collateral fibers from the axon form synapses on motor neurons in the ventral horn. When excited, the sensory neuron releases the excitatory amino acid neurotrans-mitter L-glutamate (see Chapter 15) that depolarizes the motor neurons.

The Motor Neuron Conveys Central Motor Commands to the Muscle Fiber The axon of each sensory neuron directly contacts two classes of motor neurons: those that innervate the muscle within which the sensory ending is located (the homonymous muscle) and those that innervate other muscles that cooperate in stretching the knee joint (synergistic muscles). Both types of motor neurons are located in the ventral horn of the spinal cord. Motor neurons have large cell bodies, and their nucleus is distinctive because of its large and prominent nucleolus (see Figure 4-8B). Unlike dorsal root ganglion cells, which have no dendrites, motor neurons have several dendritic trees that arise directly from the cell body. Each dendritic tree is complex, generated by extensive branching of primary dendrites (Figure 4-12). The total number of terminal dendritic branches per cell is often more than 100. The average length of a dendrite from the motor neuron's cell body to its end is about 20 cell-body diameters (1 mm), but some branches are twice as long. The branches project radially, so that the entire dendritic structure of a single motor neuron can extend within the spinal cord over an area about 2 to 3 mm in diameter. Such extensive dendritic structures are characteristic of central neurons, whose firing is regulated by input from many neurons. Short specialized dendritic extensions called spines serve to increase the area of the neuron available for synaptic inputs. Dendritic spines provide a biochemical and electrical compartment where incoming signals are initially received and processed; their morphology is discussed later in this chapter.

Figure 4-13 The axon of a spinal motor neuron has branches that make synaptic contact with several interneurons and, rarely, a recurrent (feedback) connection on the motor neuron. A. An electron micrograph of a cat's spinal motor neuron shows the cell body, axon hillock (AH), initial segment (IS), and the first part of the myelinated portion of the axon. Glial cells surround the initial part of the axon. A cross-section of a capillary (C) is also visible. The inset shows two dendrites emerging from opposite sides of the cell body. (From Conradi 1969.) B. The axons of motor neurons typically give off from one to five recurrent branches that usually make synaptic contact with inhibitory interneurons. In rare instances an axonal branch (a recurrent collateral) makes direct contact with its own cell body. (Courtesy of R. E. Burke.)

Messenger RNAis transported along dendrites and appears to be concentrated at the base of dendritic spines. Some protein synthesis occurs in dendrites, indicating that the dendrites are functional extensions of the P.78 cell body, where most proteins are synthesized. Consistent with this view, the cytoskeleton of dendrites more closely resembles that of the cell body than that of axons. Local protein synthesis at dendrites is thought to play an important role in synaptic plasticity.

Figure 4-14 Pyramidal cells in the CA1 and CA3 regions of the hippocampus. A. A composite illustration of the rat hippocampus and dentate gyrus. A major experimental advantage of the hippocampus for neuroscience research is its highly laminar organization. A Nisslstained section shows dark bands representing accumulations of neuronal cellbodies in the pyramidal cell layer (stratum pyramidale) of the hippocampus. The hippocampus can be divided into three separate regions—CA1, CA2, CA3—based on the size and connections of the resident pyramidal cells. Typical CA3 and CA1 pyramidal cells are drawn on the Nissl-stained section. Each cell has been traced with an intracellular marker (horseradish peroxidase or Phaseolus vulgaris leukoagglutinin) through adjacent 400 µm slices and reconstructed by computer. The CA3 cell dendrites are shown as thin lines and the axon collaterals as thicker lines. The CA3 axon collaterals innervate other CA3 cells (the associational axon collaterals) and the CA1 pyramidal cells (the Schaffer collaterals). These axons run in the stratum radiatum. Only the dendrites of the CA1 pyramidal cell are illustrated. (Courtesy of D. G. Amaral.) B. Schematic diagram of the hippocampus showing the connection between the two pyramidal neurons through the Schaffer axon collaterals.

Each motor neuron gives rise to only one axon, about 20 µ m in diameter, from a specialized region of the cell body called the axon hillock. The axon hillock and the initial (unmyelinated) segment of the axon extend the length of about one cell-body diameter (Figure 4-13). About half the surface area of the axon hillock and cell body and three-quarters of the dendritic membrane are covered by synaptic boutons, the knob-like terminals of the axons of presynaptic neurons (see Figure 4-8B). The axon hillock and the initial segment of the axon function as a trigger zone, the site at which the many incoming signals from other neurons are integrated and the action potential, the output signal of the neuron, is generated (see Chapter 9). Close to the cell body the axon gives off several recurrent collateral branches (Figure 4-13). These branches are called recurrent because many of them project back to the motor neuron and modify the activity of the cell. More often, however, recurrent collaterals form synapses on a particular type of interneuron in the spinal cord, the Renshaw cell. These interneurons hyperpolarize the motor neurons, using the neurotransmitter L-glycine, and thus inhibit firing in the motor neurons. In addition, motor neurons receive recurrent excitatory inputs from other motor neurons, and both excitatory and inhibitory inputs from interneurons driven by descending fibers from the brain that control and coordinate movement. These synaptic inputs, together with the excitatory input from the primary sensory neurons and inhibitory input from Renshaw cells, are integrated by mechanisms that are described in Chapter 12.

A Single Motor Neuron Forms Synapses With Several Muscle Cells One striking difference between motor and sensory neurons is the location of their synaptic inputs. The sensory neuron has few if any boutons on its cell body or P.79 along the peripheral branch of its axon. Its primary input is from sensory receptors at the terminal of the peripheral axon. In contrast, the motor neuron receives primary and modifying inputs throughout its dendrites and cell body. (Almost all presynaptic boutons on motor neurons are located on the dendritic branches; only 5% are located on the cell body.) The synapses on the motor neuron are distributed in a functional pattern. Most inhibitory synapses are on the cell body or close to it, whereas excitatory ones are located farther out along the dendrites. Inhibitory inputs are strategically placed close to the trigger zone to have maximal influence on the final tally of inputs to the neuron (see Chapter 12).

Figure 4-15 Pyramidal cells in the CA3 region of the hippocampus form synapses on the dendrites of CA1 cells in the stratum radiatum. Left: Micrograph of a Golgi-stained CA1 pyramidal cell is shown with dendrites extending downward 350 µm into the stratum radiatum. Right: Three micrographs show synapses formed on this CA1 cell by CA3 cells. A. Axons of two CA3 neurons form synapses on a dendrite 50 µm from the CA1 neuron's cell body. B. A single CA3 axon forms synapses on dendrites 259 µm from the cell body. C. A single CA3 axon forms synapses on two dendrites 263 µm from the cell body. (From Sorra and Harris 1993.)

The information flow from sensory neurons to motor neurons is both divergent and convergent. Each sensory neuron contacts 500–1000 motor neurons and typically forms two to six synapses on a single motor neuron (divergence of information). At the same time each motor neuron receives input from many sensory neurons (convergence of information); inputs from more than 100 sensory neurons are needed for a motor neuron to reach the threshold for firing. The axons that mediate the stretch reflex in the leg leave the lumbosacral region of the spinal cord and join the femoral nerve. (The motor axons and sensory fibers travel along the same peripheral path to the muscle.) P.80 P.81 When the motor neuron enters the muscle it ramifies into many unmyelinated branches, each with a diameter of only a few micrometers. These terminal fibers run along the surface of a muscle fiber and form many synaptic contacts called neuromuscular junctions. These synapses are the most completely characterized and best understood of all synapses in the nervous system (see Chapter 11).

Figure 4-16 The dendrites of pyramidal cells in the CA1 region of the hippocampus bear a variety of spines. Left: The diversity of dendritic spine shapes is evident along even a short segment of the mature dendrite in this three-dimensional reconstruction from a series of electron micro-graphs. (From Harris and Stevens 1989.) Right: Three micrographs illustrate the details of different types of dendritic spines. A. A thin dendritic spine from the postnatal day-15 rat hippocampus. The postsynaptic density shows as the thickened receptive surface (open arrow) located across from the presynaptic axon, which has round clear vesicles. B. Stubby spines containing postsynaptic densities (open arrow) are both small and rare in the mature hippocampus. Their larger counterparts (not shown) predominate in the immature brain. C. Mushroom-shaped spines have a larger head. These spines are present by day 15 as shown here. The immature spines contain flat cisternae of smooth endoplasmic reticulum, some with a beaded appearance (bd). Synapse with postsynaptic density is indicated by the open arrow. Branched spines did not occur in this dendritic segment. (From Harris et al. 1992.)

Figure 4-17 The axons of both central and peripheral neurons are insulated by a myelin sheath. A. An axon in the central nervous system receives its myelin sheath from an oligodendrocyte. (Adapted from Bunge 1968.) B. An electron micrograph of a transverse section through an axon (Ax) in the sciatic nerve of a mouse. The spiraling lamellae of the myelin sheath (Ml) start at a structure called the inner mesaxon (IM; circled). The spiraling sheath is still developing and is seen arising from the surface membrane (SM) of the Schwann cell, which is continuous with the outer mesaxon (OM; circled). The Schwann cell cytoplasm (Sc Cyt) is still present, next to the axon; eventually it is squeezed out and the sheath becomes compact. (From Dyck et al. 1984.) C. A peripheral nerve fiber is myelinated by a Schwann cell. (Adapted from Williams et al. 1989.)

Each muscle fiber is contacted by only a single axon, but a single motor axon innervates several muscle fibers. The axon and the muscle fibers it innervates constitute a motor unit. The muscle fibers innervated by any one motor axon are widely spread, overlapping muscle fibers of other motor units. The number of muscle fibers innervated by a single motor axon varies throughout the body, depending on the mass of the body part to be moved. Thus, in the leg a single motor axon innervates more than 1000 muscle fibers, while in the eye an axon contacts fewer than 100 muscle fibers. A lower innervation ratio permits greater precision of movement control. The sensory and motor neurons that mediate the stretch reflex differ in appearance, location in the nervous system, the distribution of their axons and dendrites, and the inputs they receive. All of these cytological P.82 P.83 P.84 P.85 features have important behavioral consequences. In addition, the two types of cells differ biochemically because they use different neurotransmitters (although both transmitters are excitatory). For example, the motor neuron, which uses acetylcholine as a transmitter, requires a set of macromolecules that includes the biosynthetic enzyme choline acetyltransferase and a specific membrane transporter for choline, an essential precursor in the synthesis of acetylcholine (Chapter 15).

Box 4-1 Defects in Myelin Proteins Disrupt Conduction of Nerve Signals Because normal conduction of the nerve impulse depends on the insulating properties of the myelin sheath surrounding the axon, defective myelin can result in severe disturbances of motor and sensory function. Myelin in both the central and peripheral nervous systems contains a major class of proteins, myelin basic proteins (MBP), which have an important role in myelin compaction. At least seven related proteins are produced from a single MBPgene by alternative RNA splicing. Myelin basic proteins are capable of eliciting a strong immune response. When injected into animals they cause experimental allergic encephalomyelitis, a syndrome characterized by local inflammation and by destruction of the myelin sheaths (demyelination) in the central nervous system. This experimental disease has been used as a model for multiple sclerosis, a common demyelinating disease in humans. Because demyelination slows down conduction of the action potential in the affected neurons' processes, multiple sclerosis and other demyelinating diseases (for example, Guillain-Barré syndrome) can have devastating effects on the function of neuronal circuits in the brain and spinal cord (see Chapter 35).

Many diseases that affect myelin, including some animal models of demyelinating disease, have a genetic basis. The shiverer (or shi) mutant mice have tremors and frequent convulsions and tend to die at young ages. In these mice the myelination of axons in the central nervous system is greatly deficient and the myelination that does occur is abnormal. The mutation that causes this disease is a deletion of five of the six exons of the gene for myelin basic protein, which in the mouse is located on chromosome 18. The mutation is recessive; a mouse will develop the disease only if it has inherited the defective gene from both parents. Shiverer mice that inherit both defective genes have only about 10% of the myelin basic protein found in normal mice. When the wild-type gene is injected into fertilized eggs of the shiverer mutant with the aim of rescuing the mutant, the resulting transgenic mice express the wild-type gene but produce only 20% of the normal amounts of myelin basic proteins. Nevertheless, myelination of central neurons in the transgenic mice is much improved. Although they still have occasional tremors, the transgenic mice do not have convulsions and live a normal life span (Figure 4-18). Central and peripheral myelin also contain a distinct protein termed myelin-associated glycoprotein (MAG). MAG belongs to a superfamily that is related to the immunoglobulins and includes several important cell surface proteins thought to be involved in cell-to-cell recognition (for example, the major histocompatibility complex of antigens, T-cell surface antigens, and the neural cell adhesion molecule or NCAM). MAG is expressed by Schwann cells early during peripheral myeli-nation and eventually becomes a component of mature (compact) myelin. It is situated primarily at the margin of the mature myelin sheath just adjacent to the axon. Its early expression, subcellular location, and structural similarity to other surface recognition proteins suggest that it is an adhesion molecule important for the initiation of the myelination process. Two isoforms of MAG are produced from a single gene through alternative RNA splicing.

Figure 4-18 A genetic disorder of myelination in mice (shiverer mutant) can be partially cured by transfection of the normal gene that encodes myelin basic protein. A. Electron micrographs show the state of myelination in the optic nerve of a normal mouse, a shiverer mutant, and a mutant transfected with the gene for myelin basic protein. (From Readhead et al. 1987.) B. Myelination is incomplete in the shiverer mutant. As a result, the shiverer mutant exhibits poor posture and weakness. Injection of the wild-type gene into the fertilized egg of the mutant improves myelination. A normal mouse and a transfected shiverer mutant look perky.

More than half of the total protein in central myelin is a characteristic proteolipid, PLP, which has five membrane-spanning domains. Proteolipids differ from lipoproteins in that they are insoluble in water. Proteolipids are soluble only in organic solvents because they contain long chains of fatty acids that are covalently linked to amino acid residues throughout the proteolipid molecule. In contrast, lipoproteins are noncovalent complexes of proteins with lipids so structured that many serve as soluble carriers of the lipid moiety in the blood.

Many mutations of the proteolipid PLPare known, in humans as well as in other mammals (for example, the jimpy mouse). Pelizaeus-Merzbacher disease, a heterogeneous X-linked disease in humans, results from a PLP mutation. Almost all of these mutations occur in a membrane-spanning domain of the molecule. All of these mutant animals have reduced amounts of the mutated protein and show hy-pomyelination and degeneration and death of oligodendrocytes. These observations suggest that the proteolipid is involved in the compaction of myelin. The major protein in mature peripheral myelin, myelin protein zero (MPZ or P0), spans the plasmalemma of the Schwann cell. It has a basic intracellular domain and, like myelin-associated glycoprotein, is a member of the immunoglobulin superfamily. The glycosylated extracellular part of the protein, which contains the immunoglobulin domain, functions as a homophilic adhesion protein during myelin spiraling and compaction by interacting with identical domainsonthesurfaceoftheopposedmembrane.Genetically engineered P0 mice in which the function of myelin protein P0 has been eliminated have poor motor coordination, tremors, and occasional convulsions. Observation of trembler mouse mutants led to the identification of peripheral myelin protein 22 (PMP22). This Schwann cell protein spans the membrane four times and is normally present in compact myelin. PMP22 is altered by a single amino acid. Asimilar protein is found in humans, encoded by a gene on chromosome 17. Although several hereditary peripheral neuropathies result from mutations of the PMP22 gene on chromosome 17, one form of Charcot-Marie-Tooth disease is caused by the DNA duplication of this gene (Figure 4-19). Charcot-Marie-Tooth disease, the most common inherited peripheral neuropathy, is characterized by progressive muscle weakness, greatly decreased conduction in peripheral nerves, and cycles of demyelination and remyelination. Since both duplicated genes are active, the disease results from increased production of PMP22 (a two- to three-fold increase in gene dosage) rather than from a reduction in a mutant protein.

Figure 4-19 Charcot-Marie-Tooth disease (type 1A) results from gene dosage effects. A. A patient with Charcot-Marie-Tooth shows impaired gait and deformities (from Charcot's original description of the disease, 1886). B. Sural nerve biopsies from a normal individual (from AP Hays, Columbia University) and from a patient with Charcot-Marie-Tooth (from Lupski and Garcia 1993). C. The disordered myelination in Charcot-Marie-Tooth disease results from the increased production of the peripheral myelin protein PMP22. The increase is caused by a duplication of a normal 1.5 megabase region of the DNA on the short arm of chromosome 17 at 17p11.2-p12. The PMP22 gene is flanked by two similar repeat sequences, as shown in the representation of a normal chromosome 17. Normal individuals have two normal chromosomes. In patients with the disease the duplication results in two functiong PMP22 genes, each flanked by the repeat sequence. The normal and duplicated regions are shown in the expanded diagrams indicated by the dashed lines. (The repeats are thought to have given rise to the original duplication, which was then inherited. The presence of two similar flanking sequences with homology to a transposable element is believed to increase the frequency of unequal crossing-over in this region of chromosome 17 because the repeats enhance the probability of mispairing of the two parental chromosomes in a fertilized egg.) D-E. Although a large duplication, 3 megabases cannot be detected in routine examination of chromosomes in the light microscope, but microscopic evidence for the duplication can be obtained using fluorescence in situ hybridization. With this technique, the PMP22 gene is detected with an oligonucleotide probe tagged with the dye Texas Red. An oligonucleotiede probe tagged with fluoroscein, a green fluorescent dye that hybridizes with DNA from region 11.2 (indicated in green closer to the centromere), is used for in situ hybridization on the same sample. A nucleus from a normal individual (D)

shows a pair of chromosomes, each with one red site (PMP22 gene) for each green site. In a nucleus from a patient with the disease (E) there is one extra red site, indicating that one chromosome has one PMP22 gene and the other has two PMP22 genes.

Pyramidal Neurons in the Cerebral Cortex Have More Extensive Dendritic Trees Than Spinal Motor Neurons Whereas motor neurons are the major excitatory projection neurons of the spinal cord, pyramidal cells are the excitatory projection neurons in the cerebral cortex. Pyramidal cells in different cortical regions are morphologically similar and use L-glutamate as a transmitter. We shall focus here on the pyramidal cells of the hippocampus, a structure important for memory storage. The hippocampus is divided into two major regions, CA3 and CA1. In both regions the cell bodies of pyramidal cells are situated in a single continuous layer, the stratum pyramidale (Figure 4-14). In contrast to the motor neurons of the spinal cord, pyramidal cells have not one but two dendritic trees, and these emerge from opposite sides of the cell body: the basal dendrites arise from the side that gives rise to the axon, and the apical dendrites arise from the opposite side of the cell body. Excitatory input to CA1 pyramidal neurons is extensive. About 5000 CA3 pyramidal cell axons—comprising the Schaffer collateral pathway—converge on a single CA1 cell. These Schaffer collaterals form synapses at all levels of the CA1 cell's dendritic tree close to the cell body and at more distant levels (Figure 4-15). The connections formed by the Schaffer collaterals are called en passant synapses because CA3 axons continue to pass through the stratum radiatum, making contact with the dendrites of many other CA1 pyramidal cells. Most of the synapses are made on dendritic spines. In many parts of the brain, spines have two inputs, one excitatory and the other inhibitory. In area CA1, however, each pyramidal cell spine has only one synapse, which is excitatory. These spines have four principal shapes: thin, mushroom, branched, and stubby (Figure 4-16). The neck of the spine restricts diffusion between the head of the spine and the rest of the dendrite. Thus, each spine may function as a separate biochemical region. As we shall see later, this compartmentalization may be important for selectively altering the strength of synaptic connections during learning and memory.

Glial Cells Produce the Insulating Myelin Sheath Around Signal-Conducting Axons The signal-conducting axons of both sensory and motor neurons are ensheathed in myelin along most of their length (see Figure 4-11). Acting as insulation, myelin speeds transmission along axons and thus is critical for quick reflex movements like the knee jerk. The myelin sheath is arranged in concentric bimolecular layers of lipids interspersed between protein layers (Figure 4-17). Biochemical analysis shows that myelin has a composition similar to that of plasma membranes, consisting of 70% lipid and 30% protein, with a high concentration of cholesterol and phospholipid. Both the regular lamellar structure and biochemical composition of the myelin sheath are consequences of how myelin is formed from plasma membrane. In the development of the peripheral nervous system, before myelination takes place, the sensory cell axon lies along a peripheral nerve in a trough formed by a class of glia called Schwann cells. Schwann cells line up along the axon at intervals that will eventually become the nodes of Ranvier. The external cell membrane of each Schwann cell surrounds a single axon and forms a double-membrane structure called the mesaxon, which elongates and spirals around the axon in concentric layers (Figure 4-17C). The cytoplasm of the Schwann cell appears to be squeezed out during the ensheathing process when the Schwann cell's processes condense into the compact lamellae of the mature myelin sheath. In the femoral nerve, which carries the sensory and motor axons that mediate the stretch reflex, the primary sensory axon is about 0.5 m long and the internodal distance is 1-1.5 mm; thus approximately 300-500 nodes of Ranvier occur along a primary afferent fiber between the thigh muscle and the dorsal root ganglion, where the cell body lies. Since each internodal segment is formed by a single Schwann cell, as many as 500 Schwann cells participate in the myelination of a single peripheral sensory axon. In the central nervous system myelination of the central branch of dorsal root ganglion cell axons and the axons of motor neurons differs somewhat from myelination in the peripheral system. The glial cell responsible for elaborating central myelin is the oligodendrocyte, which typically ensheathes several axon processes. Schwann cells and oligodendrocytes differ developmentally and biochemically. The expression of myelin genes by Schwann cells in the peripheral nervous system is regulated by the contact between the axon and the myelinating Schwann cell. In contrast, the expression of myelin genes by oligodendrocytes in the central nervous system appears to depend on the presence of P.86 astrocytes, the other major type of glial cell in the central nervous system. Specific diseases can arise from dysfunction of the specialized properties of neurons. In particular, defective myelination of the axon produces severe disturbances of motor and sensory function. Thus, understanding the biochemistry of myelin formation provides important insight into the basis of certain neurological diseases (Box 4-1).

An Overall View Nerve cells have four distinctive compartments: dendrites, for receiving signals from other neurons; the cell body, which contains the DNA encoding neuronal proteins and the complex apparatus for synthesizing them; the axon, which projects over long distances to target cells (for example, other neurons or muscle); and nerve terminals, for release of neurotransmitters at synapses with targets. In this chapter we have illustrated this basic cellular plan by describing three types of neurons. Although all of these cells conform to a basic plan, each type differs considerably, most obviously by location in the nervous system—peripheral or central, spinal cord, or brain. They also differ in the location of synaptic inputs on the cell and in the types of target cells to which they project. Furthermore, they differ in cell body size and shape, distribution of their dendritic trees and number of axon branches, and in their degree of myelination. Biochemically, they differ most obviously in transmitter type, and, as we shall see throughout this book, in many other constituents (for example, in the enzymes that synthesize neurotransmitters, the pumps that exchange ions or recapture neurotransmitter substances, and the receptors that transduce physical or biochemical inputs). The functional significance of many morphological differences is plainly evident. For example, the dorsal root sensory neuron must extend a process in the peripheral nervous system, as must the spinal motor neuron. It also is clear why the motor neuron has a more complex dendritic tree than the sensory neuron: Even simple reflex activity requires coordination of inputs, both excitatory and inhibitory, to regulate specific motor units, and purposeful movements need still more integration because of inputs from the brain. The functional significance of some other cytological differences is not so obvious, but can be understood in the context of the electrophysiological activities of the particular neurons. Thus the large number of dendrites and axonal branches in cortical pyramidal neurons must contribute to the complexity of information processing in the brain.

Selected Readings

Baldissera F, Hultborn H, Illert M. 1981. Integration in spinal neuronal systems. In: VB Brooks (ed). Handbook of Physiology: A Critical, Comprehensive Presentation of Physiological Knowledge and Concepts. Sect. 1, The Nervous System. Vol. 2, Motor Control, pp. 509-595. Bethesda, MD: American Physiological Society.

Burke RE. 1990. Spinal cord: ventral horn. In: GM Shepherd (ed). The Synaptic Organization of the Brain, 3rd ed., pp. 88-132. New York: Oxford University Press.

Dyck PJ, Thomas PK, Griffin JW, Low PA, Poduslo JF (eds). 1993. Peripheral Neuropathy, 3rd ed. Philadelphia: Saunders.

Lemke G. 1992. Myelin and myelination. In: Z Hall (ed). An Introduction to Molecular Neurobiology, pp. 281-312. Sunderland, MA: Sinauer.

Peters A, Palay SL, Webster H deF. 1991. The Fine Structure of the Nervous System: Neurons and Their Supporting Cells, 3rd ed. New York: Oxford Univ. Press.

Rothwell J. 1994. Control of Human Voluntary Movement, 2nd ed. London: Chapman & Hall.

Siegel GJ, Agranoff BW, Albers RW, Molinoff PB (eds). 1999. Basic Neurochemistry: Molecular, Cellular, and Medical Aspects, 6th ed. Philadelphia: Lippincott-Raven.

References Amaral DG, Ishizuka N, Claiborne B. 1990. Neurons, numbers and the hippocampal network. Prog Brain Res 83:1–11.

Amaral DG. 1993. Emerging principles of intrinsic hippocampal organization. Curr Opin Neurobiol 3:225–229.

Bershadsky AD, Vasiliev JM. 1988. Cytoskeleton. New York: Plenum.

Boyd IA, Smith RS. 1984. The muscle spindle. In: PJ Dyck, PK Thomas, EH Lambert, R Bunge (eds). Peripheral Neuropathy, 2nd ed., 1:171-202. Philadelphia: Saunders. P.87

Brown AG, Fyffe RE. 1981. Direct observations on the contacts made between Ia afferent fibres and -motoneu rones in the cat's lumbosacral spinal cord. J Physiol (Lond) 313:121–140.

Brown AG, Fyffe REW. 1984. Intracellular Staining of Mammalian Neurones. London: Academic.

Bunge RP. 1968. Glial cells and the central myelin sheath. Physiol Rev 48:197–251.

Burke RE. 1981. Motor units: anatomy, physiology, and functional organization. In: VB Brooks (ed). Handbook of Physiology: ACritical, Comprehensive Presentation of Physiological Knowledge and Concepts. Sect. 1, The Nervous System. Vol. 2, Motor Control, pp. 345-422. Bethesda, MD: American Physiological Society.

Burke RE, Dum RP, Fleshman JW, Glenn LL, Lev-Tov A, O'Donovan MJ, Pinter MJ. 1982. An HRP study of the relation between cell size and motor unit type in cat ankle extensor motoneurons. J Comp Neurol 209:17–28.

Cameron PL, Sudhof TC, Jahn R, De Camilli P. 1991. Colocalization of synaptophysin with transferrin receptors: implications for synaptic vesicle biogenesis. J Cell Biol 115:151–164.

Charcot J-M, Marie P. 1886. Sur une forme particulière d'atrophie musculaire progressive, souvent familiale, débutant par les pieds et les jambes et atteignant plus tard les mains. Rev Med 6:97–138.

Conradi S. 1969. Ultrastructure and distribution of neuronal and glial elements on the motoneuron surface in the lumbosacral spinal cord of the adult cat. Acta Physiol Scand 332:5-48 (Suppl.).

De Camilli P, Moretti M, Donini SD, Walter U, Lohmann SM. 1986. Heterogeneous distribution of the cAMP receptor protein RII in the nervous system: evidence for its intracellular accumulation on microtubules, microtubule-organizing centers, and in the area of the Golgi complex. J Cell Biol 103:189–203.

Dogiel AS. 1908. Der Bau der Spinalganglien des Menschen und der Säugetiere. Jena: Fischer.

Dyck PJ, Thomas PK, Lambert EH, Bunge R (eds). 1984. Peripheral Neuropathy, 2nd ed. Vols. 1, 2. Philadelphia: Saunders.

Gulyas AI, Miles R, Hájos N, Freund TF. 1993. Precision and variability in postsynaptic target selection of inhibitory cells in the hippocampal CA3 region. Eur J Neurosci 5:1729–1751.

Harris KM, Stevens JK. 1989. Dendritic spines of CA1 pyramidal cells in the rat hippocampus: serial electron microscopy with reference to their biophysical characteristics. J Neurosci 9:2982–2997.

Harris KM, Jensen FE, Tsao B. 1992. Three-dimensional structure of dendritic spines and synapses in rat hippocampus (CA1) at postnatal day 15 and adult ages: implications for the maturation of synaptic physiology and long-term potentiation. J Neurosci 12:2685–2705.

Ishizuka N, Weber J, Amaral DG. 1990. Organization of intrahippocampal projections originating from CA3 pyramidal cells in the rat. J Comp Neurol 295:580-623. Lemke G. 1988. Unwrapping the genes of myelin. Neuron 1:535–543.

Lemke G. 1993. The molecular genetics of myelination: an update. Glia 7:263–271.

Lorente de Nó R. 1934. Studies on the structure of the cerebral cortex. II. Continuation of the study of the ammonic system. J Psychol Neurol 46:113–177.

Lupski JR, Garcia CA. 1992. Molecular genetics and neuropathology of Charcot-Marie-Tooth disease type 1A. Brain Pathol 2:337–349.

Lupski JR, de Oca-Luna RM, Slaugenhaupt S, Pentao L, Guzzetta V, Trask BJ, Saucedo-Cardenas O, Barker DF, Killian JM, Garcia CA, Chakravarti A, Patel PI. 1991. DNA duplication associated with Charcot-Marie-Tooth disease type 1A. Cell 66:219–232.

Ramón y Cajal S. [1901] 1988. Studies on the human cerebral cortex. IV. Structure of the olfactory cerebral cortex of man and mammals. In: J DeFelipe, EG Jones (eds, transl). Cajál on the Cerebral Cortex, pp. 289-362. New York: Oxford Univ. Press.

Ramón y Cajal S. [1909] 1995. Histology of the Nervous System of Man and Vertebrates. N Swanson, LW Swanson (transl). Vols. 1, 2. New York: Oxford Univ. Press.

Readhead C, Popko B, Takahashi N, Shine HD, Saavedra RA, Sidman RL, Hood L. 1987. Expression of a myelin basic protein gene in transgenic Shiverer mice: correction of the dysmyelinating phenotype. Cell 48:703–712.

Roa BB, Lupski JR. 1994. Molecular genetics of Charcot-Marie-Tooth neuropathy. Adv Human Genet 22:117-152. Sorra KE, Harris KM. 1993. Occurrence and three-dimensional structure of multiple synapses between individual radiatum axons and their target pyramidal cells in hippocampal area CA1. J Neurosci 13:3736–3748.

Ulfhake B, Kellerth J-O. 1981. A quantitative light microscopic study of the dendrites of cat spinal α-motoneurons after intracellular staining with horseradish peroxidase. J Comp Neurol 202:571–583.

Williams PL, Warwick R, Dyson M, Bannister LH (eds). 1989. Gray's Anatomy, 37th ed, pp. 859-919. Edinburgh: Churchill Livingstone.

Back

5 Synthesis and Trafficking of Neuronal Protein James H. Schwartz Pietro De Camilli The cell body is an important site of synaptic input in most neurons. As discussed in the preceding chapter, the cell body is close to the trigger zone, and inhibitory input is especially effective there. But in some neurons, such as the sensory neurons of the dorsal root ganglion, the cell body does not receive synaptic input. What then is the function of the cell body beyond its role as a postsynaptic site? An answer to this question was suggested by Augustus Waller in the mid-nineteenth century. Waller cut the various roots and nerves of the spinal cord and observed which fibers degenerated as a result. From the patterns of degeneration Waller concluded that the cell body of a dorsal root ganglion cell maintains the vitality of its axons. In a lecture delivered to the Royal Institution of Great Britain in 1861, he said, “A nerve-cell would be to its effluent nerve fibers what a fountain is to the rivulet which trickles from it—a centre of nutritive energy.” For the most part, this nourishment is provided in the form of proteins Almost all of the macromolecules of a neuron are synthesized in the cell body from mRNAs originating in the nucleus. Because the cell body is only one of the four critical regions of the neuron, and because the axons and terminals often lie at great distances from the cell body, transport mechanisms are crucial for the functioning of neurons. In this chapter we shall examine the synthesis of neuronal proteins and the mechanisms for distributing them to their proper destinations throughout the membranous organelles and functional compartments of the neuron.

Most Proteins Are Synthesized in the Cell Body The cell body and the proximal portion of dendrites are the sites at which most macromolecules are assembled. Information for the synthesis of proteins is encoded in the DNA within the cell's nucleus. As we saw in Chapter 3, all nuclei contain the same genetic information and this information is passed from parent cell to daughter cell during cell division. Only a selected portion of this genetic information, however, is transcribed in a given cell to generate mRNAs and eventually proteins. Which proteins are expressed is determined by regulatory DNA-binding proteins (transcription factors) P.89 synthesized in the cytosol and taken up into the nucleus through the nuclear pores (Figure 5-1).

Figure 5-1 Some of the components of a spinal motor neuron that participate in the synthesis of macromolecules are shown in this electron micrograph. The nucleus (N), containing masses of chromatin (Ch), is bounded by a double-layered membrane, the nuclear envelope, which contains many nuclear pores (arrows). The mRNA leaves the nucleus through these pores and attaches to ribosomes that either remain free in the cytoplasm or attach to the membranes of the endoplasmic reticulum to form the rough endoplasmic reticulum (RER). Regulating proteins synthesized in the cytoplasm are imported into the nucleus through the pores. Several parts of the Golgi apparatus (G) are seen. Also present in the cytoplasm are lysosomes (Ly) and mitochondria (Mit). (From Peters et al. 1991.)

The brain expresses more of the total genetic information encoded in DNA than does any other organ in the body. About 200,000 distinct mRNA sequences are thought to be expressed, 10-20 times more than in the kidney or liver. In part, this diversity results from the greater number and variety of cell types in the brain as compared to cells in the more homogenous body tissues. But many neurobiologists also believe that each of the brain's 1011 nerve cells actually expresses a greater amount of its genetic information than does a liver or kidney cell. Because cell division has stopped, in mature neurons the chromosomes no longer duplicate themselves and function only in gene expression. Because a large number of genes are being transcribed at any given time, the chromosomes are not arranged in compact structures but exist in a relatively uncoiled state. Thus, the contents of the nucleus, when viewed in the electron microscope, have an amorphous appearance. Ribosomal RNA is transcribed in prominent nucleoli, a characteristic of all cells with a high rate of protein synthesis. Precursor RNA is transcribed and spliced within the nucleus to generate mature mRNA. Newly synthesized ribosomes and mRNA are exported from the nucleus through the nuclear pores. Although most of the genetic information for the synthesis of proteins is encoded in the cell's nucleus, a small amount is contained in circular DNA within mitochondria. The human mitochondrial genome encodes information for mitochondrial transfer RNAs (tRNAs) and ribosomal RNAs (rRNAs), which differ from those in the rest of the cell, and for a few of the mitochondrion's proteins. The rest of the mitochondrion's proteins are encoded by genes in the nuclear chromosomes, synthesized on cytoplasmic ribosomes, and then imported into the mitochondrion.

Figure 5-2 Ribosomes are present in the cell body and throughout the dendritic arbor but are absent in the axon. A. This autoradiograph illustrates the distribution of ribosomal RNA (rRNA) in hippocampal neurons in low-density cultures as revealed by in situ hybridization. The photomicrograph is taken with dark field illumination, in which silver grains reflect light and thus appear as bright spots. Silver grains are heavily concentrated over cell bodies and dendrites, but there is no detectable labeling over the axons that criss-cross among the dendrites. B. Polyribosomes in dendrites are selectively located beneath postsynaptic sites. In spine-bearing neurons clusters of polyribosomes are generally found just at the junction of the spine and the main dendritic shaft (arrow). This electron micrograph shows a mushroom-shaped spine synapse in the hippocampal dentate gyrus. (S = spine head; T = presynaptic terminal; Den = main shaft of the dendrite containing a long mitchondrion.) Note the absence of polyribosomes in other parts of the dendritic shaft. × 60,000. (Courtesy of O. Steward, University of Virginia.)

P.90 Synthesis of proteins occurs exclusively in the cell body and in dendrites. Proteins for the axon are translated primarily in the cell body and proximal dendrites. Some translation of proteins does occur in dendrites, however, and is made possible by active transport of ribosomes and mRNA into dendrites, especially into dentritic spines (Figure 5-2). The synthesis of all proteins starts in the cytosol, where mRNA molecules become associated with free ribosomes that are generally linked into small clusters called polysomes by the mRNA (see Figures 5-3, 5-4, and 5-5). The final destination of the protein is encoded in its amino acid sequence. A major portion of newly synthesized proteins remain within the cytosol. Cytosolic proteins include the two most abundant groups of proteins in a neuron: the fibrillar elements that make up the cytoskeleton (Chapter 4) and numerous enzymes that catalyze the metabolic reactions of the cell. Translation of mRNA into protein starts from the 5′ end of the mRNA, which encodes the N-terminal end of the protein, and progresses codon by codon until the molecule is finished. Amino acid sequences at the N terminus, or those within the protein molecule, may have special functions. Thus, certain sequences act as signals and, depending on the particular sequence, ticket the proteins for import into mitochondria or peroxisomes. A special sequence within the molecule, the nuclear localization signal, targets the protein for passage into nucleoplasm through the nuclear pores. Other sequences make a protein suitable for post-translational chemical modifications, which, for example, can direct the modified protein to the membrane. Examples of this kind of modification are palmitoylation and isoprenylation, which anchor the protein to the inner leaflet of the plasmalemma. Ubiquitinylation, another post-translational modification, marks the protein for degradation. (These modifications are discussed below.) Polysomes with nascent polypeptide chains destined to become secretory proteins or proteins of the external cell membrane and vacuolar apparatus attach to the endoplasmic reticulum because of an N-terminal signal sequence. This association gives the endoplasmic reticulum a rough appearance in the electron microscope, P.91 hence the name rough endoplasmic reticulum.1 While still undergoing synthesis, these proteins are trans-located across the membrane of the endoplasmic reticulum. All other proteins are synthesized on free ribosomes.

Figure 5-3 The organelles in the cell body that are chiefly responsible for synthesis and processing of proteins are shown in these electron micrographs. Through the double-layered nuclear envelope that surrounds the nucleus (N), mRNA enters the cytoplasm, where it is translated into proteins. Free polysomes, strings of ribosomes attached to a single mRNA, generate cytosolic proteins and proteins to be imported into mitochondria (Mit) and peroxisomes. Proteins destined for the endoplasmic reticulum are formed after the polysomes attach to the membrane of the endoplasmic reticulum (ER). Both the motor neuron (left) and the dorsal root ganglion cell (right) have similar kinds of organelles. The particular region of the motor neuron shown here also includes membranes of the Golgi apparatus (G), in which membrane and secretory proteins are further processed. Some of the newly synthesized proteins leave the Golgi apparatus into vesicles that move by rapid axonal transport down the axon to synapses; other membrane proteins are incorporated into lysosomes (Ly) and other membranous organelles. The vacuolar apparatus includes the nuclear envelope, the endoplasmic reticulum, the Golgi complex, the lysosomal system, and a variety of transport vesicles. Components of the neuronal cytoskeleton are microtubules (M) and neurofilaments (Nf). (From Peters et al. 1991.)

The proper function of a protein is defined not only by its primary amino acid sequence, but also by its secondary and tertiary structure, ie, by correct folding of the polypeptide chain. Although information for a protein's tertiary structure is encoded in its amino acid sequence, proper folding may not occur spontaneously. For many proteins, folding is catalyzed by interactions with chaperones, proteins that bind to unstructured, exposed regions of the newly synthesized polypeptide. (Two common chaperones are the heat shock proteins, P.92 hsp70 and hsp60.) This binding prevents folding until appropriate regions of the protein become available to permit proper folding. Then, in an energy-dependent step, the chaperones are released from the polypeptide.

Figure 5-4 Protein synthesis on the ribosome. Translation begins at the 5′ end of the messenger RNA. Peptide bonds are formed between the nascent polypeptide chain and an aminoacyl tRNA. The tRNA aligns amino acid moieties (purple circles) on the ribosome, acting as an adapter to bind its codon in the mRNA. The nascent polypeptide chain, the last (aminoacyl) residue of which remains bound to the mRNA through its tRNA, extends down a groove in the ribosome. When a bond is formed, the tRNA of the last residue of the chain is displaced, and the mRNA is moved in the direction of its 5′ end (toward the right in the figure).

Proteins May Be Modified During or After Synthesis Proteins may undergo several modifications by cytosolic enzymes either during synthesis (cotranslational) or afterward (posttranslational). A common cotranslational modification is N-acylation, the transfer of an acyl group to the N terminus of the growing polypeptide chain. About 80% of a cell's proteins are acylated. Acylation by a myristoyl group, a 14-carbon saturated fatty acid, is a functionally important example because the modified protein can associate with membrane through the lipid chain:

Figure. No Caption Available.

In proteins that are N-myristoylated the initiator methionine is removed and the next residue becomes the N terminus of the growing chain. While the chain elongates, an acyl group is enzymatically transferred to the new N terminus. N-myristoylated proteins, in which a glycine must be the new N-terminal residue, include the small GTPase Arf; the α-subunit of some trimeric G proteins (the GTPases Gi and Go); the catalytic subunit of the cAMP-dependent protein kinase; and calcineurin, a major calcium-dependent protein phosphatase (see Chapter 13). Other fatty acids, notably palmitic acid (16-carbon, unsaturated), can also be conjugated to the sulfhydril group of cysteine residues within proteins:

Figure. No Caption Available.

Thioacylation also anchors proteins to the cytosolic leaflet of membranes. This modification occurs, for example, in the GABAsynthesizing enzyme GAD; in t-SNARE and SNAP25, proteins that facilitate the fusion of vesicles with the plasma membranes; in the growth-associated protein GAP-43, which is enriched in growing axons (growth cones) and which binds both calmodulin and actin; and in some α-subunits of trimeric G proteins. Acylation may also occur on cytosolic domains of intrinsic membrane proteins. Isoprenylation is another post-translational modification important for anchoring proteins to the cytosolic side of membranes. Isoprenylation happens shortly after synthesis is completed and involves a series of enzymatic steps that result in thioacylation by one of two long-chain hydrophobic polyisoprenyl moieties (farnesyl, with 15 carbons, or geranyl-geranyl, with 20) of the sulfhydril group of a cysteine at the C terminus of proteins. Farnesylation occurs on the GTPase Ras while geranyl-geranylation occurs on the Rab GTPases, which have an important role in vesicle transport reactions. These proteins cycle between membrane and cytosol. When soluble in the cytosol they are associated with other proteins that shield the geranyl-geranyl group in a hydrophobic pocket.

Figure 5-5 Free and membrane-bound polysomes translate mRNAs that encode proteins with a variety of destinations. Messenger RNAs, transcribed from genomic DNA in the neuron's nucleus, emerge through nuclear pores (enlargement) to form polysomes by attaching to ribosomes.

P.93 Some post-translational modifications are readily reversible and thus are used to regulate the function of a protein transiently. The most important of these modifications is phosphorylation of the hydroxyl group in Ser, Thr, or Tyr residues by protein kinases. Dephos-phorylation is catalyzed by protein phosphatases. (These reactions are discussed in Chapter 13.) As with all post-translational

modifications, the sites to be phosphorylated are determined by a particular sequence of amino acids around the residue that is being modified. Phosphorylation can change the properties of a protein (eg, its enzymatic activity or interaction properties) and is probably the most common mechanism for altering physiological processes in a reversible fashion. For example, protein phosphorylationdephosphorylation reactions regulate the kinetics of ion channels, the activity of transcription factors, the assembly of the cytoskeleton, and the activity of enzymes. Still another important post-translational modification is the addition of ubiquitin, a highly conserved protein with 76 amino acids, to the ε-amino group of Lys residues within the protein molecule:

Figure. No Caption Available.

Conjugation of ubiquitin requires the energy of ATP. Additional ubiquitin monomers are successively linked to the ε-amino group of a Lys residue within the previously added ubiquitin moiety. Addition of these multi-ubiquitin chains to a protein tags it for degradation by a proteasome, a large complex containing several different protease subunits. The ATP-ubiquitin-proteasome pathway, which is present in all regions of the neuron (dendrites, cell body, axon, and terminals), is a mechanism for the selective and regulated proteolysis of cytosolic proteins. Until recently proteolysis was thought to be primarily directed to poorly folded, denatured, or aged proteins. Recent evidence indicates, however, that ubiquitin-mediated proteolysis is important in many neuronal processes, including synaptogenesis and long-term memory storage.

Some Proteins Are Synthesized in the Cytosol and Actively Imported by the Nucleus, Mitochondria, and Peroxisomes Nuclear and peroxisomal proteins, as well as the mitochondrial proteins that are encoded by the cell's nucleus, P.94 are formed in the cytosol on free polysomes and are imported only after their synthesis is completed. Import into the nucleus takes place through the nuclear pores and does not involve transport through a membrane. Although the cytosol and nucleoplasm are theoretically continuous, the nuclear pores prevent free intermixing between the two compartments. Nuclear pores permit only molecules with a size smaller than 10 nm to pass. Most proteins involved in transcription of DNA (DNA polymerases) and in RNA processing (polymerases and splicing enzymes) have much higher molecular masses and thus cannot move passively through the pores. Nuclear uptake of these proteins depends on nuclear localization signals in the amino acid sequence of the proteins. For proteins that need to be returned to the cytosol, export signals are also required. Movement of proteins through nuclear pores requires the energy of ATP. Proteins that are synthesized in the cytosol and destined for mitochondria and peroxisomes need to cross a phospholipid bilayer. Thus, unlike nuclear proteins, which are imported after they have been folded, these polypeptides reach their native conformation only after import into the target organelle, which occurs soon after the protein is synthesized. The signal for mitochondrial import is an N-terminal amino acid sequence 20-80 residues in length that can form an amphipathic helix, ie, a helix with basic, positively charged (hydrophilic) residues on one face and nonpolar (hydrophobic) residues on the other. Import of the proteins occurs at special sites where the inner and outer mitochondrial membranes are in contact with each other, and proteins are therefore moved directly into the mitochondrial matrix. Movement of the polypeptide chain through the bilayer of the mitochondrial membranes requires special chaperones in both the cytosol and within the mitochondrion. Interactions with these chaperones result in the hydrolysis of ATP, and some of the energy released during those reactions is harvested for proper folding of the proteins within the mitochondrion.

Secretory Proteins and Proteins of the Vacuolar Apparatus and Plasmalemma Are Synthesized and Modified in the Endoplasmic Reticulum Most proteins destined to become membrane or lumenal proteins of the vacuolar apparatus, as well as secretory proteins and proteins of the plasmalemma, are translocated across the membrane of the endoplasmic reticulum during synthesis (cotranslational

transfer). As noted earlier, their mRNA is translated on polysomes attached to the surface of this organelle (see Figure 5-5). These polysomes are formed from the same population of ribosomes that produce the other proteins in the cell. A signal sequence in the nascent polypeptide induces the attachment of the ribosomes to the rough endoplasmic reticulum as soon as this portion of the nascent polypeptide chain starts protruding from the ribosomes. This attachment is mediated by a macromolecular complex called the signal recognition particle. In an energy-dependent process the growing peptide is transported through the lipid bilayer into the lumen of the endoplasmic reticulum, where the signal sequence usually is removed through proteolytic cleavage. The polypeptide continues to grow at its C-terminal end. If the protein does not contain hydrophobic sequences, cotranslational transfer continues until the C terminus itself is transferred across the membrane and the newly synthesized polypeptide becomes a free protein in the lumen (Figure 5-6A). With other proteins, cotranslational transfer through the membrane continues until a hydrophobic stop-transfer segment within the nascent polypeptide chain is reached. Stop-transfer sequences are about 20 residues in length and contain hydrophobic, or uncharged, amino acids followed by several basic residues; they may occur anywhere along the polypeptide. The result is an integral membrane protein with its C terminus on the cytoplasmic side and its N terminus on the lumenal side of the endoplasmic reticulum (Figure 5-6B). If there is an alternating series of insertion and stop-transfer sequences within a single chain, the result is an integral membrane protein with multiple membrane-spanning regions because the polypeptide traversed the membrane several times as it grew. Examples of this type of intrinsic membrane proteins are neurotransmitter receptors and ion channels (see Chapter 6). As with import into mitochondria, transfer of polypeptides into the endoplasmic reticulum requires the energy of ATP. Transfer is driven in part by the progressive addition of amino acids to the growing polypeptide. It is also assisted by chaperones in the lumen, such as BiP, a homolog of hsp70, which pulls the polypeptide into the lumen of the endoplasmic reticulum. Some of the proteins synthesized in the endoplasmic reticulum remain in this organelle as resident proteins. Others are targeted to other compartments of the vacuolar apparatus, to the plasmalemma, or to the extracellular space by secretion. Proteins within the lumen of the endoplasmic reticulum are extensively modified. One important modification is the formation of intramolecular disulfide (Cys-S-S-Cys) linkages, a process that cannot occur in the reducing environment of the cytosol. Disulfide linkages are crucial to the tertiary structure of these proteins

Figure 5-6 The configuration of proteins formed from polysomes attached to the endoplasmic reticulum is determined by the process of translocation through the reticulum's membrane. All of these proteins start with an N-terminal signal sequence with three functionally distinct portions. The first is a short hydrophilic segment that is important for the initiation of insertion but which plays little or no part in the association of the polysome to the signal receptor particle or its release from the docking protein on the membrane of the endoplasmic reticulum. This segment is not itself translocated through the membrane. The second segment is a stretch of 8-16 hydrophobic residues that is essential for translocation of the protein through the membrane. The mechanism of translocation is not yet well understood, but probably requires that some of this hydrophobic segment assume an α-helical structure and that part of it be extended because a stretch of eight hydrophobic residues is sufficient to span the 3 nm width of the membrane if fully extended but is too short in the helical configuration. The third segment, consisting of a few Cterminal amino acids of the signal sequence, usually begins with glycine or proline (residues that interrupt α-helices) and is known to be important in the removal of the signal sequence by the signal peptidase located on the luminal side of the endoplasmic reticulum. (Adapted from Alberts et al. 1994.) A. If the entire polypeptide chain is translocated through the membrane of the endoplasmic reticulum, a secretory protein results. Note that the N terminus is free because the signal sequence is cleaved, while the C terminus is free because the entire polypeptide chain is translocated. B. If translocation of the polypeptide chain through the membrane is incomplete, a membrane-spanning protein results. Incomplete translocation occurs because of the presence of a stop-transfer sequence. As in the example shown in A, the N-terminal signal sequence is cleaved while the polypeptide chain is being synthesized. The C-terminal end of the completed protein remains within the cytosol.

P.95 Another important modification is glycosylation, which occurs on the amino groups of asparagine residues (N-linked glycosylation) and results in the addition en bloc of a complex polysaccharide chain. This complex chain is then trimmed and modified within the lumen of the endoplasmic reticulum by a series of reactions controlled by chaperones, including calnexin and calreticulin. Because of the great chemical specificities of oligosaccharide moieties, these modifications can have important implications for cell function. For example, P.96 cell-to-cell interactions that occur during development rely on molecular recognition between glycoproteins present at the surface of the two interacting cells. Moreover, since the same protein can have somewhat different oligosaccharide chains, glycosylation can diversify the function of a protein. Thus, glycosylation increases the repertory of configurations a protein can have. Some membrane-anchored proteins in the endoplasmic reticulum may also be conjugated to a glycolipid (glycosylphosphatidyl inositol or GPI), resulting in a lipid tail that is anchored to the inner leaflet of the vacuolar membrane:

Figure. No Caption Available.

This modification occurs soon after synthesis and transport through the membrane of the endoplasmic reticulum. These proteins bear a C-terminal recognition sequence 20-30 residues long. In the lumen of the endoplasmic reticulum this sequence is cleaved off, exposing a new C terminus. This free carboxyl group forms a peptide bond with phosphorylethanolamine, which in turn is anchored to the inner leaflet of the membrane through the diacylglycerol moiety of a complex inositol phospholipid. This type of membrane anchor is characteristic of several proteins destined for the outer leaflet of the plasmalemma, including a form of acetylcholinesterase and the neuronal cell adhesion molecule (NCAM). These proteins are destined to face the extracellular space because, as discussed in Chapter 4, the inner leaflet of the endoplasmic reticulum is functionally continuous with the outer leaflet of the plasmalemma.

Secretory Proteins Are Processed Further in the Golgi Complex and Then Exported

Proteins exported from the endoplasmic reticulum are carried to the Golgi complex in transport vesicles that bud off from the reticulum's membrane. There they are modified and then transported to other intracellular locations or secreted. In the electron microscope the Golgi complex appears as stacks of flattened cisternae aligned with one another in long ribbons (see Figures 5-1 and 5-3) and as filamentous structures when visualized by light microscopy with cytochemical markers (see Figure 4-3). The mechanisms for vesicular transport at all stations of the secretory and endocytic pathways have been remarkably conserved from simple unicellular organisms (yeast) to complex cells (neurons). The generation of transport vesicles from a membrane is assisted by protein coats, which assemble at the cytosolic surface of the membrane patches that will form the vesicles. These coats are thought to have two functions. First, they mediate evagination of the membrane into a bud. Second, they select the protein cargo that will be incorporated into the vesicles. There are several types of coats. The clathrin coat assists in budding from the Golgi complex and from the plasmalemma. Two other coats, COPI and COPII, assist the vesicles involved in transport between the endoplasmic reticulum and the Golgi complex. The coats are rapidly lost once free vesicles have formed. Docking and fusion of vesicles with the target membrane is mediated by a hierarchy of molecular interactions, the most important of which is thought to be the reciprocal recognition of small proteins with short membrane anchors on the cytosolic surfaces of the two interacting membranes. The action of these small proteins, called v-SNARE (vesicular SNARE) and t-SNARE (target membrane SNARE), is discussed in Chapter 14 in connection with the role of synaptic vesicles in the release of neurotransmitter at synapses. Vesicles derived from the endoplasmic reticulum arrive at the cis side of the Golgi complex, fuse with the membranes of Golgi cisternae, and thereby deliver their contents into the Golgi complex. The delivered proteins are then thought to travel from one cisterna to the next, from the cis to the trans side of this organelle, through a series of vesicular transport steps. Each subcompartment (cisterna or set of cisternae) of the Golgi complex is specialized for different types of enzymatic reactions. Several types of protein modifications occur within the lumen of the Golgi complex proper or within the transport station directly adjacent to its trans side, the so-called trans-Golgi network. These modifications include addition of more N-linked oligosaccharides, O-linked (on the hydroxyl groups of amino acids) glycosylation, phosphorylation, and sulfation. These changes are aimed at increasing the hydrophilicity of the protein (useful for secretory proteins), fine-tuning their ability to bind macromolecular partners, and delaying their degradation. In addition, many membrane and secretory proteins undergo proteolytic cleavage in the trans-Golgi network to generate smaller, biologically active proteins. Thus, in assembly-line fashion, the proteins undergo stepwise changes before leaving the Golgi complex at its trans side P.97 Proteins, both soluble and membrane-bound, that travel beyond the Golgi complex next bud off the trans-Golgi network in vesicles that have different molecular compositions and destinations. Traffic from the trans-Golgi network is responsible for secretion as well as for the delivery of newly synthesized components to the plasmalemma, endosomes, and other membranous organelles (see Figure 4-1B). One class of vesicles carries newly synthesized plasmalemma proteins and proteins that are continuously secreted (constitutive secretion). These vesicles fuse with the plasmalemma in a nonregulated fashion. Neurons are thought to have at least two types of these vesicles, one targeted to dendrites and the other to the axon. Another class of vesicles, which bud from the trans-Golgi complex by being pinched off with a clathrin coat, delivers lysosomal enzymes to late endosomes. Still other classes of vesicles transport secretory proteins that are released by an extracellular stimulus (regulated secretion). One type stores secretory products, primarily peptide neurohormones, in concentrated form. These vesicles, called large dense-core vesicles because of the electron-dense appearance of their core in the electron microscope, are similar in function and biogenesis to peptide-containing granules of endocrine cells. Large dense-core vesicles are targeted primarily to axons but can be seen in all regions of the neuron. They accumulate in cortical cytoplasm and are highly concentrated in axon terminals, where they undergo calcium-regulated exocytosis. The optimal stimulus for their secretion is a train of action potentials. An important question that remains poorly understood is how the proteins that form synaptic vesicles, the small lucent vesicles responsible for the release of neurotransmitter, reach axon terminals. There is evidence to suggest that synaptic vesicles are not assembled in the trans-Golgi network but in the axon terminal, and that synaptic vesicle proteins are carried to endosomes and the plasmalemma of nerve terminals in precusor membranes. At the terminals these vesicle precursors would join existing synaptic vesicles as they pass through endosomes during the recycling process to be described in Chapter 14. Release of small-molecule neurotransmitters, stored in synaptic vesicles, occurs by an exocytotic process regulated by Ca2+ ion influx (see Chapters 14 and 15).

Surface Membrane and Extracellular Substances Are Taken Up Into the Cell by Endocytosis Since the mature neurons does not grow, vesicular traffic toward the cell surface is continuously balanced by traffic back from the plasmalemma to internal organelles. This endocytic traffic, which is essential for maintaining the area of the plasmalemma in a steady state, has several other functions. It alters the activity of many important regulatory molecules on the cell surface (for example, receptors P.98 and adhesion molecules). It also directs nutrients and molecules, such as expendable receptor ligands and aged membrane proteins, toward the degradative compartments of the cells. Finally, it is necessary for recycling synaptic vesicles at nerve terminals (Chapter 14).

Figure 5-7 Membranes of organelles involved in synaptic transmission are returned to the cell body for reuse or degradation. 1. Proteins and lipids of secretory organelles are synthesized in the endoplasmic reticulum and transported to the Golgi complex, where large dense-core vesicles (peptide-containing secretory granules) and synaptic vesicle precursor membranes are assembled. 2. Large dense-core vesicles and transport vesicles that carry synaptic vesicle membrane proteins leave the Golgi complex and travel down the axon via axonal transport. 3. In nerve terminals the synaptic vesicles are assembled and loaded with nonpeptide neurotransmitters. Synaptic vesicles and large dense-core vesicles release their contents by exocytosis. 4. Following exocytosis, large dense-core vesicle membranes are returned to the cell body for reuse or degradation. Synaptic vesicle membranes undergo several cycles of exoendocytosis (see Chapter 14) and are eventually returned to the cell body for degradation.

Box 5-1 Neuroanatomical Tracing Relies on Axonal Transport In the past 20 years the study of neuroanatomy has been revolutionized by the use of a variety of labels to trace neural projections. Previously, the projections of neurons were mapped by cutting axons, allowing them to degenerate, and then locating the affected cell bodies or axons. These studies relied on difficult and sometimes unreliable histochemical staining procedures. Axonal transport can distribute labeled material throughout the neuron. Neuroanatomists can now locate axons and terminals of specific nerve cell bodies by microinjection of dyes, expression of fluorescent proteins, or by autoradiographically tracing labeled protein soon after administering radioactively labeled amino acids, certain labeled sugars (fucose or amino sugars, precursors of glycoprotein), or specific transmitter substances. Similarly, the location of the cell bodies belonging to specific terminals can be identified by making use of particles, proteins, or dyes that are readily taken up at nerve terminals by endocytosis and transported back to cell bodies. Horse-radish peroxidase has been most widely used for this type of study because it readily undergoes retrograde transport and its reaction product is conveniently visualized histochemically (Figure 5-8). Axonal transport is also used by neuroanatomists to label material exchanged between neurons, making it possible to identify neuronal networks (Figure 5-9).

Figure 5-8 Use of horseradish peroxidase to investigate the sources of afferents to the inferior parietal lobule of the cerebral cortex in the rhesus monkey. A cell body in the magnocellular nucleus of the basal forebrain was found to be labeled two days after injection of horseradish peroxidase (HRP) into the cortex. The HRP was taken up by the cell's terminals in the cortex and transported to the cell body. Thin arrows indicate HRP reaction product in the cell body; thick arrows indicate processes (p) in which some reaction product can be seen. N = nucleus. (From Divac et al. 1977.)

Figure 5-9 Use of the herpes simplex virus to trace cortical pathways in monkeys. Depending on the strain, the virus moves in the anterograde or retrograde direction by axonal transport. In either direction it will enter a neuron with which the infected cell makes synaptic contact. Here an anterograde moving strain (HSV-1 [H129]) was used to trace the projections of cells in the primary motor cortex to the cerebellum in monkeys. Monkeys were injected in the region of the primary motor cortex representing the arm (Chapters 17 and 38). After four days the brain was sectioned and immunostained for viral antigen. The virus was transported from primary motor cortex to second-order neurons in pontine nuclei (A) and then to thirdorder neurons in the cerebellar cortex (B). A map of the connections demonstrated by this experiment is shown in the diagram of a brain. (Courtesy of Dr. P. L. Strick.)

A significant fraction of endocytic traffic is carried by clathrin-coated vesicles. Clathrin-mediated endocytosis is very selective, since components of the clathrin coat specifically interact with proteins that need to be taken into the cell from the extracellular space. For this reason clathrin-mediated internalization is often referred to as receptor-mediated endocytosis. Clathrin-coated vesicles eventually shed their coat and fuse with intracellular lysosomal vacuoles called early endosomes, where proteins to be recycled to the cell surface are separated from proteins destined for other intracellular organelles. Patches of plasmalemma membrane can also be internalized through larger, uncoated vacuoles that also fuse with early endosomes (bulk endocytosis). Early endosomes are also scattered throughout dendrites. Endocytosed material and membrane to be degraded are passed on to late endosomes. These organelles, which P.99 are transported by retrograde axonal transport (see below), are concentrated in the proximal segments of dendrites and in the cell body where they fuse with lysosomes. In the axon endocytosis occurs primarily at nerve terminals, mostly in the recycling of synaptic vesicles. Endocytosis of synaptic vesicles is mediated by the clathrin coat and dynamin. Although true endosomes exist in nerve terminals, they do not seem to play a role in synaptic vesicle recycling; rather, recycled synaptic vesicles are generated directly from clathrin-coated vesicles that lose their coat.

Proteins and Organelles Are Transported Along the Axon The secretory process in neurons is formally similar to that in other cells. But the primary site of secretion, the axon terminal, is considerably distant from the cell body and dendrites, where secretory proteins are synthesized. For example, in a motor neuron that innervates the muscle of the leg in humans, the distance of the nerve terminals from the cell body can exceed 10,000 times its diameter. The distance between cell body and P.100 nerve terminals means that newly formed membrane and secretory products must be actively transported from the Golgi complex to the end of the axon (Figure 5-7).

Figure 5-10 Early experiments on axonal transport used radioactive labeling of proteins. In the experiment illustrated here the distribution of radioactive proteins along the sciatic nerve of the cat was measured at various times after injection of [3H]leucine into dorsal root ganglia in the lumbar region of the spinal cord. In order to show transport curves from various times (2, 4, 6, 8, and 10 hours after the injection) in one figure, several ordinate scales (in logarithmic units) are used. Large amounts of labeled protein stay in the ganglion cell bodies but with time protein moves out along axons in the sciatic nerve and the advancing front of the labeled proteins is displayed progressively farther from the cell body (arrows). The velocity of transport can be calculated from the distances displayed at the various times. From experiments of this kind, Sidney Ochs found that the rate of axonal transport is constant at 410 mm per day at body temperature. (Adapted from Ochs 1972.)

In 1948 Paul Weiss tied off a sciatic nerve and observed that axoplasm in the nerve fiber accumulated with time on the proximal side of the ligature. He concluded that axoplasm moves at a slow, constant rate from the cell body toward the terminals in a process he called axoplasmic flow. Today we know that the flow Weiss observed consists of several kinetic components, both fast and slow. Membranous organelles move toward the nerve terminal (anterograde direction) and back toward the cell body (retrograde direction) by fast axonal transport, a form of transport that is faster than 400 mm/day in warm-blooded animals. Cytosolic and cytoskeletal proteins move only in the anterograde direction by a much slower form of transport, slow axonal transport. Although these transport mechanisms are prominent in the axon, they represent adaptations of transport mechanisms that facilitate intracellular transport of organelles in all secretory cells. Because of their specialized function in axons, these transport mechanisms have proved to be convenient experimental models for elucidating how organelles are moved in other cells. They have also been used by neuroanatomists to label neurons (Box 5-1).

Fast Axonal Transport Carries Membranous Organelles Large membranous organelles are transported in the axon, both to and from the cell body, by fast axonal P.101 transport. These organelles include vesicles of the constitutive secretory pathway, synaptic vesicle precursor membranes, large densecore vesicles, mitochondria, and elements of the smooth endoplasmic reticulum. Direct microscopic analysis of the movement of large particles in living axons in culture started as early as 1920. More recently, advances in video microscopy techniques have greatly helped in the visualization of this process. Continuous direct observation using video-enhanced light microscopy reveals that particles are actively transported in a stop-and-start (saltatory) fashion along linear tracks aligned with the main axis of the axon. These tracks have been convincingly shown to be microtubules.

Figure 5-11 Kinesin is the motor molecule for anterograde transport in the axon. A. This quick-freeze, deep-etched electron micrograph from rat spinal cord shows many rod-shaped structures bridging organelles (large round structures) and microtubules (MT). Several of these cross-bridges have globular ends that appear to contact the microtubules (arrows). Bar = 100 nm. B. Model for how kinesin may move organelles along microtubules. Kinesin contains a pair of globular heads that bind to microtubules and a fan-shaped tail that binds the organelle to be moved. A hinge region is present near the center of the kinesin molecule. The similarities between kinesin and muscle myosin led to the idea that kinesin moves organelles by “walking” along microtubular tracks. (Adapted from Hirokawa et al. 1989.)

Early experiments on axonal transport traced proteins synthesized in dorsal root ganglion cell bodies by labeling them with radioactive amino acids injected into the ganglion. The distribution of labeled protein along a nerve was obtained from different specimens at various times after the injection and the rate of movement was measured by counting the amount of radioactivity in uniform sequential segments along the nerve (Figure 5-10) Studies using this system showed that anterograde transport depends critically on ATP, is not affected by inhibitors of protein synthesis (once the labeled amino acid is incorporated), and does not depend on the cell body, since it occurs in nerves actually severed from their cell bodies. In fact, transport occurs in reconstituted axoplasm. Studies with isolated axonal components (in vitro motility assays) have clarified how membranes and other cellular constituents move along nerve processes. Anterograde transport in the axon depends on microtubules that provide an essentially stationary track on which specific organelles move by means of molecular motors. The saltatory nature of the movement is due to periodic dissociation of the organelle from the track or to collision with other structures. The idea that microtubules are involved first emerged from the finding that colchicine and vinblastine, alkaloids that cause the disruption of microtubules and block mitosis (which is known to depend on microtubules), also interfere with fast transport. About 30 years ago electron microscopists observed cross-bridges between microtubules and vesicular particles that were thought to play a role in moving the particles, and there is now evidence that some of these cross-bridges represent the motors. The motor molecules for anterograde transport (toward the plus end of microtubules) are kinesin and a variety of kinesin-related proteins called KIFs—a large family of ATPases, each of which transports different membrane cargoes. Kinesin is a heterotetramer composed

P.102 of two heavy chains and two light chains. Each heavy chain contains a globular head (the ATPase domain) that acts as the motor when attached to microtubules, a coil-coiled helical stalk responsible for dimerization with the other heavy chain, and a fan-like C terminus that interacts with the light chains and represents the organelle-interaction domain (Figure 5-11). These structures had suggested that kinesin moves organelles by “walking” along microtubules. However, the recent discovery of monomeric KIF motors (with only one “foot”) has challenged this model.

Figure 5-12 The two components of slow axonal transport in the axon of dorsal root ganglion (DRG) cells. Autoradiographs show the advance of different proteins in the axon 7 and 14 days after injecting [35S]methionine into the L5 DRG cells of adult rats. Each lane in these autoradiographs represents the electrophoretic separation on a polyacrilamide gel of proteins in consecutive 2-mm segments of the central and peripheral branches of the axon of injected cells. The major proteins in the slower wave of axonal transport (SCa) are the neurofilament proteins (large asterisks), with molecular weights of 200,000, 145,000, and 68,000, and the tubulin subunits of the microtubule (diamonds), α-tubulin (mol wt 53,000) and β-tubulin (mol wt 57,000). The advance of the SCa wave over one week is indicated by the distance between the peaks of the radioactivity in the neurofilaments (small asterisks) at the two time intervals. The constituents of the faster component of axonal transport (SCb) are more complex. Three identified proteins are indicated: clathrin (arrowhead), actin (open circle), and tubulin (diamonds). (Courtesy of M. Oblinger.)

Rapid transport also occurs in the retrograde direction, from nerve endings toward the cell body. The organelles transported in this direction are primarily endosomes generated by endocytic activity at nerve terminals (multivesicular bodies and other endosomes), mitochondria, and elements of the endoplasmic reticulum. Some of the material endocytosed in nerve endings is destined for the cell body (eg, the membranes of the large dense-core vesicle proteins that are shipped back for reuse). Although much of this material is degraded within lysosomes, retrograde transport is also used to deliver signals to the cell body. For example, activated growth factor receptors are thought to be carried along the axon to their site of action in the nucleus. Certain toxins (tetanus toxin) as well as pathogens (herpes simplex, rabies, and polio viruses) are also transported toward the cell body along the axon. P.103 The rate of retrograde fast transport is about one-half to two-thirds that of fast transport in the anterograde direction. As in anterograde transport, particles move along microtubules. The motor molecule for retrograde transport is a microtubule-associated ATPase called MAP-1C. This axonal motor molecule is similar to the dyneins in cilia and flagella and consists of a multimeric protein complex with two globular heads on two stalks connected to a basal structure. The globular heads attach to microtubules and act as motors, moving toward the minus end of the polymer. Like kinesin, the rest of the complex is thought to associate with the organelle being moved.

Slow Axonal Transport Carries Cytosolic Proteins and Cytoskeletal Elements

Whereas subcellular organelles are moved along the axon by fast transport, cytosolic proteins and elements of the cytoskeletal matrix are transported by slow axonal transport. Slow axonal transport occurs only in the anterograde direction (from the cell body). It consists of at least two kinetic components that transport different proteins and move at different rates along the axon. A slower component travels at a rate of 0.2-2.5 mm per day and carries the proteins that make up the fibrillar elements of the cytoskeleton: the subunits of neurofilaments and the α- and β-tubulin subunits of microtubules (Figure 5-12). These fibrous proteins constitute about 75% of the total protein moved by the slower component. Microtubules move in polymerized form by a mechanism involving microtubule sliding. Relatively short preassembled microtubules are transported from the cell body down the axon by interacting with existing microtubules. Neurofilament subunits or short polymers are thought to move passively along with the microtubules because the two polymers are cross-linked by protein bridges. The faster component of slow axonal transport is about twice as fast as the slower component. The proteins carried by this component are more complex, and include clathrin, actin, and actin-binding proteins as well as a variety of cytosolic enzymes and proteins.

An Overall View Most neuronal proteins are synthesized in the cell body. The proper function of these proteins depends not only on their primary amino acid sequence, but also on correct folding. Folding of proteins during or after synthesis is assisted by chaperones, and their final structure is often modified by permanent or reversible post-translational modifications that may affect both the distribution and function of the protein. Proteins of the cytosol and of the cytoskeleton are made on free ribosomes and moved to all cell regions by diffusion or axonal transport. Proteins of mitochondria and peroxisomes, as well as proteins of the nucleus and some proteins of the vacuolar apparatus, are made in the cytosol and targeted post-translationally to their destination by signals in their amino acid sequence. Most secretory proteins, proteins of the plasmalemma, and proteins of the vacuolar apparatus are made on ribosomes of the rough endoplasmic reticulum and are translocated across the membrane during synthesis. From the rough endoplasmic reticulum they are transported to other compartments of the vacuolar apparatus or to the cell surface by vesicular traffic (the secretory pathway). Vesicular traffic from the plasmalemma (the endocytic pathway) carries proteins to degradative compartments or back to the secretory apparatus for reuse. Vesicular transport among intracellular membranes occurs with great specificity and results in the vectorial transport of selected membrane components. Since mature neurons grow very little, vesicular transport to any type of membrane is balanced by traffic back to lysosomes for degradation. Thus, material is transported from one compartment to another without modifying the steady-state composition of any organelle. A variety of molecular motors drive organelles within the cytosol, resulting in their uneven distribution within the neuron. Concentration of dense-core and synaptic vesicles at axon terminals and their constant renewal is achieved by anterograde and retrograde axonal transport along cytoskeletal tracks, primarily microtubules.

Selected Readings Grafstein B. 1995. Axonal transport: function and mechanisms. In: SG Waxman, JD Kocsis, PK Stys (eds). The Axon: Structure, Function and Pathophysiology, pp. 185-199. New York: Oxford Univ. Press.

Hartl FU. 1996. Molecular chaperones in cellular protein folding. Nature 381:571–579.

Holtzman E. 1989. Lysosomes. New York: Plenum. P.104

Kelly RB. 1993. Storage and release of neurotransmitters. Cell/Neuron 72/10:43–53.

Kreis T, Vale R (eds). 1993. Guidebook to the Cytoskeletal and Motor Proteins. Oxford: Oxford Univ. Press.

Lodish H, Baltimore D, Berke A, Zipursky SL, Matsudaira P, Darnell T. 1995. Molecular Cell Biology, 3rd ed. New York: Scientific American Books.

Nigg EA. 1997. Nucleocytoplasmic transport: signals, mechanisms and regulation. Nature 386:779–787.

Peters A, Palay SL, Webster, H deF. 1991. The Fine Structure of the Nervous System: Neurons and Their Supporting Cells, 3rd ed. New York: Oxford Univ. Press.

Rothman JE, Wieland FT. 1996. Protein sorting by transport vesicles. Science 272:227–234.

Schatz G, Dobberstein B. 1996. Common principles of protein translocation across membranes. Science 271: 1519–1526.

Schekman R, Orci L. 1996. Coat proteins and vesicle budding. Science 271:1526–1533.

Stryer L. 1995. Biochemistry, 4th ed. New York: WH Freeman.

Varshazsky A. 1997. The ubiquitin system. Trends Biochem Sci 22:283–287.

References Alberts B, Bray D, Lewis J, Raff M, Roberts K, Watson JD. 1994. Molecular Biology of the Cell, 3rd ed. New York: Garland.

Benson DL, Cohen PA. 1996. Activity-dependent segregation of excitatory and inhibitory synaptic terminals in cultured hippocampal neurons. J Neurosci 16:6424–6432.

Brady ST. 1991. Molecular motors in the nervous system. Neuron 7:521–533.

Chain DG, Casadio A, Schacher S, Hedge AN, Valbrun M, Yamamoto N, Goldberg AL, Bartsch D, Kandel ER, Schwartz JH. 1999. Mechanisms for generating the autonomous cAMP-dependent protein kinase required for long-term facilitation in Aplysia. Neuron 22:147–156.

Cleveland DW, Hoffman PN. 1991. Slow axonal transport models come full circle: evidence that microtubule-sliding mediates axon elongation and tubulin transport. Cell 67:453–456.

Divac I, LaVail JH, Rakic P, Winston KR. 1977. Heterogeneous afferents to the inferior parietal lobule of the rhesus monkey revealed by the retrograde transport method. Brain Res 123:197–207.

Dokas LA. 1983. Analysis of brain and pituitary RNA metabolism: a review of recent methodologies. Brain Res Rev 5:177–218.

Görlich D, Mattaj IW. 1996. Nucleocytoplasmic transport. Science 271:1513–1518.

Hershko A, Ciechanover A. 1998. The ubiquitin system. Annu Revs Biochem 67:425–479.

Hirokawa N. 1997. The mechanisms of fast and slow transport in neurons: identification and characterization of the new Kinesin superfamily motors. Curr Op Neurobiol 7:605–614.

Hirokawa N, Pfister KK, Yorifuji H, Wagner MC, Brady ST, Bloom GS. 1989. Submolecular domains of bovine brain kinesin identified by electron microscopy and monoclonal antibody decoration. Cell 56:867–878.

Hoffman PN, Lasek RJ. 1975. The slow component of axonal transport: identification of major structural polypeptides of the axon and their generality among mammalian neurons. J Cell Biol 66:351–366.

Kreis T, Vale R (eds). 1993. Guidebook to the Extracellular Matrix and Adhesion Proteins. Oxford: Oxford Univ. Press.

McIlhinney RAJ. 1990. The fats of life: the importance and function of protein acylation. Trends Biochem 15:387–391.

McNew JA, Goodman JM. 1996. The targeting and assembly of peroxisomal proteins: some old rules do not apply. Trends Biochem Sci 21:54–58.

Neupert W. 1997. Protein import into mitochondria. Annu Rev Biochem 66:863–917.

Oblinger MM, Lasek RJ. 1985. Selective regulation of two axonal cytoskeletal networks in dorsal root ganglion cells. In: P O'Lague (ed). UCLA Symposium on Molecular and Cellular Biology. Vol. 24, Neurobiology: Molecular Biological Approaches to Understanding Neuronal Function and Development, pp. 135-143. New York: Liss.

Ochs S. 1972. Fast transport of materials in mammalian nerve fibers. Science 176:252–260.

Ochs S. 1975. Waller's concept of the trophic dependence of the nerve fiber on the cell body in the light of early neuron theory. Clio Med 10:253–265.

Okada Y, Yamazaki H, Sekine-Aizawa Y, Hirokawa N. 1995. The neuron-specific kinesin superfamily protein KIFIA is a unique monomeric motor for anterograde axonal transport of synaptic vesicle precursors. Cell 81:769–780.

Schnapp BJ, Reese TS. 1982. Cytoplasmic structure in rapid-frozen axons. J Cell Biol 94:667–679.

Takei K, Mundigl O, Daniell L, De Camilli P. 1996. The synaptic vesicle cycle: a single vesicle budding step involving clathrin and dynamin. J Cell Biol 133:1237–1250.

Vale RD, Fletterick RJ. 1997. Design plan of kinesin motors. Annu Rev Cell Dev Biol 13:745–777.

Vallee RB, Bloom GS. 1991. Mechanisms of fast and slow axonal transport. Annu Rev Neurosci 14:59–92.

Weiss P, Hiscoe HB. 1948. Experiments on the mechanism of nerve growth. J Exp Zool 107:315–395.

Zemanick MC, Strick PL, Dix RD. 1991. Direction of transneuronal transport of herpes simplex virus 1 in the primate motor system is strain-dependent. Proc Natl Acad Sci USA 88:8048–8051. 1Ribosomal RNA on the rough endoplasmic reticulum stains intensely with basic histological dyes (toluidine blue, cresyl violet, and methylene blue). When viewed under the light microscope, this basophilic material is called Nissl substance after the histologist who first described changes in the intensity and distribution of staining in neurons after their axons are cut. These changes, which reflect alterations in the patterns of protein synthesis in injured and regenerating neurons, are discussed in Chapter 55.

Back

6 Ion Channels Steven A. Siegelbaum John Koester NEURONAL SIGNALING DEPENDS on rapid changes in the electrical potential difference across nerve cell membranes. Individual sensory cells can generate changes in membrane potential in response to very small stimuli: receptors in the eye respond to a single photon of light; olfactory neurons detect a single molecule of odorant; and hair cells in the inner ear respond to tiny movements of atomic dimensions. Signaling in the brain depends on the ability of nerve cells to respond to these small stimuli by producing rapid changes in the electrical potential difference across nerve cell membranes. During an action potential the membrane potential changes quickly, up to 500 volts per second. These rapid changes in membrane potential are mediated by ion channels, a class of integral membrane proteins found in all cells of the body. The ion channels of nerve cells are optimally tuned for rapid information processing. The channels of nerve cells are also heterogeneous, so that different types of channels in different parts of the nervous system can carry out specific signaling tasks. Because of this selective distribution of finely tuned functional elements, malfunctioning of ion channels in nerve and skeletal muscle can cause a wide variety of neurological diseases (see Chapter 16). Diseases due to ion channel malfunction are not limited to the brain. Cystic fibrosis and certain types of cardiac arrhythmia, for example, are also caused by ion channel malfunction. Moreover, ion channels are often the site of action of drugs, poisons, or toxins. Thus ion channels have crucial roles in both the physiology and the pathophysiology of the nervous system.

Ion Channels Are Important for Signaling in the Nervous System Ion channels have three important properties: (1) They conduct ions, (2) they recognize and select specific ions, and (3) they open and close in response to specific electrical, mechanical, or chemical signals. The channels in nerve and muscle conduct ions across the cell membrane at extremely rapid rates, thereby providing a large flow of ionic current: up to 100 million ions may pass through a single channel per second. This current flow causes the rapid changes in membrane potential required for signaling, as will be discussed in Chapter 9. The fast rate of flow of ions through channels—108 per second—is comparable to the turnover rate of the fastest P.106 P.107 enzymes, catylase and carbonic anhydrase, which are limited by diffusion of substrate. (The turnover numbers of most other enzymes are considerably slower, however, ranging from 10 to 1000 per second.)

Figure 6-1 (Opposite) The ionic permeability properties of the membrane are determined by the interactions of ions with water, the membrane lipid bilayer, and ion channels. Ion channels are integral membrane proteins that span the lipid bilayer, providing a pathway for ions to cross the membrane. Phospholipids form self-sealing lipid bilayers that are the basis for all cellular membranes. Phospholipids have a hydrophilic head and a hydrophobic tail. The hydrophobic tails join to exclude water and ions, while the polar hydrophilic heads face the aqueous environment of the extracellular fluid and cytoplasm. Left enlargement: Ions in solution are surrounded by a cloud of water molecules (waters of hydration) that are attracted by the net charge of the ion. This cloud is carried along by the ion as it diffuses through solution, increasing the effective size of the ion. It is energetically unfavorable, and therefore improbable, for the ion to leave this polar environment to enter the nonpolar environment of the lipid bilayer. In the illustration, a positively charged ion (red) attracts the electronegative oxygen atoms of the surrounding water molecules. The inset also shows the structure of a phospholipid. It is composed of a backbone of glycerol in which two of its OH groups are linked by ester bonds to fatty acid molecules. The third -OH group of glycerol is linked to phosphoric acid. The phosphate group is further linked to one of a variety of small, polar, alcohol head groups (R). Bottom: A model showing how ion channels are able to select for either K+ or Na+ ions. Potassium channel (left): Although a Na+ ion itself is smaller than a K+ ion, its effective diameter in solution is larger because its local field strength is more intense, causing it to attract a larger cloud of water molecules. Thus, a channel can select for K+ over Na+ by excluding hydrated ions whose diameter is larger than the pore. Sodium channel (right): Sodium channels have a selectivity filter somewhere along the length of the channel, with a site that weakly binds Na+ ions. According to the hypothesis developed by Bertil Hille and colleagues, a Na+ ion binds transiently at an active site as it moves through the filter (right enlargement). At the binding site the positive charge of the ion is stabilized by a negatively charged amino acid residue on the channel wall and also by a water molecule that is attracted to a second polar amino acid residue on the other side of the channel wall. It is thought that a K+ ion, because of its larger diameter, cannot be stabilized as effectively by the negative charge and therefore will be excluded from the filter. (Modified from Hille 1984.)

Despite their ability to conduct ions at high rates, ion channels are surprisingly selective: Each type allows only one or a few types of ions to pass. For example, the membrane potential of nerve cells at rest is largely determined by channels that are selectively permeable to K+. Typically, these channels are 100-fold more permeable to K+ than to Na+. During the action potential, however, ion channels 10- to 20-fold more permeable to Na+ than to K+ are activated. Thus, a key to the great versatility of neuronal signaling is the activation of different classes of ion channels, each of which is selective for specific ions. Finally, many channels are regulated or gated; they open and close in response to various stimuli. Voltage-gated channels are regulated by changes in voltage, ligandgated channels by chemical transmitters, and mechanically gated channels by pressure or stretch. An individual channel is usually most sensitive to one type of signal. In addition to the gated channels, there are nongated channels that are normally open in the cell at rest. These resting channels contribute significantly to the resting potential. In this chapter we examine four questions: Why do nerve cells have channels? How can channels conduct ions at such high rates and still be selective? How are channels gated? How are the properties of these channels modified by various intrinsic and extrinsic conditions? In addition we compare the molecular structure of various channels and consider how they may have evolved. In succeeding chapters we consider how nongated channels generate the resting potential (Chapter 7), how voltage-gated channels generate the action potential (Chapter 9), and how ligand-gated channels produce synaptic potentials (Chapters 11, 12, and 13).

Ion Channels Are Proteins That Span the Cell Membrane To appreciate why nerve cells use channels, we need to understand the nature of the plasma membrane and the physical chemistry of ions in solution. The plasma membrane of all cells, including nerve cells, is about 6-8 nm thick and consists of a mosaic of lipids and proteins. The surface of the membrane is formed by a double layer of phospholipids. Embedded within this continuous lipid sheet are integral membrane proteins, including ion channels. The lipids of the membrane do not mix with water—they are hydrophobic. In contrast, the ions within the cell and those outside strongly attract water molecules—they are hydrophilic (Figure 6-1). The attraction between ions and water results because water molecules are dipolar: although the net charge on a water molecule is zero, charge is separated within the molecule. The oxygen atom in a water molecule tends to attract electrons and so bears a small net negative charge, while the hydrogen atoms tend to lose electrons and P.108 therefore carry a small net positive charge. As a result of this unequal distribution of charge, cations (positively charged ions) are strongly attracted electrostatically to the oxygen atom of water, and anions (negatively charged) are attracted to the hydrogen atoms. Similarly, ions attract water; in fact they become surrounded by electrostatically bound waters of hydration (Figure 6-1). An ion cannot move away from water into the noncharged hydrocarbon tails of the lipid bilayer in the membrane unless a large amount of energy is expended to overcome the attractive forces between the ion and the surrounding water molecules. For this reason it is extremely unlikely that an ion will move from solution into the lipid bilayer, and therefore the bilayer itself is almost completely impermeable to ions. Ions cross the membrane only through specialized pores or openings in the membrane, such as ion channels, where as we shall see, the energetics favor ion movement. Ion channels are not simply holes in the lipid membrane but are made up of protein. Although their molecular nature has been known with certainty for only about 15 years, the idea of ion channels dates to the end of the nineteenth century. At that time physiologists knew that, despite the barrier of the cell membrane, cells were nevertheless permeable to many small solutes, including some ions. To explain osmosis, the flow of water across biological membranes, Ernst Brücke proposed that membranes contain channels or pores that allow water but not larger solutes to flow across membranes. Later, William Bayliss suggested that a water-filled channel would permit ions to cross the cell membrane easily, since the ions would not need to be stripped of their waters of hydration. The idea that ions move through channels leads to a question: How can a water-filled channel conduct at high rates and yet be selective? How, for instance, does a channel allow K+ ions to pass while excluding Na+ ions? Selectivity cannot be based solely on the diameter of the ion, because K+, with a crystal radius of 0.133 nm, is larger than Na+ (crystal radius of 0.095 nm). Because ions in solution are surrounded by waters of hydration, the ease with which an ion moves in solution (its mobility or diffusion constant) does not depend simply on the size of the ion; instead it depends on its size together with the shell of water surrounding it. The smaller an ion, the more highly localized is its charge and the stronger its electric field; smaller ions such as Na+ have stronger effective electric fields than larger ions such as K+. As a result, smaller ions attract water more strongly. Thus, as Na+ moves through solution its strong electrostatic attraction for water causes it to have a larger water shell, which tends to slow it down relative to K+. Because of its larger water shell, Na+ behaves as if it is larger than K+. In fact, there is a precise relationship

between the size of an ion and its mobility in solution: the smaller the ion, the lower its mobility. We therefore can construct a model of a channel that selects K+ rather than Na+ simply on the basis of the interaction of the two ions with water in a water-filled channel (Figure 6-1). Although this model explains how a channel can select K+ and exclude Na+, it presents the puzzle of how a channel could select Na+ and exclude K+. This problem led many physiologists in the 1930s and 1940s to abandon the channel theory in favor of the idea that ions cross cell membranes by first binding to a specific carrier protein, which then transports the ion through the membrane. In this carrier model, selectivity is based on the chemical binding between the ion and the carrier protein, not on the mobility of the ion in solution. Even though we now know that ions can cross membranes by means of transporters, the Na+-K+ pump being a well-characterized example (Chapter 7), many observations on ion conductance across the cell membrane do not fit the carrier model. Most important is the rapid rate of ion transfer across membranes. This transfer rate was first examined in the early 1970s by measuring the transmembrane current initiated by binding of acetylcholine (ACh) to its receptor in the cell membrane of skeletal muscle fibers at the synapse between nerve and muscle. Using measurements of membrane-current noise (small statistical fluctuations in the mean ionic current induced by ACh), Bernard Katz and Ricardo Miledi concluded that the current initiated by a single ACh receptor is 10 million ions per second. In contrast, the Na+-K+ pump is much slower; it can transport at most 100 ions per second. If the ACh receptor acted as a carrier, it would have to shuttle an ion across the membrane in 0.1 µs (one ten-millionth of a second), an implausibly fast rate. The 100,000-fold difference in rates strongly suggests that the ACh receptor (and other ligand-gated receptors) must conduct ions through a channel. Later measurements of current in many voltage-gated pathways selective for K+, Na+, and Ca2+ also demonstrate large unitary currents, indicating that they too are channels. But we are still left with the original problem: What makes a channel selective? To explain selectivity, Bertil Hille extended the pore theory by proposing that channels have narrow regions that act as molecular sieves. At this selectivity filter an ion sheds most of its waters of hydration and, in their place, forms weak chemical bonds (electrostatic interactions) with polar (charged) amino acid residues that line the walls of the channel (Figure 6-1). Since it is energetically unfavorable for an P.109 ion to shed its waters of hydration, the ion will traverse a channel only if the energy of interaction with the selectivity filter compensates for the loss of waters of hydration. Ions traversing the channel are normally bound to the selectivity filter for only a short time (less than 1 µs), after which the electrostatic and diffusional forces propel the ion through the channel. In channels where the pore diameter is large enough to accommodate several water molecules, an ion need not be stripped completely of its water shell. How is this chemical recognition and specificity established? One theory was developed in the early 1960s by George Eisenmann to explain the properties of ionselective glass electrodes (which are similar to pH electrodes but select among the alkali metal cations). According to this theory, a binding site with a high negative field strength—for example, one formed by negatively charged carboxylic acid groups of glutamate or aspartate—will selectively bind Na+ relative to K+. This selectivity results because the electrostatic interaction between two charged groups, as governed by Coulomb's law, depends inversely on the distance between the two groups. Since Na+ has a smaller radius than K+, Na+ can approach a negative site more closely than K+ and thus will derive a more favorable free-energy change upon binding. This highly favorable free energy of binding will compensate for the requirement that Na+ lose some of its waters of hydration in order to traverse the narrow selectivity filter. In contrast, a binding site with a low field strength—one that is composed, for example, of polar carbonyl or hydroxyl oxygen atoms—would select K+ over Na+. At such a site the binding of Na+ would not provide a sufficient free energy change to compensate for the loss of the ion's waters of hydration, which Na+ holds strongly. Since the larger K+ ions interact more weakly with water, a binding site with a low field strength would be able to compensate for the loss of a K+ ion's associated water molecules. It is currently thought that ion channels are selective both because of specific chemical interactions and because of molecular sieving based on pore diameter.

Ion Channels Can Be Investigated Using Functional Methods To understand fully how channels work, we ultimately will need three-dimensional structural information, which has been informative in the study of enzymes and other soluble proteins. X-ray crystallographic and other structural analyses have only recently begun to be applied to integral membrane proteins, such as ion channels, because their transmembrane hydrophobic regions make them difficult to crystallize. However, single-channel recording has provided important functional information that has led to interesting structural interpretations. Before it became possible to resolve the small amount of current that flows through a single ion channel in biological membranes, channel function was studied in artificial lipid bilayers. In the early 1960s Paul Mueller and Donald Rudin developed a technique for forming functional lipid bilayers by painting a thin drop of phospholipid over a hole in a nonconducting barrier that separates two salt solutions. Although lipid membranes have a very high resistance to ions, ion flux across the membrane increases dramatically when certain peptide antibodies are added to the salt solution. Early studies with a 15-amino acid cyclic peptide, gramicidin A, were especially informative. Application of low concentrations of gramicidin A brings about small step-like changes in current flow across the membrane. These brief pulses of current reflect the all-or-none opening and closing of the single ion channel formed by the peptide. The current through a single gramicidin channel varies with membrane potential in a linear manner, that is, the channel behaves as a simple resistor (Figure 6-2). The amplitude of the single-channel current can thus be obtained from Ohm's law, i = V/R, where i is the current through the single channel, V is the voltage across the channel, and R is the resistance of the open channel. The slope of the relation between i and V yields a value of R for a single open channel of around 8 × 1010 ohms (Figure 6-2B). In dealing with ion channels it is more useful to speak of the reciprocal of resistance or conductance (γ = 1/R), as this provides an electrical measure of ion permeability. Thus, Ohm's law can be expressed as i = γ × V. The conductance of the gramicidin A channel is around 12 × 10-12 siemens, or 12 picosiemens (pS), where 1 siemen equals 1/ohm. The insights into basic channel properties obtained from artificial membranes were later confirmed in biological membranes by the patch-clamp technique (Box 6-1). A glass micropipette containing ACh—the neurotransmitter that activates the transmittergated ion channels in the membrane of skeletal muscle—was pressed tightly against a frog muscle membrane. Small unitary current pulses representing the opening and closing of single ACh-activated ion channels were recorded from the area of the membrane under the pipette tip (Figure 6-3A,6-3B). As with gramicidin A channels, the relation between current and voltage in these ACh-activated P.110 channels is linear, with a single-channel conductance of around 25 pS.

Figure 6-2 Characteristics of the current in a single ion channel. The data presented here were obtained from a channel formed by the addition of gramicidin A molecules to the solution bathing an artificial lipid bilayer. A. The channel opens and closes in an all-or-none fashion, resulting in brief current pulses through the membrane. If the electrical potential (Vm) across the membrane is varied, the current through the channel (i) changes proportionally. Vm is measured in millivolts (mV); i is measured in picoamperes (pA). B. A plot of the current through the channel versus the potential difference across the membrane reveals that the current is linearly related to the voltage; in other words, the channel behaves as an electrical resistor that follows Ohm's law (i = V/R or i = γ × V). (Data courtesy of Olaf Anderson and Lyndon Providence.) C. Proposed structure of the gramicidin A channel. A functional channel is formed by end-to-end dimerization of two gramicidin peptides. (From Sawyer et al. 1989.)

Ion Channels in All Cells Share Several Characteristics Most cells are capable of local intercellular signaling, but only nerve and muscle cells are specialized for rapid signaling over long distances. Although nerve and muscle cells have a particularly rich variety and high density of membrane ion channels, their channels do not appear to differ fundamentally from those of other cells in the body. In this section we describe the general properties of ion channels found in a wide variety of cells.

The Flux of Ions Through the Ion Channel Is Passive The flux of ions through ion channels is passive, requiring no expenditure of metabolic energy by the channels. The direction and eventual equilibrium for this flux is determined not by the channel itself, but rather by the electrostatic and diffusional driving forces across the membrane. Ion channels select the types of ions that they allow to cross the membrane, allowing either cations or anions to permeate. Some types of cation-selective channels allow the cations that are usually present in extracellular fluid—Na+, K+, Ca2+, and Mg2+—to pass almost indiscriminately. However, most cation-selective channels are primarily permeable to a single type of ion, whether it is Na+, K+, or Ca2+. Most types of anion-selective P.111 channels are also highly discriminating; they conduct only one physiological ion, chloride (Cl-).

Box 6-1 Recording Current Flow in Single Ion Channels: The Patch Clamp The patch-clamp technique is a refinement of voltage clamping (see Box 9-1) and was developed in 1976 by Erwin Neher and Bert Sakmann to record current flow from single ion channels. A small fire-polished glass micropipette with a tip diameter of around 1 µm is pressed against the membrane of a skeletal muscle fiber that has been treated with proteolytic enzymes to remove connective tissue from the muscle surface. The pipette is filled with a salt solution resembling that normally found in the extracellular fluid. A metal electrode in contact with the electrolyte in the micropipette connects the pipette to a special electrical circuit that measures the current flowing through channels in the membrane under the pipette tip.

Figure 6-3A Patch-clamp setup. A pipette containing acetylcholine (ACh) is used to record transmitter-gated channels in skeletal muscle. (Adapted from Alberts et al. 1989.)

In 1980 Neher discovered that applying a small amount of suction to the patch pipette greatly increased the tightness of the seal between the pipette and the membrane. The result was a seal with extremely high resistance between the inside and the outside of the pipette. The seal lowered the electronic noise and extended the utility of the technique to the whole range of channels involved in electrical excitability, including those with small conductances. Since this discovery, Neher and Sakmann, and many others, have used the patch-clamp technique to study all three major classes of ion channels—voltage-gated, transmitter-gated, and mechanically-gated—in a variety of neurons and other cells.

Figure 6-3B Patch-clamp record of the current flowing through a single ion channel as the channel switches between closed and open states. (Courtesy of B. Sakmann.) Christopher Miller independently developed a method for incorporating channels from biological membranes into planar lipid bilayers. With this technique, biological membranes are first homogenized in a laboratory blender; centrifugation of the homogenate then separates out a portion composed only of membrane vesicles. Under appropriate ionic conditions these membrane vesicles will fuse with a planar lipid membrane, incorporating any ion channel in the vesicle into the planar membrane. This technique has two experimental advantages. First, it allows recording from ion channels in regions of cells that are inaccessible to patch clamp; for example, Miller has successfully studied a K+ channel isolated from the internal membrane of skeletal muscle (the sarcoplasmic reticulum). Second, it allows researchers to study how the composition of the membrane lipids influences channel function.

The kinetic properties of ion permeation are best described by the channel's conductance, which is determined by measuring the current (ion flux) that flows through the open channel in response to a given electrochemical driving force. The net electrochemical driving force is determined by two factors: the electrical potential difference across the membrane and the concentration gradient of the permeant ions across the membrane. Changing either one can change the net driving force (see Chapter 7). As we have seen, in some channels the current flow varies linearly with driving force—that is, the channels behave as simple resistors. In others the current flow is a nonlinear function of driving force. This type of channel P.112 behaves as a rectifier—it conducts ions more readily in one direction than in the other. Whereas the conductance (δi/δV) of a resistor-like channel is constant—it is the same at all voltages—the conductance of a rectifying channel is variable and must be determined by plotting current versus voltage over the entire physiological range of membrane potential (Figure 6-4).

Figure 6-4 In many ion channels the relation between current flow through the open channel and membrane voltage is linear. Such channels are said to be “ohmic,” because they follow Ohm's law, i = Vm/R or Vm × γ, where γ is conductance (left plot). In other channels the relation between current and membrane potential is nonlinear (right plot). This kind of channel is said to “rectify,” in the sense that it tends to conduct ions more readily in one direction (here positive current) than in the other.

The rate of ion flux (current) through a channel depends on the concentration of the ions in the surrounding solution. At low concentrations the current increases almost linearly with concentration. At higher concentrations the current tends to reach a point beyond which it no longer increases with concentration. At this point the current is said to saturate. This saturation effect is consistent with the idea that ion permeation does not strictly obey the laws of electrochemical diffusion in free solution but also involves the binding of ions to specific polar sites within the pore of the channel. A simple electrodiffusion model would predict that the ionic current should continue to increase as long as the ionic concentration also increases: the more charge carriers in solution, the greater the current flow. The relation between current and ionic concentration for a wide range of ion channels is well described by a simple one-to-one binding equation, suggesting that a single ion binds to the channel during permeation. The ionic concentration at which current flow reaches half its maximum defines the dissociation constant for ion binding in the channel. The dissociation constant in plots of current vs concentration is typically quite high, around 100 mM, indicating weak binding. (In typical interactions between enzymes and substrates the dissociation constant is below 1 µM.) This weak interaction indicates that the bonds between the ion and the channel are rapidly formed and broken. In fact, an ion typically stays bound in the channel for less than 1 µs. The rapid off-rate for ion binding is necessary for the channel to achieve the very high conduction rates responsible for the rapid changes in membrane potential during signaling. Some ion channels are susceptible to occlusion by various free ions or molecules in the cytoplasm or extracellular fluid. Passage through the channel can be blocked by particles that bind either to the mouth of the aqueous pore or somewhere within the pore. If the blocker is an ionized molecule that binds to a site within the pore, it will be influenced by the membrane electric field as it enters the channel. For example, if a positively charged blocker enters the channel from outside the membrane, then making the inside of the membrane more negative—which, according to convention, corresponds to a more negative membrane potential (see Chapter 7)—will drive the blocker into the channel, increasing the block. While blocking molecules are often toxins or drugs that originate outside the body, some are common ions present in the cell or its environment under normal physiological conditions, such as Mg2+, Ca2+, and Na+, and polyamines such as spermine.

The Opening and Closing of a Channel Involve Conformational Changes In all ion channels so far studied the channel protein has two or more conformational states that are relatively stable. Each of these stable conformations represents a different functional state. For example, each ion channel has at least one open state and one or two closed states. The transition of a channel between these different states is called gating. Relatively little is known about the molecular mechanisms of gating, other than that they involve a temporary change in the channel's structure. Although the picture P.113 of a gate swinging open and shut is a convenient image, it probably is accurate only for certain channels (for example the inactivation of Na+ and K+ channels, which we shall consider in Chapter 9). More commonly, channel gating involves widespread changes in the channel's conformation. For example, evidence from highresolution electron microscopy and image analysis suggests that the opening and closing of gap junction channels (which we consider in Chapter 10) involve a concerted twisting and tilting of the six subunits that make up the channel. Similar evidence indicates that gating of the ACh-gated channels in skeletal muscle is achieved by a coordinated twisting and bending of the α-helices of each of the five subunits that form the channel pore. The molecular rearrangements that occur during P.114 the transition from closed to open states appear to enhance ion conduction through the channel not only by creating a wider lumen, but also by shifting relatively more polar amino acid constituents into the surface that lines the aqueous pore. Three general physical models of channel gating are illustrated in Figure 6-5.

Figure 6-5 Three physical models for the opening and closing of ion channels. A. A localized conformational change occurs in one region of the channel. B. A generalized structural change occurs along the length of the channel. C. A blocking particle swings into and out of the channel mouth.

Figure 6-6 Several types of stimuli control the opening and closing of ion channels. A. Ligand-gated channels open when the ligand binds to its receptor. The energy from ligand binding drives the channel toward an open state. B. Protein phosphorylation and dephosphorylation regulate the opening and closing of some channels. The energy for channel opening comes from the transfer of the high-energy phosphate, Pi. C. Changes in membrane voltage can open and close some channels. The energy for channel gating comes from a change in the electrical potential difference across the membrane, which causes a conformational change by acting on a component of the channel that has a net charge. D. Channels can be activated by stretch or pressure. The energy for gating may come from mechanical forces that are passed to the channel through the cytoskeleton.

Because the primary function of ion channels in neurons is to generate transient electrical signals, three major regulatory mechanisms have evolved to control the amount of time a channel remains open and active (Figure 6-6). Some channels are regulated by chemical ligands. A ligand can bind directly to the channel—either at an extracellular site, in the case of transmitters, or at an intracellular site, in the case of certain cytoplasmic constituents such as Ca2+ and nucleotides. Alternatively, the ligand can activate cellular signaling cascades, which can covalently modify a channel through protein phosphorylation. Other ion channels are regulated by changes in membrane potential. Finally, some channels are regulated by mechanical stretch of the membrane. Under the influence of these regulators, channels enter one of three functional states: closed and activatable (resting), open (active), or closed and nonactivatable (refractory). The rapid gating actions necessary for moment-to-moment signaling may be influenced by certain long-term changes in the metabolic state of the cell. For example, in some voltage-gated K+ channels gating is sensitive to intracellular levels of ATP, while in others the gating properties change in response to the redox state of the cell. For a stimulus to cause a channel to change from the closed to the open state, energy must be supplied. In the case of voltage-gated channels the energy is provided by the movement of a charged region of the channel protein, called the voltage-sensor, through the membrane's electric field. The voltage sensor contains a net electric charge because of the presence of basic (positively charged) or acidic (negatively charged) amino acids. The movement of the charged voltage-sensor through the electric field imparts a net change in free energy to the channel that alters the equilibrium between the closed and open states of the channel. In transmittergated channels, on the other hand, gating is driven by the change in chemical free energy that results when the transmitter binds to the receptor site on the channel. For mechanically activated channels the energy associated with membrane stretch is thought to be transferred to the channel either through the cytoskeleton or more directly by changes in tension of the lipid bilayer. The signals that gate the channel also control the rate of transition between the open and closed states of a P.115 channel. For voltage-gated channels the rates are steeply dependent on membrane potential. Although the time scale can vary from several microseconds to a minute, the transition tends to require a few milliseconds on average. Thus, once a channel opens it stays open for a few milliseconds before closing, and after closing it stays closed for a few milliseconds before reopening. Once the transition between open and closed states begins, it proceeds virtually instantaneously (in less than 10 µs, the present limit of experimental measurements), thus giving rise to abrupt, all-or-none step-like changes in current through the channel.

Figure 6-7 Three mechanisms by which voltage-gated channels become closed and nonactivatable (the refractory state). A. Many voltage-gated channels enter a refractory (inactivated) state after the transition from the resting (closed) state to a transient open state upon membrane depolarization. They recover from the refractory state and return to the resting state only after the membrane potential is restored to its original value. B. When voltage-dependent Ca2+ channels are opened in response to depolarization, the internal Ca2+ level rises. The internal Ca2+ may then inactivate the channel by binding to a specific recognition site. C. An increase in internal Ca2+ concentration in voltage-gated Ca2+ channels may produce inactivation through dephosphorylation of the channel. At pathologically high concentrations, Ca2+ may even produce an irreversible inactivation of the channel owing to the recruitment of protein-splitting enzymes activated by the Ca2+ ions.

Transmitter-gated and voltage-gated channels enter refractory states through different processes. Ligand-gated channels can enter the refractory state when their exposure to the ligand is prolonged. This process, called desensitization, is discussed in Chapter 13. The mechanisms underlying desensitization of ion channels are not yet completely understood. In some channels desensitization appears to be an intrinsic property of the interaction between ligand and channel, while in others it is due to phosphorylation of the channel molecule by a protein kinase. Many, but not all, voltage-gated channels can enter a refractory state after activation. This process is termed inactivation. In voltage-gated Na+ and K+ channels inactivation is thought to result from an intrinsic conformational change, controlled by a subunit or region of the channel separate from that which controls activation. (Applying certain proteolytic enzymes within the cell eliminates the ability of voltage-gated Na+ channels to become inactivated without affecting the channel's ability to be activated.) In contrast, the inactivation of certain voltage-gated Ca2+ channels is thought to require Ca2+ influx. An increase in internal Ca2+ concentration inactivates the Ca2+ channel either directly, by binding to a control site on the inside of the channel, or indirectly, by activating an intracellular enzyme that inactivates the channel by protein dephosphorylation (Figure 6-7). Exogenous factors, such as drugs and toxins, can affect the gating control sites of an ion channel. Most of these agents tend to close the channel; a few open it. Some compounds bind to the same site at which the endogenous gating ligand normally binds and thereby prevent the activator from exerting its usual effect. This binding can be weak and reversible, as in the blockade of the nicotinic ACh-gated channel in skeletal muscle by curare, a South American arrow poison (see Chapter 11). Or it can be strong and not reversible, as in the blockade of the same channel by the snake venom α-bungarotoxin. Other exogenous substances act in a noncompetitive manner and affect the normal gating mechanism without directly interacting with a ligand-binding site. P.116 For example, binding of the drug valium to a regulatory site on GABA-gated Cl- channels prolongs the opening of the channels in response to GABA. This type of indirect effect works not only on ligand-gating, but also on gating controlled by voltage or stretch (Figure 6-8).

Figure 6-8 The binding of exogenous ligands, such as drugs, can make an ion channel favor either an open or a closed state through a variety of mechanisms. A. In channels that are normally opened by the binding of an endogenous ligand (A1, A2), a drug or toxin may block the binding of the activator by means of either a reversible (A3) or an irreversible (A4) reaction. B. Some exogenous regulators can make a channel favor the open state by binding to a regulatory site, distinct from the endogenous site that normally opens the channel.

Figure 6-9 Ion channels are composed of several subunits. A. Ion channels can be constructed as heterooligomers from distinct subunits (left), as homooligomers from a single type of subunit (middle), or from a single polypeptide chain organized into repeating motifs, where each motif functions as the equivalent of one subunit (right). B. In addition to one or more pore-forming α subunits, which comprise a central core, some channels contain auxiliary subunits (β or δ), which modulate the inherent gating characteristics of the central core.

The Structure of Ion Channels Is Inferred From Biophysical, Biochemical, and Molecular Biological Studies What do ion channels look like? How does the channel protein span the membrane? What happens to the structure of the channel when it opens and closes? Where along the length of the channel do drugs and transmitters bind? Biochemical and molecular biological approaches have resulted in considerable progress toward an understanding of channel structure and function. All ion channels have a basic glycoprotein component consisting of a large integral-membrane protein with carbohydrate groups attached to its surface. A central aqueous pore through the middle of the protein spans the entire width of the membrane. The pore-forming region of many channels is made up of two or more subunits, which may be identical or different (Figure 6-9). In addition, some channels have auxiliary subunits that modify their functional properties. These subunits may be cytoplasmic or embedded in the membrane. The genes for most of the major classes of ion channels have now been cloned and sequenced. The primary amino acid sequence of the channel, inferred from its DNA sequence, has been used to create models of the structure of different channel proteins. These models rely on computer programs to predict regions of secondary structure, such as the arrangement of the amino acid residues into α-helices and β-sheets that are likely to correspond to membrane-spanning domains of the channel (Figure 6-10). The predictions, in turn, are based on existing information from proteins whose actual structure is known from electron and x-ray diffraction analysis. The first membrane protein whose structure was well understood is bacteriorhodopsin, a photopigment in the cell membrane of Halobacterium. (Photopigment converts sunlight into electrochemical energy.) Bacteriorhodopsin contains regions with charged (hydrophilic) amino acids and other regions with uncharged (hydrophobic) amino acids. There are, in all, seven hydrophobic regions. Each of these is about 15-20 amino acids long and spans the membrane in the form of αhelices. These membrane-spanning regions are in turn P.117 linked by six hydrophilic loops—three that extend outside the cell and three within it.

Figure 6-10 Secondary structure of membrane-spanning proteins. A. A proposed secondary structure for a subunit of the nicotinic ACh-gated receptor channel. Each cylinder represents a putative membrane-spanning α-helix containing around 20 hydrophobic amino acid residues. The membrane segments are connected by cytoplasmic or extracellular segments (loops) of hydrophilic residues. B. The membrane-spanning regions of an ion channel can be identified using a hydrophobicity plot. Here a running average of the hydrophobicity is plotted for the entire amino acid sequence for the α subunit of the nicotinic ACh receptor. Each point in the plot represents the average hydrophobic index of a 19-amino acid-long window plotted at the amino acid residue position corresponding to the midpoint of the window. This plot is based on the inferred amino acid sequence obtained from the nucleotide sequence of the cloned ACh receptor. Four of the hydrophobic regions (M1-M4) correspond to the membrane-spanning segments. The first hydrophobic region is the signal sequence that is required during protein synthesis to position the hydrophilic amino terminus of the protein on the extracellular surface of the cell. The signal sequence is cleaved from the mature protein. (From Schofield et al. 1987.)

Additional insights into channel structure and function have been obtained by comparing the primary amino acid sequences of the same type of channel from different species. Regions that show a high degree of similarity (ie, have been highly conserved through evolution) are likely to be important in maintaining the effective structure and function of the channel. Likewise, conserved regions in different, but related, channels are likely to serve a common biophysical function in different channels. For example, all voltage-gated channels have a specific membrane-spanning domain that contains positively charged amino acids (lysine or arginine) spaced at every third position along an α-helix. This motif is observed in all voltage-gated channels, but not in transmitter-gated channels, suggesting that this charged region is important for voltage gating (see Chapter 9). Once a structure for a channel has been proposed, it can be tested in several ways. For example, antibodies can be raised against synthetic peptides that correspond to different hydrophilic regions in the protein sequence. Immunocytochemistry can then be used to determine whether the antibody binds to the extracellular or cytoplasmic surface of the membrane, thus defining whether a particular region of the channel is extracellular or intracellular. The functional consequences of changes in a channel's primary amino acid sequence can be explored through a variety of techniques. One particularly versatile approach is to use genetic engineering to construct channels in which various parts are derived from the genes of different species—so-called chimeric channels. This technique takes advantage of the fact that channels in different species have somewhat different properties. For example, the bovine ACh-gated receptor-channel has a slightly greater single-channel conductance than the same channel in electric fish. By comparing the properties of a chimeric channel to those of the two original channels, we can assess which regions of the channel are involved in which functions. This technique has been used to identify a specific membrane-spanning segment of the ACh-gated channel as the region that forms the lining of the pore (see Chapter 11). The roles of different amino acid residues or stretches of residues can be tested using site-directed mutagenesis, a type of genetic engineering in which P.118 specific amino acid residues are substituted or deleted. Finally, one can exploit the naturally occurring mutations in channel genes that underlie neurological diseases. Changes in functional phenotype are known to result from a number of spontaneously arising mutations in the genes that encode ion channels in nerve or muscle. Many of these effects have been localized to changes in single amino acids within channel proteins.

Figure 6-11 Three families of ion channels. A. Certain ligand-gated channels, including the nicotinic acetylcholine (ACh) receptor-channel, have five subunits, and each subunit consists of four transmembrane regions (M1-M4). Each cylinder represents a single transmembrane α-helix. A three-dimensional model of the channel is shown on the right. B. The gap-junction channel, found at electrical synapses, is formed from a pair of hemichannels in the pre- and postsynaptic membranes that join in the space between two cells. Each hemichannel is made of six subunits, each with four transmembrane regions. A three-dimensional model of the two apposite hemichannels is illustrated on the right. C. The voltage-gated Na+ channel is formed from a single (α) polypeptide chain that contains four homologous domains or repeats (motifs I-IV), each with six αhelical membrane-spanning regions (S1 to S6) and one P region thought to line the pore. The figure at the right shows a hypothetical model of the channel.

Ion Channels Can Be Grouped Into Gene Families Most of the ion channels that have been described in nerve and muscle cells fall into a few gene families (Figure 6-11). Members of each gene family have similar amino acid sequences and transmembrane topology. Each family is thought to have evolved from a common ancestral gene by gene duplication and divergence. Genes that encode ligand-gated ion channels that are activated by acetylcholine, γ-aminobutyric acid (GABA), and glycine belong to one family. Each of these channels is composed of five closely related subunits. Each subunit has four transmembrane α-helixes (M1-M4). The members of the ligand-gated channel family can differ from each other in their ion selectivity in addition to their ligand specificity. The genes that encode the glutamate-activated channels may form a family distinct from other ligand-gated channels (see Chapter 12) The genes coding for gap junction channels belong to a separate family. Each gap junction channel is composed of 12 identical subunits, each of which has four P.119 membrane-spanning segments. These specialized channels bridge the cytoplasm of two cells at electrical synapses (see Chapter 10).

Figure 6-12 Three related families of K+-selective ion channels. A. Voltage-gated K+ channels are composed of four polypeptide subunits. Each subunit corresponds to one repeated domain of a voltage-gated Na+ or Ca2+ channel, with six transmembrane segments and a loop through the extracellular, face of the membrane (the so-called P region). B. Inward-rectifier K+ channels are composed of four polypeptide subunits. Each subunit has only two transmembrane segments, connected by a P-region loop. C. A third family of K+ channels has a characteristic subunit structure corresponding to two repeats of the inward-rectifier K+ channel architecture, with two Pregions in tandem. The subunit composition of these channels is not known.

The genes that encode the voltage-gated ion channels responsible for generating the action potential all belong to a third family. These channels are activated by depolarization and are selective for Ca2+, Na+, or K+. All voltage-gated channels have a similar architecture. They contain four repeats of a basic motif composed of six transmembrane segments (S1-S6). The S5 and S6 segments are connected by a loop, through the extracellular face of the membrane, the P-region, that forms the selectivity filter of the channel. A single subunit of voltage-gated Na+ and Ca2+ channels contains four of these repeats. Potassium channels are composed of four separate subunits, each containing one repeat. The major gene family encoding the voltage-gated K+ channels is more distantly related to two other families of K+-selective channels with distinctive properties and structure (Figure 6-12). One family consists of the genes encoding inward rectifying K+ channels, which are activated by hyperpolarization. Each channel subunit has only two transmembrane segments, connected by a pore-forming P-region. A second family of K+-selective channels is composed of subunits with two repeated poreforming segments. These channels may also contribute to the resting K+ conductance. The fast pace of molecular biological research is rapidly leading to the identification of additional ion channel gene families. These include Cl- channels important for determining the resting potential of certain nerve and skeletal muscle cells and a class of ligand-gated channels activated by ATP, which functions as a neurotransmitter at certain synapses. As the genes for additional ion channels are sequenced, more channel families will likely be revealed. Since most channels are made up of multiple subunits that can be combined in different permutations to produce channel with different functional properties, the number of different channel types is enormous. P.120 More than a dozen basic types of channels are known to exist in neurons, and each type includes several closely related forms (isoforms) that differ in their rate of opening or closing and their sensitivity to different activators. This variability is produced either by differential expression of two or more closely related genes, by alternative splicing of mRNA transcribed from the same gene, or by editing of mRNA. As with enzyme isoforms, variants of a channel type are differentially expressed at specific developmental stages (Figure 6-13), in different cell types throughout the brain (Figure 6-14), and even in different regions within a cell. These subtle variations in structure and function presumably allow channels to perform highly specific functions The complexity of ion channels in a multicellular organism is underscored by the recent sequencing of the entire genome of the nematode Caenorhabditis elegans. The genome contains five genes for voltage-gated Ca+ channels, over 60 genes for K+-selective channels, 90 genes for ligand-gated channels, and six genes for Cl-selective channels. C. elegans has no voltage-gated Na+ channels. The rich variety of ion channels in different types of cells may make it possible to develop drugs that can activate or block channels in selected regions of the nervous system. Such drugs would, in principle, have maximum therapeutic effectiveness with a minimum of side effects.

The Structure of a Potassium-Selective Ion Channel Has Been Solved by X-ray Crystallography Rod MacKinnon and his colleagues have recently provided the first high-resolution X-ray crystallographic analysis of the molecular architecture of an ion-selective channel. To overcome the difficulties inherent in obtaining crystals of integral membrane proteins, they used a bacterial K+ channel that is a member of the inwardrectifier type of K+ channels that are also present in higher organisms, including mammals. These channels have the advantage of having a relatively small size and a simple transmembrane topology (see Figure 6-12). The structure of the channel was further simplified using molecular engineering to truncate cytoplasmic regions

that are not essential for forming the ion-selective pore. The crystal structure determined from the resulting protein provides several important insights into the mechanisms by which the channel facilitates selectively the movement of K+ ions across the hydrophobic lipid bilayer. The channel is made up of four identical subunits arranged symmetrically around a central pore (Figure 615). Each subunit contributes two membrane-spanning α-helices that are connected by a loop, the P region, that forms the selectivity filter of the channel. P.121 The two α-helices are tilted away from the central axis of the pore at the extracellular side of the channel. The resulting structure has the appearance of an inverted teepee.

Figure 6-13 The functional properties of ion channels can change over the course of development. These examples of conductance in individual acetylcholine-activated channels were recorded from frog skeletal muscle at three stages of development: early (1.1 days), intermediate (2.4 days), and late (48 days). In immature muscle the single channels have a small conductance and a relatively long open time. In mature muscle the channel conductance is larger, and the average open time is shorter. At intermediate stages of development the population of channel variants is mixed; both long and short openings and both large and small classes of conductance are evident. (From Owens and Kullberg 1989.)

Figure 6-14 Variants of the voltage-gated potassium channel in the rat are expressed in different regions of the brain. When one of the genes (KShIII) that encodes voltage-gated K+ channels in the rat is transcribed, the pre-RNA molecule is alternatively spliced in four different versions. The four transcripts vary widely in their distributions throughout the nervous system (A-D), thereby contributing to the regional specialization of neuronal function. Each panel shows the expression pattern for one transcript. Dark areas of these autoradiograms represent high densities of the corresponding mRNA transcript. The brain was sectioned at the level of the posterior thalamus. Thalamic nuclei: VPL, ventral posterior lateral; VPM, ventral posterior medial; MD, medial dorsal; LD, lateral dorsal; VM, ventromedial; PO, posterior; RT, reticular. Hippocampal regions CA1, CA2, CA3; DG, dentate gyrus; ZI, zona incerta.

The four inner α-helices from each of the subunits line the region of the pore on the cytoplasmic end. At the extracellular end of the channel the two helices from each subunit are connected by a region consisting of three elements: (1) a chain of amino acids that surrounds the mouth of the channel (the turret region); (2) an abbreviated α-helix (the pore helix) about 10 amino acids in length that projects into the membrane around the wall of the pore between the inner membranespanning helices; and (3) a 10-amino acid chain that forms a loop that lines the selectivity filter (Figure 6-15A, B). The shape and structure of the pore determine its ion-conducting properties. Both the inner and outer mouths of the pore are lined by acidic amino acids, whose negative charge helps to attract selectively cations from the bulk solution. Going from inside to outside, the pore consists of a medium width, 18 Å-long tunnel, which leads into a wider (10 Å diameter) spherical inner chamber, both of which are lined predominantly by the side chains of hydrophobic amino acids. A high throughput rate is insured by the fact that the inner 28 Å of the channel lacks polar groups that could delay ion passage by binding and unbinding reactions with the channel wall. These relatively wide regions are followed by the very narrow selectivity filter, which is rate-limiting for the passage of ions and only 12 Å in length. As an ion passes from the polar bulk solution into a nonpolar medium like the lipid bilayer, the energetically most unfavorable region is in the middle of the bilayer. This high energetic cost is minimized by two details of channel structure: the enlarged, water filled inner chamber provides a highly polar environment, which is enhanced by the fact that the pore helices provide a dipole whose electronegative carboxyl end is pointing towards this inner chamber (Figure 6-15C, D). The selectivity filter is lined by three main-chain carbonyl atoms of the protein backbone of each of the four subunits. The negative polarization of these 12 carbonyl groups provides a highly polar environment for the K+ ions as they traverse the channel. The amino acid side groups of the selectivity filter, which are directed away from the central axis of the channel, help to stabilize the filter at a critical width, such that it provides optimal electrostatic interactions with K+ ions as they pass, but is too wide for smaller Na+ ions to interact effectively with all four carbonyl oxygens at any point along the length of the filter (Figure 6-15C). X-ray analysis also shows that the channel is occupied P.122 P.123 by three K+ ions. One K+ ion is found in the wide, inner chamber. Up to two K+ ions can occupy the selectivity filter at any one time (Figure 6-15D). If only one K+ ion were in the channel the ion would be bound rather tightly, and the throughput rate for ion permeation would be compromised. But the mutual electrostatic repulsion that occurs when two K+ ions occupy the two nearby sites insures that they can linger only briefly, thus ensuring a high overall K+ conductance.

Figure 6-15 The X-ray crystal structure of a bacterial member of the inward rectifying K+ channel family. (From Doyle et al., 1998) A. A view looking down at the channel from the outside of the membrane. Each of the four subunits contributes two long membrane spanning helixes (in blue and red). The P-region is shown in white. It consists of a short α-helix (pore helix) and a loop that forms the selectivity filter of the channel. A K+ ion is shown in the middle of the pore. B. A view of the channel in cross section in the plane of the membrane. The four subunits are shown, with each subunit in a different color. The membrane-spanning helixes are arranged as an inverted teepee. C. Another view in the same orientation as B, showing only two of the four subunits. The selectivity filter (red region) is formed by three carbonyl oxygen atoms from the main chain backbone of three amino acid residues—glycine (G), tyrosine (Y), and glycine (G). Other residues important for binding of channel-blocking toxins and drugs are labeled in white. D. A side-view of the channel illustrating three K+ sites within the channel. The pore helixes contribute a negative dipole that helps stabilize the K+ ion in the waterfilled inner chamber. The two outer K+ ions are loosely bound to the selectivity filter formed by the P-region.

Thus we see that channels have developed multiple strategies for achieving both high selectivity and high throughput. Based on the homology of the bacterial K+ channel pore with the pore in channels of higher organisms, we also find that this strategy has been conserved from prokaryotes through humans.

An Overall View Ion channels regulate the flow of ions across the membrane in all cells. In nerve and muscle cells they are important for controlling the rapid changes in membrane potential associated with the action potential and with the postsynaptic potentials of target cells. In addition, the influx of Ca2+ ions controlled by these channels can alter many metabolic processes within cells, leading to the activation of various enzymes and other proteins, as well as release of neurotransmitter (see Chapter 15). Channels differ from one another in their ion selectivity and in the factors that control their opening and closing, or gating. Ion selectivity is achieved through physicalchemical interaction between the ion and various amino acid residues that line the walls of the channel pore. Gating involves a change of the channel's conformation in response to an external stimulus, such as voltage, a ligand, or stretch or pressure. Three methodological advances have greatly increased our understanding of channel function. First, the patch-clamp technique has made it possible to record the current flow through single open channels. Second, gene cloning and sequencing have determined the primary amino acid sequences of many genes that encode ion channels. From these results, many of the channels described so far can be grouped into three major gene families: voltage-gated channels and their related subfamilies, a large family of ligand-gated channels, and gap-junction channels. Finally, X-ray crystallography has provided a detailed view of the three-dimensional structure of one simple type of K+- selective channel. The activity of channels can be modified by cellular metabolic reactions, including protein phosphorylation; by various ions that act as blockers; and by toxins, poisons, and drugs. Channels are also important targets in various diseases. Certain autoimmune neurological disorders, such as myasthenia gravis, result from the actions of specific antibodies that interfere with channel function (see Chapter 16). Other diseases, such as hyperkalemic periodic paralysis, involve ion channel defects resulting from genetic mutations. Detailed knowledge of the genetic basis of channel structure and function may one day make it possible to devise new pharmacological therapies for specific neurological and psychiatric disorders.

Selected Readings Andersen OS, Koeppe RE II. 1992. Molecular determinants of channel function. Physiol Rev 72:S89-S158.

Catterall WA. 1993. Structure and function of voltage-gated ion channels. Trends Neurosci 16:500–506.

Eisenberg RS. 1990. Channels as enzymes. J Membr Biol 115:1–12.

Hille B. 1992. Ionic Channels of Excitable Membranes, 2nd ed. Sunderland, MA: Sinauer.

Miller C. 1987. How ion channel proteins work. In: LK Kaczmarek, IB Levitan (eds). Neuromodulation: The Biological Control of Neuronal Excitability, pp. 39-63. New York: Oxford Univ. Press.

References Alberts B, Bray D, Lewis J, Raff M, Roberts K, Watson JD. 1994. Molecular Biology of the Cell, 3rd ed. New York: Garland.

Anderson CR, Stevens CF. 1973. Voltage clamp analysis of acetylcholine produced end-plate current fluctuations at frog neuromuscular junction. J Physiol (Lond) 235: 655–691.

Armstrong CM. 1981. Sodium channels and gating currents. Physiol Rev 61:644–683.

Armstrong DL. 1989. Calcium channel regulation by calcineurin, a Ca2+-activated phosphatase in mammalian brain. Trends Neurosci 12:117–122.

Bargmann, CI. 1998. Neurobiology of the Caenorhabditis elegans genome. Science 282:2028–2033.

Bayliss WM. 1918. Principles of General Physiology, 2nd ed., rev. New York: Longmans, Greene.

Brücke E. 1843. Beiträge zur Lehre von der Diffusion tropfbarflüssiger Korper durch poröse Scheidenwände. Ann Phys Chem 58:77–94. P.124

Doyle DA, Cabral JM, Pfuetzner RA, Kuo A, Gulbis JM, Cohen SL, Chait BT, MacKinnon R. 1998. The structure of the potassium channel: molecular basis of K+ conduction and selectivity. Science 280:69–77.

Eisenman G. 1962. Cation selective glass electrodes and their mode of operation. Biophys J 2(Suppl 2):259–323.

Frech GC, VanDongen AM, Schuster G, Brown AM, Joho RH. 1989. A novel potassium channel with delayed rectifier properties isolated from rat brain by expression cloning. Nature 340:642–645.

Guharay F, Sachs F. 1984. Stretch-activated single ion channel currents in tissue-cultured embryonic chick skeletal muscle. J Physiol (Lond) 352:685–701.

Hamill OP, Marty A, Neher E, Sakmann B, Sigworth FJ. 1981. Improved patch-clamp techniques for high-resolution current recording from cells and cell-free membrane patches. Pflügers Arch 391:85–100.

Henderson R, Unwin PNT. 1975. Three-dimensional model of purple membrane obtained by electron microscopy. Nature 257:28–32.

Hladky SB, Haydon DA. 1970. Discreteness of conductance change in bimolecular lipid membranes in the presence of certain antibiotics. Nature 225:451–453.

Horn R, Patlak J. 1980. Single channel currents from excised patches of muscle membrane. Proc Natl Acad Sci U S A 77:6930–6934.

Huang K-S, Radhakrishnan R, Bayley H, Khorana HG. 1982. Orientation of retinal in bacteriorhodopsin as studied by cross-linking using a photosensitive analog of retinal. J Biol Chem 257:13616–13623.

Imoto K, Methfessel C, Sakmann B, Mishina M, Mori Y, Konno T, Fukuda K, Kurasaki M, Bujo H, Fujita Y, Numa S. 1986. Location of a δ-subunit region determining ion transport through the acetylcholine receptor channel. Nature 324:670–674.

Katz B, Miledi R. 1970. Membrane noise produced by acetylcholine. Nature 226:962–963.

Katz B, Thesleff S. 1957. A study of the ‘desensitization’ produced by acetylcholine at the motor end-plate. J Physiol (Lond) 138:63–80.

Kyte J, Doolittle RF. 1982. A simple method for displaying the hydropathic character of a protein. J Mol Biol 157:105–132.

MacKinnon R. 1995. Pore loops: an emerging theme in ion channel structure. Neuron 14:889–892.

Miller C (ed). 1986. Ion Channel Reconstitution. New York: Plenum.

Mueller P, Rudin DO, Tien HT, Wescott WC. 1962. Reconstitution of cell membrane structure in vitro and its transformation into an excitable system. Nature 194:979–980.

Mullins LJ. 1961. The macromolecular properties of excitable membrane. Ann NY Acad Sci 94:390–404.

Neher E, Sakmann B. 1976. Single-channel currents recorded from membrane of denervated frog muscle fibres. Nature 260:799–802.

Noda M, Takahashi H, Tanabe T, Toyosato M, Kikyotani S, Furutani Y, Hirose T, Takashima H, Inayama S, Miyata T, Numa S. 1983. Structural homology of Torpedo californica acetylcholine receptor subunits. Nature 302:528–532.

Owens JL, Kullberg R. 1989. In vivo development of nicotinic acetylcholine receptor channels in Xenopus myotomal muscle. J Neurosci 9:1018–1028.

Sawyer DB, Koeppe RE II, Andersen OS. 1989. Induction of conductance heterogeneity in gramicidin channels. Biochemistry 28:6571–6583.

Schofield PR, Darlison MG, Fujita N, Burt DR, Stephenson FA, Rodriguez H, Rhee LM, Ramachandran J, Reale V, Glencorse TA, Seeburg PH, Barnard EA. 1987. Sequence and functional expression of the GABAA receptor shows a ligand-gated receptor super-family. Nature 328:221–227.

Tempel BL, Papazian DM, Schwarz TL, Jan YN, Jan LY. 1987. Sequence of a probable potassium channel component encoded at Shaker locus of Drosophila. Science 237:770–775.

Urry DW. 1971. The gramicidin A transmembrane channel: a proposed (L, D) helix. Proc Natl Acad Sci U S A 68:672–676.

Weiser M, Vega-Saenz de Miera E, Kentros C, Moreno H, Franzen L, Hillman D, Baker H, Rudy B. 1994. Differential expression of Shaw-related K+ channels in the rat central nervous system. J Neurosci 14:949–972.

Back

7 Membrane Potential John Koester Steven A. Siegelbaum INFORMATION IS CARRIED WITHIN and between neurons by electrical and chemical signals. Transient electrical signals are particularly important for carrying time-sensitive information rapidly and over long distances. These electrical signals—receptor potentials, synaptic potentials, and action potentials—are all produced by temporary changes in the current flow into and out of the cell that drive the electrical potential across the cell membrane away from its resting value. This current flow is controlled by ion channels in the cell membrane. We can distinguish two types of ion channels—resting and gated—by their distinctive roles in neuronal signaling. Resting channels normally are open and are not influenced significantly by extrinsic factors, such as the potential across the membrane. They are primarily important in maintaining the resting membrane potential, the electrical potential across the membrane in the absence of signaling. Most gated channels, in contrast, are closed when the membrane is at rest. Their probability of opening is regulated by the three factors we considered in the last chapter: changes in membrane potential, ligand binding, or membrane stretch. In this and succeeding chapters we consider how transient electrical signals are generated in the neuron. We begin by discussing how resting ion channels establish and maintain the resting potential. We also briefly describe the mechanism by which the resting potential can be perturbed, giving rise to transient electrical signals such as the action potential. In Chapter 8 we shall consider how the passive properties of neurons—their resistive and capacitive characteristics—contribute to local signaling within the neuron. In Chapter 9 we shall examine how voltage-gated Na+, K+, and Ca2+ channels generate the action potential, the electrical signal conveyed along the axon. Synaptic and receptor potentials are considered in Chapters 10,11,12,13 in the context of synaptic signaling between neurons. P.126

The Resting Membrane Potential Results From the Separation of Charges Across the Cell Membrane Every neuron has a separation of charges across its cell membrane consisting of a thin cloud of positive and negative ions spread over the inner and outer surfaces of the cell membrane (Figure 7-1). At rest a nerve cell has an excess of positive charges on the outside of the membrane and an excess of negative charges on the inside. This separation of charge is maintained because the lipid bilayer of the membrane blocks the diffusion of ions, as explained in Chapter 6. The charge separation gives rise to a difference of electrical potential, or voltage, across the membrane called the membrane potential. The membrane potential (Vm) is defined as

where Vin is the potential on the inside of the cell and Vout the potential on the outside. The membrane potential of a cell at rest is called the resting membrane potential. Since, by convention, the potential outside the cell is defined as zero, the resting potential (Vr) is equal to Vin. Its usual range in neurons is -60 mV to -70 mV. All electrical signaling involves brief changes from the resting membrane potential due to alterations in the flow of electrical current across the cell membrane resulting from the opening and closing of ion channels. The electric current that flows into and out of the cell is carried by ions, both positively charged (cations) and negatively charged (anions). The direction of current flow is conventionally defined as the direction of net movement of positive charge. Thus, in an ionic solution cations move in the direction of the electric current, anions in the opposite direction. Whenever there is a net flow of cations or anions into or out of the cell, the charge separation across the resting membrane is disturbed, altering the polarization of the membrane. A reduction of charge separation, leading to a less negative membrane potential, is called depolarization. An increase in charge separation, leading to a more negative membrane potential, is called hyperpolarization. Changes in membrane potential that do not lead to the opening of gated ion channels, are called electrotonic potentials and are said to be passive responsives of the membrane. Hyperpolarizing responses are almost always passive, as are small depolarizations. However, when depolarization approaches a critical level, called the threshold, the cell responds actively with the opening of voltage-gated ion channels, which at threshold produces an all-or-none action potential (Box 7-1).

Figure 7-1 The membrane potential results from a separation of positive and negative charges across the cell membrane. The excess of positive charges (red circles) outside the membrane and negative charges (blue circles) inside the membrane of a nerve cell at rest represents a small fraction of the total number of ions inside and outside cell.

We begin examining the membrane potential by analyzing how the passive flux of individual ion species through resting channels generates the resting potential. We shall then be able to understand how the selective gating of different types of ion channels generates the action potential, as well as the receptor and synaptic potentials.

The Resting Membrane Potential Is Determined by Resting Ion Channels No single ion species is distributed equally on the two sides of a nerve cell membrane. Of the four most abundant ions found on either side of the cell membrane, Na+ and Cl- are more concentrated outside the cell, and K+ and organic anions (A-) are more concentrated inside. The organic anions are primarily amino acids and proteins. Table 7-1 shows the distribution of these ions inside and outside one particularly well-studied nerve cell process, the giant axon of the squid, whose blood has a salt concentration similar to sea water. Although the absolute values of the ionic concentrations for vertebrate nerve cells are two- to threefold lower than those for the squid giant axon, the concentration gradients (the ratio of the external ion concentration to internal ion concentration) are about the same. The unequal distribution of ions raises several important questions. How do ionic gradients contribute to the resting membrane potential? How are they maintained? What prevents the ionic gradients from dissipating by diffusion of ions across the membrane through P.127 P.128 the passive (resting) channels? These questions are interrelated, and we shall answer them by considering two examples of membrane permeability: the resting membrane of glial cells, which is permeable to only one species of ions, and the resting membrane of nerve cells, which is permeable to three. For the purposes of this discussion we shall consider only the resting ion channels, which are always open.

Box 7-1 Recording the Membrane Potential Reliable techniques for recording the electrical potential across cell membranes were developed in the late 1940s. These techniques allow accurate recordings of both the resting and the action potentials and make use of glass micropipettes filled with a concentrated salt solution that serve as electrodes. These microelectrodes are placed on either side of the cell membrane. Wires inserted into the back ends of the pipettes are connected via an amplifier to an oscilloscope, which displays the amplitude of the membrane potential in volts. Because the tip diameter of a microelectrode is very small (>PCl or PNa, as in glial cells, the equation becomes

Alan Hodgkin and Bernard Katz used the Goldman equation to analyze changes in membrane potential. They first measured the variation in membrane potential of a squid giant axon while systematically changing the extracellular concentrations of Na+, Cl-, and K+. They found that if Vm is measured shortly after the extracellular concentration is changed (before the internal ionic concentrations are altered), [K+]o has a strong effect on the resting potential, [Cl-]o has a moderate effect, and [Na+]o has little effect. The data for the membrane at rest could be fit accurately by the Goldman equation using the following permeability ratios:

At the peak of the action potential, however, the variation of Vm with external ionic concentrations was fit best if a quite different set of permeability ratios were assumed:1

Figure 7-5 Electrical properties of a single K+ channel. A. A single K+ channel can be represented as a conductor or resistor (conductance, γ, is the inverse of resistance, r). B. The current-voltage relation for a single K+ channel in the absence of a concentration gradient. The slope of the relation is equal to γK.

Figure 7-6 Chemical and electrical forces contribute to current flow. A. A concentration gradient for K+ gives rise to an electromotive force, with a value equal to the K+ Nernst potential. This can be represented by a battery, EK. In this circuit the battery is in series with a conductor, γK, representing the conductance of a channel that is selectively permeable to K+ ions. B. The current-voltage relation for a K+ channel in the presence of both electrical and chemical driving forces. The potential at which the current is zero is equal to the K+ Nernst potential.

For these values of permeabilities the Goldman equation approaches the Nernst equation for Na+:

Thus at the peak of the action potential, when the membrane is much more permeable to Na+ than to any other ion, Vm approaches ENa, the Nernst potential for Na+. P.134 However, the finite permeability of the membrane to K+ and Cl- results in K+ efflux and Cl- influx that oppose Na+ influx, thereby preventing Vm from quite reaching ENa.

Figure 7-7 All of the passive K+ channels in a nerve cell membrane can be lumped into a single equivalent electrical structure comprising a battery (EK) in series with a conductor (gK). The conductance is gK = NK × γK, where N K is the number of passive K+ channels and γ K is the conductance of a single K+ channel.

The Functional Properties of the Neuron Can Be Represented in an Electrical Equivalent Circuit The Goldman equation is limited because it cannot be used to determine how rapidly the membrane potential changes in response to a change in permeability. Moreover, it is inconvenient for determining the magnitude of the individual Na+, K+, and Cl- currents. This information can be obtained with a simple mathematical model derived from electrical circuits. Within this model, called an equivalent circuit, all of the important functional properties of the neuron are represented by an electrical circuit consisting only of conductors or resistors (representing the ion channels), batteries (representing the concentration gradients of relevant ions), and capacitors (the ability of the membrane to store charge). Equivalent circuits provide us with an intuitive understanding as well as a quantitative description of how current flow due to the movement of ions generates signals in nerve cells. The first step in developing a circuit is to relate the membrane's discrete physical properties to its electrical properties. (A review of elementary circuit theory in Appendix A may be helpful before proceeding to the discussion that follows.)

Each Ion Channel Acts as a Conductor and Battery in Parallel As described in Chapter 6, the lipid bilayer of the membrane is a poor conductor of ionic current because it is not permeable to ions. Even a large potential difference will produce practically no current flow across a pure lipid bilayer. Consider the cell body of a typical spinal motor neuron, which has a membrane area of about 10-4 cm2. If the membrane were composed solely of lipid bilayer, its electrical conductance would be only about 1 pS. In reality, however, the membrane contains thousands of resting ion channels through which ions constantly diffuse, so that the actual conductance of the membrane at rest is about 40,000 pS or 40 × 10-9 S, ie, 40,000 times greater than it would be if no ion channels were present. In an equivalent circuit each K+ channel can be represented as a resistor or conductor of ionic current with a single-channel conductance of γK (remember, conductance = 1/resistance) (Figure 7-5). If there were no K+ concentration gradient, the current through the K+ channel would be given by Ohm's law: iK = γK × Vm. Since there is normally a K+ concentration gradient, there will be a chemical force driving K+ across the membrane. In the equivalent circuit this chemical force is represented by a battery, whose electromotive force is given by the Nernst potential for K+, EK (Figure 7-6). (A source of electrical potential is called an electromotive force and an electromotive force generated by a difference in chemical potentials is called a battery.)

Figure 7-8 Each population of ion channels selective for Na+, K+, or Cl- can be represented by a battery in series with a conductor. Note the directions of poles of batteries, indicating a negative electromotive force for K+ and Cl- and a positive one for Na+.

Figure 7-9 The passive current flow in a neuron can be modeled using an electrical equivalent circuit. The circuit includes elements representing the ion-selective membrane channels and the short-circuit pathways provided by the cytoplasm and extracellular fluid.

P.135 In the absence of voltage across the membrane the normal K+ concentration gradient will cause an outward K+ current flow. According to our conventions for electrical current flow an outward movement of positive charge corresponds to a positive electric current. From the Nernst equation, we also saw that when the concentration gradient for a positively charged ion, such as K+, is directed outward (ie, there is a higher K+ concentration inside than outside the cell), the equilibrium potential for that ion is negative. Thus, the K+ current that flows solely because of its concentration gradient is given by iK = -γK × EK (the negative sign is required because a negative equilibrium potential produces a positive current).

Finally, for a real neuron that has both a membrane voltage and K+ concentration gradient, the net K+ current is given by the sum of the currents due to the electrical and chemical driving forces:

The term Vm - EK is called the electrochemical driving force. It determines the direction of ionic current flow and (along with the conductance) the magnitude of current flow. This equation is a modified form of Ohm's law that takes into account that ionic current flow through a membrane is determined not only by the voltage across the membrane but also by the ionic concentration gradients. So far we have used two terms to indicate the ability of ions to cross membranes: permeability and conductance. Although they are related, we should be careful not to confuse them. The permeability of a membrane to an ion is an intrinsic property of the membrane that is a measure of the ease with which the ion passes through the membrane (in units of cm/s). Permeability depends only on the types and numbers of ion channels present in the membrane. Conductance, on the other hand, measures the ability of the membrane (or channel) to carry electrical current (in units of 1/ohms). Since current is carried by ions, the conductance of a membrane will depend not only on the properties of the membrane but also on the concentration of ions in solution. A membrane can have a very high permeability to K+ ions, but if there is no K+ in solution there can be no K+ current flow and so the conductance of the membrane will be zero. In practice, permeability is used in the Goldman equation whereas conductance is used in electrical measurements and equivalent circuits. A cell membrane has many resting K+ channels, all of which can be combined into a single equivalent circuit consisting of a conductor in series with a battery (Figure 7-7). In this equivalent circuit the total conductance of all the K+ channels (gK), ie, the K+ conductance of the cell membrane in its resting state, is equal to the number N of resting K+ channels multiplied by the conductance of an individual K+ channel (γK):

Since the battery in this equivalent circuit depends solely on the concentration gradient for K+ and is independent of the number of K+ channels, its value is the equilibrium potential for K+, EK (Figure 7-7).

Figure 7-10 Under steady state conditions the passive Na- and K+ currents are balanced by active Na+ and K+ fluxes (I′Na and I′K) driven by the Na+-K+ pump. The lipid bilayer endows the membrane with electrical capacitance (C m). Note I′Na is 50% greater than IK (and therefore INa is 50% greater than IK) since the Na+-K- pump transports three Na+ ions out for every two K+ ions it transports into the cell.

Box 7-2 Using the Equivalent Circuit Model to Calculate Resting Membrane Potential The equivalent circuit model of the resting membrane can be used to calculate the resting potential. To simplify the calculation we shall initially ignore Clchannels and begin with just two types of passive channels, K+ and Na+, as illustrated in Figure 7-11. Moreover, we ignore the electrogenic influence of the Na+-K+ pump because it is small. Because we will consider only steady-state conditions, where Vm is not changing, we can also ignore membrane capacitance. (Membrane capacitance and its delaying effect on changes in Vm are discussed in Chapter 8.) Because there are more passive channels for K+ than for Na+, the membrane conductance for current flow carried by K+ is much greater than that for Na+. In the equivalent circuit in Figure 7-11, gK is 20 times higher than gNa (10 × 10-6 S compared to 0.5 × 10-6 S). Given these values and the values of EK and ENa, the membrane potential, Vm, is calculated as follows. Since Vm is constant in the resting state, the net current must be zero, otherwise the separation of positive and negative charges across the membrane would change, causing Vm to change. Therefore INa is equal and opposite to IK: or We can easily calculate INa and IK in two steps. First, we add up the separate potential differences across the Na+ and K+ branches of the circuit. Going from the inside to the outside across the Na+ branch, the total potential difference is the sum of the potential differences across ENa and across gNa:*

Similarly, for the K+ conductance branch Next, we rearrange and solve for I:

As these equations illustrate, the ionic current through each conductance branch is equal to the conductance of that branch multiplied by the net electrical driving force. For example, the conductance for the K+ branch is proportional to the number of open K+ channels, and the driving force is equal to the difference between Vm and EK. If Vm is more positive than EK (-75 mV), the driving force is positive (outward); if Vm is more negative than EK, the driving force is negative (inward).

Figure 7-11 This electrical equivalent circuit omits the Cl- pathway and Na+-K+ pump for simplicity in calculating the resting membrane potential.

In Equation 7-1 we saw that INa + IK = 0. If we now substitute Equations 7-2a and 7-2b for INa and IK in Equation 7-1, multiply through, and rearrange, we obtain the following expression: Solving for Vm, we obtain an equation for the resting membrane potential that is expressed in terms of membrane conductances and batteries:

From this equation, using the values in our equivalent circuit (Figure 7-11), we calculate Vm = -69 mV. Equation 7-3 states that Vm will approach the value of the ionic battery that is associated with the greater conductance. This principle can be illustrated by considering what happens during the action potential. At the peak of the action potential gK is essentially unchanged from its resting value, but gNa increases as much as 500-fold. This increase in gNa is caused by the opening of voltage-gated Na+ channels. In the equivalent circuit example shown in Figure 7-11 a 500-fold increase would change gNa from 0.5 × 10-6 S to 250 × 10-6 S. If we substitute this new value of gNa into Equation 7-3 and solve for Vm, we obtain +50 mV, a value much closer to ENa than to EK. Vm is closer to ENa than to EK at the peak of the action potential because, since gNa is now 25-fold greater than gK, the Na+ battery becomes much more important than the K+ battery in determining Vm.

Figure 7-12 This electrical equivalent circuit includes the Cl- pathway. However, no current flows through the Cl- channels in this example because Vm is at the Cl- equilibrium (Nernst) potential.

The real resting membrane has open channels not only for Na+ and K+, but also for Cl-. One can derive a more general equation for Vm, following the steps outlined above, from an equivalent circuit that includes a conductance pathway for Cl- with its associated Nernst battery (Figure 7-12):

This equation is similar to the Goldman equation presented earlier in this chapter. As in the Goldman equation, the contribution to Vm of each ionic battery is weighted in proportion to the conductance of the membrane for that particular ion. In the limit, if the conductance for one ion is much greater than that for the other ions, Vm will approach the value of that ion's Nernst potential. The contribution of Cl- ions to the resting potential can now be determined by comparing Vm calculated for the circuits for Na+ and K+ only (Figure 7-11) and for all three ions (Figure 7-12). For most nerve cells the value of gCl ranges from one-fourth to one-half of gK. In addition, ECl is typically quite close to EK, but slightly less negative. In the circuit in Figure 7-12, Cl- ions are passively distributed across the membrane, so that ECl is equal to the value of Vm, which is determined by Na+ and K+. Note that if ECl = Vm (-69 mV in this case), no net current flows through the Cl- channels. If we include gCl and ECl from Figure 7-12 in the calculation of Vm, the calculated value of Vm does not differ from that for Figure 7-11. On the other hand, if Cl- were not passively distributed but actively transported out of the cell, then ECl would be more negative than -69 mV. Adding the Cl- pathway to the calculation would then shift Vm to a slightly more negative value. The equivalent circuit can be further simplified by lumping the conductance of all the resting channels that contribute to the resting potential into a single conductance gl and replacing the battery for each conductance channel with a single battery whose value, El, is that predicted by Equation 7-4 (Figure 7-13). This simplification will prove useful when we consider the effects of gated channels in later chapters.

Figure 7-13 The complement of Na+, K+, and Cl- resting channels can be represented by a single equivalent conductance and battery. In this simplified equivalent circuit the total resting membrane conductance gl = gCl + gNa + gK, and the electromotive force or battery (El) is the resting potential predicted by Equation 7-4.

P.136 P.137 P.138

An Equivalent Circuit Model of the Membrane Includes Batteries, Conductors, a Capacitor, and a Current Generator Like the population of resting K+ channels, all the resting Na+ channels can be represented by a single conductor in series with a single battery, as can the resting Cl- channels (Figure 7-8). Since the K+, Na+, and Cl- channels account for the bulk of the passive ionic current through the membrane in the cell at rest, we can calculate the resting potential by incorporating these three channels into a simple equivalent circuit of a neuron. To construct this circuit we need only connect the elements representing each type of channel at their two ends with elements representing the extracellular fluid and cytoplasm. The extracellular fluid and cytoplasm are both excellent conductors because they have relatively large cross-sectional areas and many ions available to carry charge. Both can be approximated by a short circuit— a conductor with zero resistance (Figure 7-9). The equivalent circuit of the neuron can be made more accurate by adding a current generator. As described earlier in this chapter, steady fluxes of Na+ and K+ ions through the passive membrane channels are exactly counterbalanced by active ion fluxes driven by the Na+-K+ pump, which extrudes three Na+ ions from the cell for every two K+ ions it pumps in. This electrogenic ATP-dependent pump, which keeps the ionic batteries charged, can be added to the equivalent circuit in the form of a current generator (Figure 7-10). Finally, we can complete the equivalent circuit of the neuron by incorporating its capacitance, the third important passive electrical property of the neuron. Capacitance is the property of an electric nonconductor (insulator) that permits the storage of charge when opposite surfaces of the nonconductor are maintained at a difference of potential. For the neuron, the nonconductor (or capacitor) is the cell membrane, which separates the cytoplasm and extracellular fluid, both of which are highly conductive environments. Strictly speaking, the membrane is a leaky capacitor because it is penetrated by ion channels. However, since the density of the ion channels is low, the insulating portion of the membrane—the lipid bilayer—occupies at least 100 times the area of all the ion channels combined. Membrane capacitance is included in the equivalent circuit in Figure 7-10. The electrical potential difference across a capacitor, V, is expressed as:

where Q is the excess of positive or negative charges on each side of the capacitor and C is the capacitance. Capacitance is measured in units of farads, F, where a charge separation of 1 coulomb across a 1 farad capacitor produces a 1 volt potential difference. A typical value of membrane capacitance for a nerve cell is about 1 µF/cm2 of membrane area. The excess of positive and negative charges separated by the membrane of a spherical cell body with a diameter of 50 µm and a resting potential of -60 mV is 29 × 106 ions. Although this number may seem large, it represents only a tiny fraction (1/200,000) of the total number of positive or negative charges in solution within the cytoplasm. The bulk of the cytoplasm and the bulk of the extracellular fluid are electroneutral. The use of the equivalent circuit model of the neuron to analyze neuronal properties quantitatively is illustrated in Box 7-2.

An Overall View The lipid bilayer, which is virtually impermeant to ions, is an insulator separating two conducting solutions, the cytoplasm and the extracellular fluid. Ions can cross the lipid bilayer only by passing through ion channels in the cell membrane. When the cell is at rest, the passive ionic fluxes into and out of the cell are balanced, so that the charge separation across the membrane remains constant and the membrane potential remains at its resting value. The value of the resting membrane potential in nerve cells is determined primarily by resting channels selective for K+, Cl-, and Na+. In general, the membrane potential will be closest to the equilibrium (Nernst) potential of the ion (or ions) with the greatest membrane permeability. The permeability for an ion species is proportional to the number of open channels that allow passage of that ion. At rest, the membrane potential is close to the Nernst potential for K+, the ion to which the membrane is most permeable. The membrane is also somewhat permeable to Na+, however, and therefore an influx of Na+ drives the membrane potential slightly positive to the K+ Nernst potential. At this potential the electrical and chemical driving forces acting on K+ are no longer in balance, so K+ diffuses out of the cell. These two passive fluxes are each counterbalanced by active fluxes driven by the Na+-K+ pump. Chloride is actively pumped out of some, but not all, cells. When it is not, it is passively distributed so as to be at equilibrium inside and outside the cell. Under most physiological conditions the bulk concentrations of Na+, K+, and Cl- inside and outside the cell are constant. During signaling the changes in membrane potential P.139

(action potentials, synaptic potentials, and receptor potentials) are caused by substantial changes in the membrane's relative permeabilities to these three ions, not by changes in the bulk concentrations of ions, which are negligible. These changes in permeability, caused by the opening of gated ion channels, cause changes in the net charge separation across the membrane.

Selected Readings Finkelstein A, Mauro A. 1977. Physical principles and formalisms of electrical excitability. In: ER Kandel (ed). Handbook of Physiology: A Critical, Comprehensive Presentation of Physiological Knowledge and Concepts, Sect. 1, The Nervous System. Vol. 1, Cellular Biology of Neurons, Part 1, pp. 161213. Bethesda, MD: American Physiological Society.

Hille B. 1992. Ionic Channels of Excitable Membranes, 2nd ed. Sunderland, MA: Sinauer.

Hodgkin AL. 1992. Chance and Design. Cambridge: Cambridge Univ. Press.

References Bernstein J. [1902] 1979. Investigations on the thermodynamics of bioelectric currents. Pflügers Arch 92:521-562. Translated in: GR Kepner (ed). Cell Membrane Permeability and Transport, pp. 184-210. Stroudsburg, PA: Dowden, Hutchinson & Ross.

Goldman DE. 1943. Potential, impedance, and rectification in membranes. J Gen Physiol 27:37–60.

Hodgkin AL, Katz B. 1949. The effect of sodium ions on the electrical activity of the giant axon of the squid. J Physiol (Lond) 108:37–77.

Nernst W. [1888] 1979. On the kinetics of substances in solution. Z Physik Chem. 2:613-622, 634-637. Translated in: GR Kepner (ed). Cell Membrane Permeability and Transport, pp. 174-183. Stroudsburg, PA: Dowden, Hutchinson & Ross.

Orkand RK. 1977. Glial cells. In: ER Kandel (ed). Handbook of Physiology: A Critical, Comprehensive Presentation of Physiological Knowledge and Concepts, Sect. 1, The Nervous System. Vol. 1, Cellular Biology of Neurons, Part 2, pp. 855-875. Bethesda, MD: American Physiological Society.

Siegel GJ, Agranoff BW, Albers RW (eds). 1999. Basic Neurochemistry: Molecular, Cellular, and Medical Aspects, 6th ed, Philadelphia: Lippincott-Raven. 1At

the peak of the action potential threr is an instant in time when Vm is not changing and the Goldman equation is applicable.

*Because we have defined Vm as Vin - Vout, the following convention must be used for these equations. Outward current (in this case IK) is positive and inward current is negative. Batteries with their positive poles toward the inside of the membrane (eg, ENa) are given positive values in the equations. The reverse is true for batteries that have their negative poles toward the inside, such as the K+ battery.

Back

8 Local Signaling: Passive Electrical Properties of the Neuron John Koester Steven A. Siegelbaum WHILE ALL CELLS OF THE body have a membrane potential, only neurons (and muscle cells) generate electrical signals that can be conducted rapidly over long distances. In the last chapter we saw how these electrical signals are generated by the flux of ions across the cell membrane through specialized ion channels, and how to calculate the expected membrane potential for any set of ionic concentration gradients and membrane permeabilities using the Goldman equation. This description does not, however, provide any information about changes in the membrane potential in response to a stimulus, since the Goldman equation applies only to the steady state when the voltage does not change. During signaling, when the neuron generates action potentials, synaptic potentials, or sensory generator potentials in response to a stimulus, the membrane voltage changes constantly. What determines the rate of change in potential? Will a brief synaptic current always produce a similar potential change, regardless of the size of the postsynaptic cell? What determines whether a stimulus will or will not produce an action potential? Here we consider how a neuron's passive electrical properties and geometry, which are relatively constant, affect the cell's electrical signaling. In the next chapter we shall consider how the properties of the ion channels that generate the active ionic currents also help determine changes in membrane potential. Neurons have three passive electrical properties that are important to electrical signaling: the resting membrane resistance, the membrane capacitance, and the intracellular axial resistance along axons and dendrites. Because these elements provide the return pathway to complete the electrical circuit when active currents flow into or out of the cell, they determine the time course and amplitude of the synaptic potential change generated by the synaptic current. They also determine whether a synaptic potential generated in a dendrite will result in a suprathreshold depolarization at the trigger zone on the axon hillock. Still further, the passive properties influence the speed at which an action potential is conducted.

Input Resistance Determines the Magnitude of Passive Changes in Membrane Potential The difference between the effects of passive and active properties of neurons can be demonstrated by injecting P.141 current pulses into the cell body (see Box 7-1). Injecting a negative charge through an electrode increases the charge separation across the membrane, making the membrane potential more negative, or hyperpolarized. The larger the negative current, the greater is the hyperpolarization. In most neurons there is a linear relation between the size of the negative current and the steady-state hyperpolarization (Figure 8-1). The relation between current and voltage defines a resistance, Rin, the neuron's input resistance.

Figure 8-1 Current-voltage relationships. By passing subthreshold, graded, inward and outward current pulses into a cell, one can determine the relationship between current injected into the cell and the resulting changes in membrane potential, Vm. A. Increases in outward or inward current pulses (A1) produce proportional and symmetrical changes in Vm (A2). Note that the potential changes more slowly than the step current pulses. B. An I-V curve is obtained by plotting the steady state voltage against the injected current. The slope of the I-V curve defines the input resistance of the neuron. The I-V curve shown here is linear; Vm changes by 10 mV for every 1 nA change in current, yielding a resistance of 10 mV/1 nA, or 10 × 106 ω (10 Mω).

Likewise, when a positive charge is injected into the cell, producing depolarization, the neuron behaves as a simple resistor, but only over a limited voltage range. A large enough positive current will produce a depolarization that exceeds threshold, at which point the neuron generates an action potential. When this happens the neuron no longer behaves as a simple resistor because of the special properties of its voltage-gated channels considered in Chapter 9. Still, much of a neuron's behavior in the hyperpolarizing and subthreshold depolarizing range of voltages can be explained by simple equivalent circuits made up of resistors, capacitors, and batteries. The input resistance of the cell determines how much the cell will depolarize in response to a steady current. The magnitude of the depolarization, δV, is given by Ohm's law:

Thus, of two neurons receiving identical synaptic current inputs, the cell with the higher input resistance will show a greater change in membrane voltage. For an idealized spherical neuron with no processes, the input resistance depends on both the density of the resting ion channels in the membrane (that is, the number of channels per unit area of membrane) and the size of the cell. The larger the neuron, the greater will be its membrane surface area and the lower the input resistance, since there will be more resting channels to conduct ions. To compare the membrane properties of neurons of differing sizes, electrophysiologists often use the resistance of a unit area of membrane, the specific membrane resistance, Rm, measured in units of ωcm2. The specific membrane resistance depends only on the density of the resting ion channels (the number of channels per square centimeter) and their conductance. To obtain the total input resistance of the cell we divide the specific membrane resistance by the membrane area of the cell because the greater the area of a cell, the lower its resistance. For the spherical neuron we obtain

where a is the radius of the neuron. Thus, for a spherical cell the input resistance is inversely proportional to the square of the radius. For a real neuron with extensive dendrites and axons, the input resistance also depends P.142 on the membrane resistance of its processes as well as on the intracellular cytoplasmic resistance between the cell body and those processes (discussed below).

Membrane Capacitance Prolongs the Time Course of Electrical Signals In Figure 8-1 the magnitude of the steady state changes in the cell's voltage in response to subthreshold current resembles the behavior of a simple resistor, but the time course of the changes does not. A true resistor responds to a step change in current with a similar step change in voltage, but the cell in Figure 8-1 shows a voltage response that rises and decays more slowly than the step change in current. This property of the membrane is due to its capacitance. To understand how the capacitance slows down the voltage response we need to recall that the voltage across a capacitor is proportional to the charge stored on the capacitor:

where Q is the charge in coulombs and C is the capacitance in farads. To alter the voltage, charge must either be added or removed from the capacitor:

The change in charge (δQ) is the result of the flow of current across the capacitor (Ic). Since current is the flow of charge per unit time (Ic = δQ/δt), we can calculate the change in voltage across a capacitor as a function of current and the time that the current flows (δt):

The magnitude of the change in voltage across a capacitor in response to a current pulse depends on the duration of the current, as time is required to deposit and remove charge on the plates of the capacitor. Capacitance is directly proportional to the area of the plates of the capacitor. The larger the area of a capacitor, the more charge it will store for a given potential difference. The value of the capacitance also depends on the insulation medium and the distance between the two plates of the capacitor. Since all biological membranes are composed of lipid bilayers with similar insulating properties that provide a similar separation between the two plates (4 nm), the specific capacitance per unit area of all biological membranes, Cm, has the same value, approximately 1 µF/cm2 of membrane. The total input capacitance of a spherical cell, Cin, is therefore given by the capacitance per unit area multiplied by the area of the cell:

Because capacitance increases with the size of the cell, more charge, and therefore current, is required to produce the same change in membrane potential in a larger neuron than in a smaller one. According to Equation 8-1 the voltage across a capacitor continues to increase with time as long as a current pulse is applied. But in neurons the voltage levels off after some time (Figure 8-1) because the membrane of a neuron acts as a resistor (owing to its ion-conducting channels) and a capacitor (owing to the phospholipid bilayer) in parallel. In the equivalent circuit developed in Chapter 7 to model current flow in the neuron, we placed the resistance and capacitance in parallel, since current crossing the membrane can flow either through ion channels (the resistive pathway) or across the capacitor (Figure 8-2). The resistive current carried by ions flowing across the membrane through ion channels—for example, Na+ ions moving through Na+ channels from outside to inside the cell—is called the ionic membrane current. The current carried by ions that change the net charge stored on the membrane is called the capacitive membrane current. An outward capacitive current, for example, adds positive charges to the inside of the membrane and removes P.143 an equal number of positive charges from the outside of the membrane. The total current crossing the membrane, Im, is given by the sum of the ionic current (Ii) and the capacitive current:

Figure 8-2 A simplified electrical equivalent circuit is used to examine the effects of membrane capacitance (Cin) on the rate of change of membrane potential in response to current flow. All resting ion channels are lumped into a single element (Rin). Batteries representing the electromotive forces generated by ion diffusion are not included because they affect only the absolute value of membrane potential, not the rate of change. This equivalent circuit represents the experimental setup shown in Box 7-1 (Figure 7-2C), in which pairs of electrodes are connected to the current generator and the membrane potential monitor.

The capacitance of the membrane has the effect of reducing the rate at which the membrane potential changes in response to a current pulse. If the membrane had only resistive properties, a step pulse of outward current passed across it would change the membrane potential instantaneously. On the other hand, if the membrane had only capacitive properties, the membrane potential would change linearly with time in response to the same step pulse of current. Because the membrane has both capacitive and resistive properties in parallel, the actual change in membrane potential combines features of the two pure responses. The initial slope of the relation between Vm and time reflects a purely capacitive element, whereas the final slope and amplitude reflect a purely resistive element (Figure 8-3). It is now easy to explain why a step change in current produces the slowly rising voltage waveform seen in Figure 8-3. Since the resistance and capacitance of the membrane are in parallel, the voltage across each element must always be the same and equal to the membrane potential. Assume that the membrane potential starts off at 0 mV and that at time t = 0 a depolarizing current step is applied from a current generator with magnitude Im. Initially the voltage across the resistor and capacitor are both equal to 0 mV. Since the ionic current through the resistor is given by Ohm's law (Ii = V/R in), initially no current will flow through the resistor

(since V starts off at 0 mV) and all the current will flow through the capacitor (ie, Ic = Im). As a result of the large initial capacitive current, the potential across the capacitor, and hence the membrane potential, will rapidly become more positive. As Vm increases, the voltage difference across the membrane begins to drive current across the membrane resistance. As the voltage across the membrane becomes more positive, more current flows through the resistor and less flows across the capacitor, since Ic plus Ii is constant (and equal to Im). As a result, the membrane potential begins to rise more slowly. Eventually, the membrane potential reaches a value where all the membrane current flows through the resistor (Ii = Im). From Ohm's law this voltage is given by Vm = Im · Rin. At this point the capacitative current is zero and, following Equation 8-1, the membrane potential no longer changes. Once the step of current is turned off, the total membrane current Im equals zero, so that the positive ionic current flowing through the resistor must flow back into the cell as an equal and opposite capacitive current, ie, Ii = - Ic. With no applied current, the charge on the capacitor dissipates by flowing in a loop around the circuit through the resistive pathway, and the membrane potential returns to zero.

Figure 8-3 The rate of change in the membrane potential is slowed by the membrane capacitance. The response of the membrane potential (δVm) to a step current pulse is shown in the upper plot. The actual shape of the response (red line c) combines the properties of a purely resistive element (dashed line a) and a purely capacitive element (dashed line b). The lower plot shows the total membrane current (Im) and its ionic (Ii) and capacitive (Ic) components (Im = Ii = Ic) in relation to the current pulse. The time taken to reach 63% of the final voltage defines the membrane time constant, τ. The time constants of different neurons typically range from 20 to 50 ms.

The rising phase of the potential change can be described by the following equation:

where e, which has a value of around 2.72, is the base of the system of natural logarithms, and τ is the membrane time constant, the product of the input resistance and capacitance of the membrane (Rin Cin). The time constant can be measured experimentally (Figure 8-3). It is the time it takes the membrane potential to rise to (1 - 1/e), about 63% of its steady state value. We shall return to the time constant when we consider the temporal summation of synaptic inputs in a cell in Chapter 12.

Membrane and Axoplasmic Resistance Affect the Efficiency of Signal Conduction So far we have considered the effects of the passive properties of neurons on signaling only within the cell body. Because the neuron's soma can be approximated P.144 as a simple sphere, the effect of distance on the propagation of a signal does not matter. However, in electrical signaling along dendrites, axons, and muscle fibers, a subthreshold voltage signal decreases in amplitude with distance from its site of initiation. To understand how this attenuation occurs we will again have need of an equivalent circuit, one that shows how the geometry of a neuron influences the distribution of current flow.

Figure 8-4 A neuronal process can be represented by an electrical equivalent circuit. The process is divided into unit lengths. Each unit length of the process is a circuit with its own membrane resistance (rm) and capacitance (cm). All the circuits are connected by resistors (ra), which represent the axial resistance of segments of cytoplasm, and a short circuit, which represents the extracellular fluid.

Synaptic potentials that originate in dendrites are conducted along the dendrite toward the cell body and the trigger zone. The cytoplasmic core of a dendrite offers significant resistance to the longitudinal flow of current, because it has a relatively small cross-sectional area, and ions flowing down the dendrite collide with other molecules. The greater the length of the cytoplasmic core, the greater the resistance, since the ions experience more collisions the further they travel. Conversely, the larger the diameter of the cytoplasmic core, the lower will be the resistance in a given length, since the number of charge carriers at any cross section of dendrite increases with the diameter of the core. To represent the incremental increase in resistance along the length of the dendritic core, the dendrite can be divided into unit lengths, each of which is a circuit with its own measurable membrane resistance and capacitance as well as an axial resistance within the cytoplasmic core. Because of its large volume, the extracellular fluid has only negligible resistance and therefore can be ignored. The equivalent circuit for this simplified model is shown in Figure 8-4.

If current is injected into the dendrite at one point, how will the membrane potential change with distance along the dendrite? For simplicity, consider the variation of membrane potential with distance after a constant-amplitude current pulse has been on for some time (t >>> τ). Under these conditions the membrane potential will have reached a steady value, so capacitive current will be zero. When Ic = 0, all of the membrane current is ionic (Im = Ii). The variation of the potential with distance thus depends solely on the relative values of the membrane resistance, rm (units of ωcm), and the axial resistance, ra (units of ω/cm), per unit length of dendrite. The injected current flows out through several parallel pathways across successive membrane cylinders along the length of the process (Figure 8-5). Each of these current pathways is made up of two resistive components in series: the total axial resistance, rx, and the membrane resistance, rm, of the unit membrane cylinder. For each outflow pathway the total axial resistance is the resistance between the site of current injection and the site of the outflow pathway. Since resistors in series are added, rx = rax, where x is the distance along the dendrite from the site of current injection. The membrane resistance, rm, has the same value at each outflow pathway along the cell process. More current flows across a membrane cylinder near the site of injection than at more distant regions because current always tends to follow the path of least resistance, and the total axial resistance, rx, increases with distance from the site of injection (Figure 8-5). Because Vm = Imrm, the change in membrane potential produced by the current across a membrane cylinder at position x, δVm(x), becomes smaller with distance down the dendrite away from the current electrode. This decay with distance is exponential (Figure 8-5) and expressed by

where λ is the membrane length constant, x is the distance from the site of current injection, and δV0 is the change in membrane potential produced by the current flow at the site of injection (x = 0). The length constant λ is defined as the distance along the dendrite to the site where δVm has decayed to 1/e, or 37% of its initial value (Figure 8-5), and it is determined as follows:

The better the insulation of the membrane (that is, the greater rm) and the better the conducting properties of the inner core (the lower ra), the greater the length constant of the dendrite. That is, current is able to spread P.145 farther along the inner conductive core of the dendrite before leaking across the membrane. To consider how neuronal geometry affects signaling, it will be helpful first to consider how the diameter of a process affects rm and ra. Both rm and ra are measures of resistance that apply to a 1 cm segment of an individual neuronal process with a certain radius α. The axial resistance of a neuronal process depends on the intrinsic resistive properties of the cytoplasm, expressed as the specific resistance, r, of a 1 cm3 cube of cytoplasm (in units of ωcm), and the cross-sectional area of the process, which determines the total volume in a unit length of the process and hence the number of charge carriers. Thus, ra is given by

and ra has the required units of ω/cm. The diameter of the process also affects rm since the total number of channels in a unit length of membrane is directly proportional to both the channel density (number of channels per unit area) and the membrane area. Since rm is inversely related to the total number of channels in a unit length of membrane and the area in a unit length of cylinder depends on the circumference, rm is given by

where Rm is the specific resistance of a unit area of membrane (units of ωcm2) and rm has the units of ωcm. Neuronal processes vary greatly in diameter, from as much as 1 mm for the giant axon of the squid down to 1 µm for fine dendritic branches in the mammalian brain. These variations in diameter control the efficiency of neuronal signaling because the diameter determines the length constant. For processes with similar intrinsic properties (that is with similar values of Rm and ρ), the larger the diameter of the process (dendrite or axon), the longer the length constant, because rm/ra is directly related to the radius (Equations 8-4 and 8-5). Thus, the length constant is expressed in terms of the intrinsic (size invariant) properties Rm and ρ as follows:

That is, the length constant is proportional to the square root of the radius (or diameter) of a process. Thus, thicker axons and dendrites will have longer length constants than do narrower processes and hence will transmit electrotonic signals for greater distances. Typical values for neuronal length constants range from 0.1 to 1.0 mm. The length constant is a measure of the efficiency of the passive spread of voltage changes along the neuron, or electrotonic conduction. The efficiency of electrotonic conduction has two important effects on neuronal function. First, it influences spatial summation, the process by which synaptic potentials generated in different regions of the neuron are added together at the trigger zone, the decision-making component of the neuron (see Chapter 12).

Figure 8-5 The voltage response in a passive neuronal process decays with distance due to electronic conduction. Current injected into a neuronal process by a microelectrode follows the path of least resistance to the return electrode in the extracellular fluid (A). The thickness of the arrows represents membrane current density at any point along the process. Under these conditions the change in Vm decays exponentially with distance from the site of current injection (B). The distance at which δVm has decayed to 37% of its value at the point of current injection defines the length constant, λ.

Second, electrotonic conduction is a factor in the propagation of the action potential. Once the membrane at any point along an axon has been depolarized beyond threshold, an action potential is generated in that region in response to the opening of voltage-gated Na+ channels (see Chapter 9). This local depolarization spreads electrotonically down the axon, causing the adjacent region of the membrane to reach the threshold for generating an action potential (Figure 8-6). Thus the depolarization spreads along the length of the axon by “local-circuit” current flow resulting from the potential difference between active and inactive regions of the axon membrane. In cells with longer length constants the local-circuit current has a greater spread and therefore the action potential propagates more rapidly.

Figure 8-6 Passive conduction of depolarization along the axon contributes to propagation of the action potential. A. The waveform of an action potential propagating from right to left. The difference in potential along the length of the axon creates a local-circuit current flow that causes the depolarization to spread passively from the active region (2) to the inactive region ahead of the action potential (1), as well as to the area behind the action potential (3). However, because there is also an increase in gK in the wake of the action potential (see Chapter 9), the buildup of positive charge along the inner side of the membrane in area 3 is more than balanced by the local efflux of K+, allowing this region of membrane to repolarize. B. A short time later the voltage waveform and the current distributions have shifted down the axon and the process is repeated.

P.146

Large Axons Are More Easily Excited Than Small Axons by Extracellular Current Stimuli In examination of a neurological patient for diseases of peripheral nerves the nerve often is stimulated by passing current between a pair of extracellular electrodes placed over the nerve, and the population of resulting action potentials (the compound action potential) is recorded farther along the nerve by a second pair of voltage-recording electrodes. In this situation the total number of axons that generate action potentials varies with the amplitude of the current pulse. To drive a cell to threshold, the current must pass through the cell membrane. In the vicinity of the positive electrode, current flows across the membrane into the axon. It then flows along the axoplasmic core, eventually flowing out through more distant regions of axonal membrane to the second (negative) electrode in the extracellular fluid. For any given axon, most of the stimulating current bypasses the fiber, moving instead through other axons or through the low-resistance pathway provided by the extracellular fluid. The axons into which current can enter most easily are the most excitable. In general, axons with the largest diameter have the lowest threshold for extracellular current. The larger the diameter of the axon, the lower the axial resistance to the flow of longitudinal current because of the greater number of intracellular charge carriers (ions) per unit length of the axon. Therefore a greater fraction of total current enters the larger axon, so it is depolarized more efficiently than a smaller axon. For these reasons, larger axons are recruited at low values of current; smallerdiameter axons are recruited only at relatively greater current strengths.

Figure 8-7 Axial resistance and membrane capacitance limit the rate of spread of depolarization during the action potential. A. The electrical equivalent circuit represents two adjacent segments of the resting membrane of an axon connected by a segment of axoplasm (ra). B. An action potential is spreading from the membrane segment on the left to the segment on the right. Purple lines indicate pathways of current flow.

P.147

Passive Membrane Properties and Axon Diameter Affect the Velocity of Action Potential Propagation The passive spread of depolarization during conduction of the action potential is not instantaneous. In fact, the electrotonic conduction is a rate-limiting factor in the propagation of the action potential. We can understand this limitation by considering a simplified equivalent circuit of two adjacent membrane segments connected by a segment of axoplasm (Figure 8-7). As described above, an action potential generated in one segment of membrane supplies depolarizing current to the adjacent membrane, causing it to depolarize gradually toward threshold. According to Ohm's law, the larger the axoplasmic resistance, the smaller the current flow around the loop (I = V/R) and the longer it takes to change the charge on the membrane of the adjacent segment. Recall that since δV = δQ/C, the membrane potential changes slowly if the current is small because δQ changes slowly. Similarly, the larger the membrane capacitance, the more charge must be deposited on the membrane to change the potential across the membrane, so the current must flow for a longer time to produce a given depolarization. Therefore, the time it takes for depolarization to spread along the axon is determined by both the axial resistance, ra, and the capacitance per unit length of the axon cm (units F/cm). The rate of passive spread varies inversely with the product racm. If this product is reduced, the rate of passive spread increases and the action potential propagates faster. Rapid propagation of the action potential is functionally important, and two distinct mechanisms have evolved to increase it. One adaptive strategy is to increase conduction velocity by increasing the diameter of the axon core. Because ra decreases in proportion to the square of axon diameter, while cm increases in direct proportion to diameter, the net effect of an increase in diameter is a decrease in racm. This adaptation has been carried to an extreme in the giant axon of the squid, which can reach a diameter of 1 mm. No larger axons have evolved, presumably because of the opposing need to keep neuronal size small so that many cells can be packed into a limited space. A second mechanism for increasing conduction velocity is myelination of the axon, the wrapping of glial cell membranes around an axon (see Chapter 4). This process is functionally equivalent to increasing the thickness of the axonal membrane by as much as 100 times. Because the capacitance of a parallel-plate capacitor such as the membrane is inversely proportional to the thickness of the insulation material, myelination decreases cm and thus racm. Myelination results in a proportionately much greater decrease in racm than does the same increase in the diameter of the axon core. For this reason, conduction in myelinated axons is typically faster than in nonmyelinated axons of the same diameter. P.148 In a neuron with a myelinated axon the action potential is triggered at the nonmyelinated segment of membrane at the axon hillock. The inward current that flows through this region of membrane is then available to discharge the capacitance of the myelinated axon ahead of it. Even though the thickness of myelin makes the capacitance of the axon quite small, the amount of current flowing down the core of the axon from the trigger zone is not enough to discharge the capacitance along the entire length of the myelinated axon. To prevent the action potential from dying out, the myelin sheath is interrupted every 1-2 mm by bare patches of axon membrane about 2 µm in length, the nodes of Ranvier (see Chapter 4). Although the area of membrane at each node is quite small, the nodal membrane is rich in voltage-gated Na+ channels and thus can generate an intense depolarizing inward Na+ current in response to the passive spread of depolarization down the axon. These regularly distributed nodes thus boost the amplitude of the action potential periodically, preventing it from dying out. The action potential, which spreads quite rapidly along the internode because of the low capacitance of the myelin sheath, slows down as it crosses the highcapacitance region of each bare node. Consequently, as the action potential moves down the axon it jumps quickly from node to node (Figure 8-8A). For this reason, the action potential in a myelinated axon is said to move by saltatory conduction (from the Latin saltare, to jump). Because ionic membrane current flows only at the nodes in myelinated fibers, saltatory conduction is also favorable from a metabolic standpoint. Less energy must be expended by the Na+-K+ pump in restoring the Na +

and K+ concentration gradients, which tend to run down as a result of action-potential activity.

Various diseases of the nervous system, such as multiple sclerosis and Guillain-Barre syndrome, cause demyelination (see Box 4-1). Because the lack of myelin slows down the conduction of the action potential, these diseases can have devastating effects on behavior (Chapter 35). As an action potential goes from a myelinated region to a bare stretch of axon, it encounters a region of relatively high cm and low rm. The inward current generated at the node just before the demyelinated segment may be too small to provide the capacitive current required to depolarize the demyelinated membrane to threshold. In addition, this local-circuit current does not spread as far as it normally would because it is flowing into a segment of axon that, because of its low rm, has a short length constant (Figure 8-8B). These two factors can combine to slow, and in some cases actually block, the conduction of action potentials.

Figure 8-8 Action potentials in myelinated nerves are regenerated at the nodes of Ranvier. A. In the axon capacitive and ionic membrane current densities (membrane current per unit area of membrane) are much higher at the nodes of Ranvier than in the internodal regions. The density of membrane current at any point along the axon is represented by the thickness of the arrows. Because of the higher capacitance of the axon membrane at the unmyelinated nodes, the action potential slows down as it approaches each node and thus appears to skip rapidly from node to node. B. In regions of the axon that have lost their myelin, the spread of the action potential is slowed down or blocked. The local-circuit currents must charge a larger membrane capacitance and, because of the low rm, they do not spread well down the axon.

An Overall View Two competing needs determine the functional design of neurons. First, to maximize the computing power of the nervous system, neurons must be small so that large numbers of them can fit into the brain and spinal cord. Second, to maximize the ability of the animal to respond to changes in its environment, neurons must conduct signals rapidly. These two design objectives are constrained by the materials from which neurons are made. Because the nerve cell membrane is very thin and is surrounded by a conducting medium, it has a very high capacitance, which slows down the conduction of voltage P.149 signals. In addition, the currents that change the charge on the membrane capacitance must flow through a relatively poor conductor—a thin column of cytoplasm. The ion channels that give rise to the resting potential also degrade the signaling function of the neuron. They make the cell leaky and, together with the high membrane capacitance, they limit the distance that a signal can travel passively. As we shall see in the next chapter, neurons use voltage-gated channels to compensate for these physical constraints when generating all-or-none action potentials, which are continually regenerated and conducted without attenuation. For pathways in which rapid signaling is particularly important, the conduction velocity of the action potential is enhanced either by myelination or by an increase in axon diameter, or by both.

Selected Readings Hodgkin AL. 1964. Chapter 4. In: The Conduction of the Nervous Impulse, pp. 47-55. Springfield, IL: Thomas.

Jack JJB, Noble D, Tsien RW. 1975. Chapters 1, 5, 7, and 9. In: Electric Current Flow in Excitable Cells, pp. 1-4, 83-97, 131-224, 276-277. Oxford: Clarendon.

Johnston D, Wu M-S. 1995. Functional properties of dendrites. In: Foundations of Cellular Neurophysiology, pp. 55-120. Cambridge: MIT Press.

Koch C. 1999. Biophysics of Computation, pp. 25-48. New York: Oxford University Press.

Moore JW, Joyner RW, Brill MH, Waxman SD, Najar-Joa M. 1978. Simulations of conduction in uniform myelinated fibers: relative sensitivity to changes in nodal and internodal parameters. Biophys J 21:147–160.

Rall W. 1977. Core conductor theory and cable properties of neurons. In: ER Kandel (ed). Handbook of Physiology: A Critical, Comprehensive Presentation of Physiological Knowledge and Concepts, Sect. 1, The Nervous System. Vol. 1, Cellular Biology of Neurons, Part 1, pp. 39-97. Bethesda, MD: American Physiological Society.

References Hodgkin AL, Rushton WAH. 1946. The electrical constants of a crustacean nerve fibre. Proc R Soc Lond Ser B. 133:444–479.

Huxley AF, Stämpfli R. 1949. Evidence for saltatory conduction in peripheral myelinated nerve fibres. J Physiol 108:315–339.

Back

9 Propagated Signaling: The Action Potential John Koester Steven A. Siegelbaum NERVE CELLS ARE ABLE TO carry signals over long distances because of their ability to generate an action potential—a regenerative electrical signal whose amplitude does not attenuate as it moves down the axon. In Chapter 7 we saw how an action potential arises from sequential changes in the membrane's selective permeability to Na+ and K+ ions. In Chapter 8 we considered how the membrane's passive properties influence the speed at which action potentials are conducted. In this chapter we focus on the voltage-gated ion channels that are critical for generating and propagating action potentials and consider how these channels are responsible for many important features of a neuron's electrical excitability.

The Action Potential Is Generated by the Flow of Ions Through Voltage-Gated Channels An important early clue about how action potentials are generated came from an experiment performed by Kenneth Cole and Howard Curtis. While recording from the giant axon of the squid they found that the ion conductance across the membrane increases dramatically during the action potential (Figure 9-1). This discovery provided the first evidence that the action potential results from changes in the flux of ions through the channels of P.151 the membrane. It also raised the question: Which ions are responsible for the action potential? A key to this problem was provided by Alan Hodgkin and Bernard Katz, who found that the amplitude of the action potential is reduced when the external Na+ concentration is lowered, indicating that Na+ influx is responsible for the rising phase of the action potential. Their data also suggested that the falling phase of the action potential was caused by a later increase in K+ permeability. Hodgkin and Katz proposed that depolarization of the cell above threshold causes a brief increase in the cell membrane's permeability to Na+, during which Na+ permeability overwhelms the dominant permeability of the resting cell membrane to K+ ions.

Sodium and Potassium Currents Through Voltage-Gated Channels Are Recorded With the Voltage Clamp To test this hypothesis, Hodgkin and Andrew Huxley conducted a second series of experiments. They systematically varied the membrane potential in the squid giant axon and measured the resulting changes in the membrane conductance to Na+ and K+ through voltage-gated Na+ and K+ channels. To do this they made use of a new apparatus, the voltage clamp. Prior to the availability of the voltage-clamp technique, attempts to measure Na+ and K+ conductance as a function of membrane potential had been limited by the strong interdependence of the membrane potential and the gating of Na+ and K+ channels. For example, if the membrane is depolarized sufficiently to open some of the voltage-gated Na+ channels, inward Na+ current flows through these channels and causes further depolarization. The additional depolarization causes still more Na+ channels to open and consequently induces more inward Na+ current:

Figure. No Caption Available.

This positive feedback cycle, which eventually drives the membrane potential to the peak of the action potential, makes it impossible to achieve a stable membrane potential. A similar coupling between current and membrane potential complicates the study of the voltage-gated K+ channels. The basic function of the voltage clamp is to interrupt the interaction between the membrane potential and the opening and closing of voltage-gated ion channels. The voltage clamp does so by injecting a current into the axon that is equal and opposite to the current flowing through the voltage-gated membrane channels. In this way the voltage clamp prevents the charge separation across the membrane from changing. The amount of current that must be generated by the voltage clamp to keep the membrane potential constant provides a direct measure of the current flowing across the membrane (Box 9-1). Using the voltage-clamp technique, Hodgkin and Huxley provided the first complete description of the ionic mechanisms underlying the action potential.

Figure 9-1 A net increase in ionic conductance in the membrane of the axon accompanies the action potential. This historic recording from an experiment conducted in 1938 by Kenneth Cole and Howard Curtis shows the oscilloscope record of an action potential superimposed on a simultaneous record of the ionic conductance.

One advantage of the voltage clamp is that it readily allows the total membrane current to be separated into its ionic and capacitive components. As described in Chapter 8, the membrane potential Vm, is proportional to the charge Qm on the membrane capacitance (Cm). When Vm is not changing, Qm is constant and no capacitive current (δQm/δt) flows. Capacitive current flows only when Vm is changing. Therefore, when the membrane potential changes in response to a very rapid step of command potential, capacitive current flows only at the beginning and end of the step. Since the capacitive current is essentially instantaneous, the ionic currents that flow through the gated membrane channels can be analyzed separately. Measurements of these ionic membrane currents can be used to calculate the voltage and time dependence of changes in membrane conductances caused by the opening and closing of Na+ and K+ channels. This information provides insights into the properties of these two types of channels. A typical voltage-clamp experiment starts with the membrane potential clamped at its resting value. If a 10 mV depolarizing potential step is commanded, we P.152 P.153 observe that an initial, very brief outward current instantaneously discharges the membrane capacitance by the amount required for a 10 mV depolarization. This capacitive current (Ic) is followed by a smaller outward ionic current that persists for the duration of this pulse. At the end of the pulse there is a brief inward capacitive current, and the total membrane current returns to zero (Figure 9-3A). The steady ionic current that persists throughout the depolarization is the current that flows through the resting ion channels of the membrane (see Chapter 6) and is called the leakage current, Il. The total conductance of this population of channels is called the leakage conductance (gl). These resting channels, which are always open, are responsible for generating the resting membrane potential (see Chapter 7). In a typical neuron most of the resting channels are permeable to K+ ions; the remaining channels are permeable to Cl- or Na+ ions.

Box 9-1 Voltage-Clamp Technique The voltage-clamp technique was developed by Kenneth Cole in 1949 to stabilize the membrane potential of neurons for experimental purposes. It was used by Alan Hodgkin and Andrew Huxley in the early 1950s in a series of experiments that revealed the ionic mechanisms underlying the action potential. The voltage clamp permits the experimenter to “clamp” the membrane potential at predetermined levels. The voltage-gated ion channels continue to open or close in response to changes in membrane potential, but the voltage clamp prevents the resultant changes in membrane current from influencing the membrane potential. This technique thus permits measurement of the effect of changes in membrane potential on the conductance of the membrane to individual ion species. The voltage clamp consists of a source of current connected to two electrodes, one inside and the other outside the cell (Figure 9-2A). By passing current across the cell membrane, the membrane potential can be stepped rapidly to a predetermined level of depolarization.

Figure 9-2A A The voltage clamp is a current generator that is connected to a pair of electrodes. It is used to change the charge separation, and thus the electrical potential difference, across the membrane. Monitoring the additional current that is passed to clamp the membrane potential at its new value then provides a measure of the membrane current passing through the ion channels in the membrane.

These depolarizations open voltage-gated Na+ and K+ channels. The resulting movement of Na+ and K+ across the membrane would ordinarily change the membrane potential, but the voltage clamp maintains the membrane potential at its commanded level. When Na+ channels open in response to a moderate depolarizing voltage step, an inward ionic current develops because Na+ ions flow through these channels as a result of their electrochemical driving force. This Na +

influx normally depolarizes the membrane by increasing the positive charge on the inside of the membrane and reducing the positive charge on the outside.

The voltage clamp intervenes in this process by simultaneously withdrawing positive charges from the cell and depositing them in the external solution. By generating a current that is equal and opposite to the ionic current, the voltage-clamp circuit automatically prevents the ionic current from changing the membrane potential from the commanded value (Figure 9-2A). As a result, the net amount of charge separated by the membrane does not change and therefore no significant change in Vm can occur. The voltage clamp is a negative feedback system. A negative feedback system is one in which the value of the output of the system (Vm in this case) is “fed back” to the input of the system, where it is compared to a command signal for the desired output. Any difference between the command potential and the output signal activates a “controller” device that automatically reduces the difference. Thus the membrane potential automatically follows the command potential exactly (Figure 9-2B). For example, assume that an inward Na+ current through the voltage-gated Na+ channels causes the membrane potential to become more positive than the command potential. The input to the feedback amplifier is equal to (Vcommand - Vm). Thus, both the input and the resulting output voltage at the feedback amplifier will be negative. This negative output voltage will make the internal current electrode negative, withdrawing net positive charge from the cell through the voltageclamp circuit. As the current flows around the circuit, an equal amount of net positive charge will be deposited into the external solution through the other current electrode. A refinement of the voltage clamp, the patch-clamp technique, allows the functional properties of individual ion channels to be analyzed (see Box 6-1).

Figure 9-2B The negative feedback mechanism by which the voltage clamp operates. Membrane potential is measured by one amplifier connected to an intracellular electrode and to an extracellular electrode in the bath. The membrane potential signal is displayed on an oscilloscope and is also fed into one terminal of the “feedback” amplifier. This amplifier has two inputs, one for membrane potential (Vm) and the other for the command potential. The command potential, which comes from a signal generator, is selected by the experimenter and can be of any desired amplitude and waveform. The feedback amplifier subtracts the membrane potential from the command potential. Any difference between these two signals is amplified several thousand times at the feedback amplifier. The output of this amplifier is connected to a current electrode, a thin wire that runs the length of the axon. To accurately measure the current-voltage relationship of the cell membrane, the membrane potential must be uniform along the entire surface of the axon. This is achieved by using a highly conductive current electrode, which short circuits the axoplasmic resistance, reducing the axial resistance to zero (see Chapter 8). This low-resistance pathway within the axon eliminates all potential differences along the axon core.

If a larger depolarizing step is commanded, the current record becomes more complicated. The capacitive and leakage currents both increase in amplitude. In addition, shortly after the end of the capacitive current and the start of the leakage current, an inward current develops; it reaches a peak within a few milliseconds, declines, and gives way to an outward current. This outward current reaches a plateau that is maintained for the duration of the pulse (Figure 9-3B). A simple interpretation of these results is that the depolarizing voltage step sequentially turns on active conductance channels for two separate ions: one type of channel for inward current and another for outward current. Because these two oppositely directed currents partially overlap in time, the most difficult task in analyzing voltage-clamp experiments is to determine their separate time courses. Hodgkin and Huxley achieved this separation by changing ions in the bathing solution. By substituting a larger, impermeant cation (choline ·H+) for Na+, they eliminated the inward Na+ current. Subsequently, the task of separating inward and outward currents was made easier by selectively blocking the voltage-sensitive conductance channels with drugs or toxins. Tetrodotoxin, a poison from certain Pacific puffer fish, blocks the voltage-gated Na+ channel with a very high potency in the nanomolar range of concentration. (Ingestion of only a few milligrams of tetrodotoxin from improperly prepared puffer fish, consumed as the Japanese sushi delicacy fugu, can be fatal.) The cation tetraethylammonium specifically blocks the voltage-gated K+ channel (Figure 9-4). When tetraethylammonium is applied to the axon to block the K+ channels, the total membrane current (Im) consists of Ic, Il, and INa. The leakage conductance, P.154 gl, is constant; it does not vary with Vm or with time. Therefore, Il, the leakage current, can be readily calculated and subtracted from Im, leaving INa and Ic. Because Ic occurs only briefly at the beginning and end of the pulse, it can be easily isolated by visual inspection, leaving the pure INa. The full range of current flow through the voltage-gated Na+ channels (INa) is measured by repeating this analysis after stepping Vm to many different levels. With a similar process, IK can be measured when the Na+ channels are blocked by tetrodotoxin (Figure 9-3C).

Figure 9-3 A voltage-clamp experiment demonstrates the sequential activation of two types of voltage-gated channels. A. A small depolarization is accompanied by capacitive and leakage currents (Ic and Il, respectively). B. A larger depolarization results in larger capacitive and leakage currents, plus an inward current followed by an outward current. C. Depolarizing the cell in the presence of tetrodotoxin (which blocks the Na+ current) and again in the presence of tetraethylammonium (which blocks the K+ current), reveals the pure K+ and Na+ currents (IK and INa, respectively) after subtracting Ic and Il.

Figure 9-4 Drugs that block voltage-gated Na+ and K+ channels. Tetrodotoxin and saxitoxin both bind to Na+ channels with a very high affinity. Tetrodotoxin is produced by certain puffer fish, newts, and frogs. Saxitoxin is synthesized by the dinoflagellates Gonyaulax that are responsible for red tides. Consumption of clams or other shellfish that have fed on the dinoflagellates during a red tide causes paralytic shellfish poisoning. Cocaine, the active substance isolated from coca leaves, was the first substance to be used as a local anesthetic. It also blocks Na+ channels but with a lower affinity and specificity than tetrodotoxin. Tetraethylammonium is a cation that blocks certain voltage-gated K+ channels with a relatively low affinity. The red plus signs represent positive charge.

Voltage-Gated Sodium and Potassium Conductances Are Calculated From Their Currents The Na+ and K+ currents depend on two factors: the conductance for each ion and the electrochemical driving force acting on the ion. Since the Na+ and K+ membrane conductance is directly proportional to the number of open Na+ and K+ channels, we can gain insight into how membrane voltage controls channel opening by calculating the amplitudes and time courses of the Na+ and K+ conductance changes in response to voltage-clamp depolarizations (Box 9-2). Measurements of Na+ and K+ conductances at various levels of membrane potential reveal two functional similarities and two differences between the Na+ and K+ channels. Both types of channels open in response to depolarizing steps of membrane potential. Moreover, as the size of the depolarization increases, the probability and rate of opening increase for both types of channels. The Na+ and K+ channels differ, however, in their rates of opening and in their responses to prolonged depolarization. At all levels of depolarization the Na+ channels open more rapidly than do the K+ channels (Figure 9-6). When the depolarization is maintained for some time, the Na+ channels begin to close, leading to a decrease of inward current. The process by which Na+ channels close during a maintained depolarization is termed inactivation. In contrast, the K+ channels in the squid axon do not inactivate; they remain open as long as the membrane is depolarized (Figure 9-7). Thus, depolarization causes Na+ channels to undergo transitions among three different states, which represent three different conformations of the Na+ channel protein: resting, activated, or inactivated. Upon depolarization the channel goes from the resting (closed) state to the activated (open) state (see Figure 6-6C). If the depolarization is brief, the channels go directly back to the resting state upon repolarization. If the depolarization is maintained, the channels go from the open to the inactivated (closed) state. Once the channel is inactivated it cannot be opened by further depolarization. The inactivation can be reversed only by repolarizing the membrane to its negative resting potential, which allows the channel to switch from the inactivated to the resting state. This switch takes some time because channels leave the inactivated state relatively slowly (Figure 9-8). These variable, time-dependent effects of depolarization on gNa are determined by the kinetics of the gating reactions that control the Na+ channels. Each Na+ channel has two kinds of gates that must be opened simultaneously for the channel to conduct Na+ ions. An activation gate is closed when the membrane is at its negative resting potential and is rapidly opened by depolarization; P.155 an inactivation gate is open at the resting potential and closes slowly in response to depolarization. The channel conducts only for the brief period during a depolarization when both gates are open. Repolarization reverses the two processes, closing the activation gate rapidly and opening the inactivation gate more slowly. After the channel has returned to the resting state, it can again be activated by depolarization (Figure 9-9).

Box 9-2 Calculation of Membrane Conductances From Voltage-Clamp Data Membrane conductance can be calculated from voltage-clamp currents using equations derived from an equivalent circuit of the membrane that includes the

membrane capacitance (Cm) and leakage conductance (gl), as well as gNa and gK (Figure 9-5). In this context gl represents the conductance of all of the resting K +,

Na+, and Cl- channels (see Chapter 7); gNa and gK represent the conductances of the voltage-gated Na+ and K+ channels. The ionic battery of the resting

(leakage) channels, El, is equal to the resting potential. The voltage-sensitive Na+ and K+ conductances are in series with their appropriate ionic batteries. The current through each class of voltage-gated channel may be calculated from Ohm's law:

and Rearranging and solving for g gives two equations that can be used to compute the conductances of the active Na+ and K+ channel populations:

and

To solve these equations, one must know Vm, EK, ENa, IK, and INa. The independent variable, Vm, is set by the experimenter. The dependent variables, IK and INa, can be calculated from the records of voltage-clamp experiments (see Figure 9-3C). The remaining variables, EK and ENa, are constants; they can be determined empirically by finding the values of Vm at which IK and INa reverse their polarities, that is, their reversal potentials. For example, as Vm is stepped to very positive values, the inward INa becomes smaller because of the smaller inward electrochemical driving force on Na+. When Vm equals ENa, INa is zero owing to the lack of a net driving force. At potentials that are positive to ENa, INa becomes outward (corresponding to a net efflux of Na+ ions from the axon) because of a net outward driving force on Na+.

Figure 9-5 Electrical equivalent circuit of a nerve cell being held at a depolarized potential under voltage-clamp conditions. The voltage-gated conductance pathways (gK and gNa) are represented by the symbol for variable conductance—a conductor (resistor) with an arrow through it.

The Action Potential Can Be Reconstructed From the Properties of Sodium and Potassium Channels Hodgkin and Huxley were able to fit their measurements of membrane conductance changes to a set of empirical equations that completely describe variations in membrane Na+ and K+ conductances as functions of membrane potential and time. Using these equations P.156 and measured values for the passive properties of the axon, they computed the expected shape and the conduction velocity of the propagated action potential. The calculated waveform of the action potential matched the waveform recorded in the unclamped axon almost perfectly! This close agreement indicates that the voltage and time dependence of the active Na+ and K+ channels, calculated from the voltage-clamp data, accurately describe the properties of the channels that are essential for generating and propagating the action potential. A half century later, the Hodgkin-Huxley model stands as the most successful quantitative computational model in neural science if not in all of biology.

Figure 9-6 Voltage-clamp experiments show that Na+ channels turn on and off more rapidly than K+ channels over a wide range of membrane potentials. The increases and decreases in the Na+ and K+ conductances (gNa and gK) shown here reflect the shifting of thousands of voltage-gated channels between the open and closed states.

Figure 9-7 Sodium and potassium channels respond differently to long-term depolarization. If the membrane is repolarized after a brief depolarization (line a), both gNa and gK return to their initial values. If depolarization is maintained (line b), the Na+ channels close (or inactivate) before the depolarization is terminated, whereas the K+ channels remain open and gK increases throughout the depolarization.

According to the Hodgkin-Huxley model, an action potential involves the following sequence of events. A depolarization of the membrane causes Na+ channels to open rapidly (an increase in gNa), resulting in an inward Na+ current. This current, by discharging the membrane capacitance, causes further depolarization, thereP.157 by opening more Na+ channels, resulting in a further increase in inward current. This regenerative process drives the membrane potential toward ENa, causing the rising phase of the action potential.1 The depolarizing state of the action potential then limits the duration of the action potential in two ways: (1) It gradually inactivates the Na+ channels, thus reducing gNa, and (2) it opens, with some delay, the voltage-gated K+ channels, thereby increasing gK. Consequently, the inward Na +

current is followed by an outward K+ current that tends to repolarize the membrane (Figure 9-10).

Figure 9-8 Sodium channels remain inactivated for a few milliseconds after the end of a depolarization. Therefore if the interval between two depolarizing pulses (P1 and P2) is brief, the second pulse produces a smaller increase in gNa because many of the Na+ channels are inactivated. The longer the interval between pulses, the greater the increase in gNa, because a greater fraction of channels will have recovered from inactivation and returned to the resting state when the second pulse begins. The time course of recovery from inactivation contributes to the time course of the refractory period.

Figure 9-9 Voltage-gated Na+ channels have two gates, which respond in opposite ways to depolarization. In the resting (closed) state the activation gate is closed and the inactivation gate is open (1). Upon depolarization a rapid opening of the activation gate allows Na+ to flow through the channel (2). As the inactivation gates close, the Na+ channels enter the inactivated (closed) state (3). Upon repolarization, first the activation gate closes, then the inactivation gate opens as the channel returns to the resting state (1).

In most nerve cells the action potential is followed by a transient hyperpolarization, the after-potential. This brief increase in membrane potential occurs because the K+ channels that open during the later phase of the action potential close some time after Vm has returned to its resting value. It takes a few milliseconds for all of the voltage-gated K+ channels to return to the closed state. During this time, when the permeability of the membrane to K+ is greater than during the resting state, Vm is hyperpolarized slightly with respect to its normal resting value, resulting in a Vm closer to EK (Figure 9-10). The action potential is also followed by a brief period of diminished excitability, or refractoriness, which can be divided into two phases. The absolute refractory period comes immediately after the action potential; during this period it is impossible to excite the cell no matter how great a stimulating current is applied. This phase is followed directly by the relative refractory period, during which it is possible to trigger an action potential but only by applying stimuli that are stronger than those normally required to reach threshold. These periods of refractoriness, which together last just a few milliseconds, are caused by the residual inactivation of Na+ channels and increased opening of K+ channels.

Figure 9-10 The sequential opening of voltage-gated Na+ and K+ channels generates the action potential. One of Hodgkin and Huxley's great achievements was to separate the total conductance change during an action potential, first detected by Cole and Curtis (see Figure 9-1) into separate components attributable to the opening of Na+ and K+ channels. The shape of the action potential and the underlying conductance changes can be calculated from the properties of the voltagegated Na+ and K+ channels.

P.158 Another feature of the action potential predicted by the Hodgkin-Huxley model is its all-or-none behavior. A fraction of a millivolt can be the difference between a subthreshold depolarizing stimulus and a stimulus that generates an action potential. This all-or-none phenomenon may seem surprising when one considers that the Na +

conductance increases in a strictly graded manner as depolarization is increased (see Figure 9-6). Each increment of depolarization increases the number of voltage-

gated Na+ channels that switch from the closed to the open state, thereby causing a gradual increase in Na+ influx. Why then is there an abrupt threshold for generating an action potential? Although a small subthreshold depolarization increases the inward INa, it also increases two outward currents, IK and Il, by increasing the electrochemical driving force on K+ and Cl-. In addition, the depolarization augments the K+ conductance, gK, by gradually opening more voltage-gated K+ channels (see Figure 9-6). As IK and Il increase with depolarization, they tend to resist the depolarizing action of the Na+ influx. However, because of the great voltage sensitivity and rapid kinetics of activation of the Na+ channels, the depolarization eventually reaches a point where the increase in inward INa exceeds the increase in outward IK and Il. At this point there is a net inward current producing a further depolarization so that the depolarization becomes regenerative. The specific value of Vm at which the net ionic current (INa + IK + Il) just changes from outward to inward, depositing a net positive charge on the inside of the membrane capacitance, is the threshold.

Variations in the Properties of Voltage-Gated Ion Channels Increase the Signaling Capabilities of Neurons The basic mechanism of electrical excitability identified by Hodgkin and Huxley in the squid giant axon—whereby voltage-gated ion channels conduct an inward ionic current followed by an outward ionic current—appears to be universal in all excitable cells. However, dozens of different types of voltage-gated ion channels have been identified in other nerve and muscle cells, and the distribution of specific types varies not only from cell to cell but also from region to region within a cell. These differences in the pattern of ion channel expression have important consequences for the details of membrane excitability, as we shall now explore.

The Nervous System Expresses a Rich Variety of Voltage-Gated Ion Channels Although the voltage-gated Na+ and K+ channels in the squid axon described by Hodgkin and Huxley have been found in almost every type of neuron examined, several other kinds of channels have also been identified. For example, most neurons contain voltage-gated Ca2+ channels that open in response to membrane depolarization. A strong electrochemical gradient drives Ca2+ into the cell, so these channels give rise to an inward ICa. Some neurons and muscle cells also have voltage-gated Cl- channels. Finally, many neurons have monovalent cation-permeable channels that are slowly activated by hyperpolarization and are permeable to both K+ and Na+. The net effect of the mixed permeability of these rather nonselective channels, called h-type, is the generation of an inward, depolarizing current in the voltage range around the resting potential. Each basic type of ion channel has many variants. For example, there are four major types of voltage-activated K+ channels that differ in their kinetics of activation, voltage activation range, and sensitivity to various ligands. These variants are particularly common in the nervous system. (1) The slowly activating channel described by Hodgkin and Huxley is called the delayed rectifier. (2) A calcium-activated K+ channel is activated by intracellular Ca2+, but its sensitivity to intracellular Ca2+ is enhanced by depolarization. It requires both a rise in internal Ca2+ (mediated by voltage-gated Ca2+ channels) and depolarization to achieve a maximum P.159 probability of opening. (3) The A-type K+ channel is activated rapidly by depolarization, almost as rapidly as the Na+ channel; like the Na+ channel, it also inactivates rapidly if the depolarization is maintained. (4) The M-type K+ channel is very slowly activated by small depolarizations from the resting potential. One distinctive feature of the M-type channels is that they can be closed by a neurotransmitter, acetylcholine (ACh). Similarly, there are at least five subtypes of voltage-gated Ca2+ channels and two or more types of voltage-gated Na+ channels. Moreover, each of these subtypes has several structurally and functionally different isoforms. The squid axon can generate an action potential with just two types of voltage-gated channels. Why then are so many different types of voltage-gated ion channels found in the nervous system? The answer is that neurons with an expanded set of voltage-gated channels have much more complex information-processing abilities than those with only two types of channels. Some ways in which this large variety of voltage-gated channels influences neuronal function are described below.

Gating of Voltage-Sensitive Ion Channels Can Be Influenced by Various Cytoplasmic Factors In a typical neuron the opening and closing of certain voltage-gated ion channels can be modulated by various cytoplasmic factors, resulting in increased flexibility of the neuron's excitability properties. Changes in such cytoplasmic modulator substances may result from the normal intrinsic activity of the neuron itself or from the influences of other neurons. The flow of ionic current through membrane channels during an action potential generally does not result in appreciable changes in the intracellular concentrations of most ion species. Calcium is a notable exception to this rule. Changes in the intracellular concentration of Ca2+ can have important modulatory influences on the gating of various channels. The concentration of free Ca2+ in the cytoplasm of a resting cell is extremely low, about 10-7 M, several orders of magnitude below the external Ca2 +

concentration. For this reason the intracellular Ca2+ concentration may increase significantly as a result of inward current flow through voltage-gated Ca2+ channels.

The transient increase in Ca2+ concentration near the inside of the membrane has several effects. It enhances the probability that Ca2+-activated K+ channels will open. Some Ca2+ channels are themselves sensitive to levels of intracellular Ca2+ and are inactivated when incoming Ca2+ binds to their intracellular surface. In other

channels the influx of Ca2+ activates a Ca2+-sensitive protein phosphatase, calcineurin, which dephosphorylates the channel, thereby inactivating it (see Figure 6-7C). Thus, in some cells the Ca2+ influx during an action potential can have two opposing effects: (1) The positive charge that it carries into the cell contributes to the regenerative depolarization, while (2) the increase in cytoplasmic Ca2+ concentration results in the opening of more K+ channels and the closing of Ca2+ channels. Because of the opening of K+ channels and the closing of Ca2+ channels, outward ionic current increases while inward ionic current decreases; the resulting net efflux of positive charge causes the cell to repolarize. In this way the depolarizing influx of Ca2+ through voltage-gated Ca2+ channels is self-limited by two processes that aid repolarization: an increase in K+ efflux and a decrease in Ca2+ influx. Calcium's role in modulating the gating of ion channels is the simplest example of a variety of second-messenger systems that control channel activity. Gating of ion channels can also be modulated by changes in the cytoplasmic level of small organic second-messenger compounds as a result of synaptic input from other neurons. The gating properties of several voltage-gated channels that are directly involved in generating action potentials are modified when their phosphorylation state is changed by a protein kinase (eg, the cAMP-dependent protein kinase) whose activity is controlled by changes in the concentration of synaptically activated second messengers (eg, cAMP). The importance of Ca2+ and other second messengers in the control of neuronal activity will become evident in many contexts throughout this book.

Excitability Properties Vary Between Regions of the Neuron Different regions of the cell perform specific signaling tasks. The axon, for example, usually specializes in carrying signals faithfully over long distances. As such, it functions as a relatively simple relay line. In contrast, the input, integrative, and output regions of a neuron (see Figure 2-8) typically perform more complex processing of the information they receive before passing it along. The signaling function of a discrete region of the neuron depends on the particular set of ion channels that it expresses. In many types of neurons the dendrites have voltage-gated ion channels, including Ca2+, K+, and in some cases Na+ channels. When activated, these channels modify the passive, electrotonic conduction of synaptic potentials. In some neurons action potentials may be propagated from their site of initiation at the P.160 trigger zone back into the dendrites, thereby influencing synaptic integration in the dendrites. In other neurons the density of dendritic voltage-gated channels may even support the orthograde propagation of a dendritic impulse to the cell soma and axon hillock. The trigger zone of the neuron has the lowest threshold for action potential generation, in part because it has an exceptionally high density of voltage-gated Na+ channels. In addition, it typically has voltage-gated ion channels that are sensitive to relatively small deviations from resting potential. These channels are important in determining whether synaptic input will drive the membrane potential to spike threshold. They thus play a critical role in the transformation of graded, analog changes in synaptic or receptor potentials into a temporally patterned, digital train of all-or-none action potentials. Examples include the M-type and certain A-type K+ channels, the hyperpolarization-activated h-type channels, and a class of low voltage-activated Ca2+ channels (see below). As the action potential is carried down the axon it is mediated primarily by voltage-gated Na+ and K+ channels that function much like those in the squid axon. At the nodes of Ranvier of myelinated axons the mechanism of action potential repolarization is particularly simple—the spike is terminated by fast inactivation of Na+ channels combined with a large outward leakage current. Voltage-gated K+ channels do not play a significant role in action potential repolarization at the nodal membrane. Presynaptic nerve terminals at chemical synapses commonly have a high density of voltage-gated Ca2+ channels. Arrival of an action potential in the terminal opens these channels, causing Ca2+ influx, which in turn triggers transmitter release.

Excitability Properties Vary Among Neurons The computing power of an entire neural circuit is enhanced when cells in the circuit represent a wide range of functional properties, because specific functions within the circuit can be assigned to cells with the most appropriate dynamic properties. Thus, while the function of a neuron is determined to a great extent by its anatomical relationships to other neurons (its inputs and its outputs), the biophysical properties of the cell also play a critical role. How a neuron responds to synaptic input is determined by the proportions of different types of voltage-gated channels in the cell's integrative and trigger zones. Cells with different combinations of channels respond to a constant excitatory input differently. Some cells respond with only a single action potential, others with a constantfrequency train of action potentials, and still others with either an accelerating or decelerating train of action potentials. Some neurons even fire spontaneously in the absence of any external input because of the presence of h-type channels that generate endogenous pacemaker currents (Figure 9-11). In certain neurons small changes in the strength of synaptic inputs produce a large increase in firing rate, whereas in other cells large changes in synaptic input are required to modulate the firing rate. In many neurons a steady hyperpolarizing input makes the cell less responsive to excitatory input by reducing the resting inactivation of the A-type K+ channels. In other neurons such a steady hyperpolarization makes the cell more excitable, because it removes the inactivation of a particular class of voltage-gated Ca2+ channels. In many cases the firing properties of a neuron can be modulated by second messenger-mediated changes in the function of voltage-gated ion channels (Figure 9-11).

The Signaling Functions of Voltage-Gated Channels Can Be Related to Their Molecular Structures The empirical equations derived by Hodgkin and Huxley are quite successful in describing how the flow of ions through the Na+ and K+ channels generates the action potential. However, these equations describe the process of excitation primarily in terms of changes in membrane conductance and current flow. They tell little about the molecular structure of the voltage-gated channels and the molecular mechanisms by which they are activated. Fortunately, technical advances such as those described in Chapter 6 have made it possible to examine the structure and function of the voltage-gated Na+, K+, and Ca2+ channels in detail at the molecular level. One of the first clues that Na+ channels are distinct physical entities came from studies that measured the binding of radiolabeled tetrodotoxin to nerve membranes. The density of voltage-gated Na+ channels in different nerves was estimated by measuring the total amount of tritium-labeled tetrodotoxin bound when specific axonal binding sites are saturated. In nonmyelinated axons the density of channels is quite low, ranging from 35 to 500 Na+ channels per square micrometer of axon membrane in different cell types. In myelinated axons, where the Na+ channels are concentrated at the nodes of Ranvier, the density is much higher—between 1000 and 2000 channels per square micrometer of nodal membrane. The greater the density of Na+ channels in the membrane of an axon, the greater the velocity at P.161 which the axon conducts action potentials. A higher density of voltage-gated Na+ channels allows more current to flow through the excited membrane and along the axon core, thus rapidly discharging the capacitance of the unexcited membrane downstream (see Figure 8-6).

Figure 9-11 Repetitive firing properties vary widely among different types of neurons because the neurons differ in the types of voltage-gated ion channels they express. A. Injection of a depolarizing current pulse into a neuron from the nucleus tractus solitarius normally triggers an immediate train of action potentials (1). If the cell is first held at a hyper-polarized membrane potential, the depolarizing pulse triggers a spike train after a delay (2). The delay is caused by the A-type K+ channels, which are activated by depolarizing synaptic input. The opening of these channels generates a transient outward K+ current that briefly drives Vm away from threshold. These channels typically are inactivated at the resting potential (-55 mV), but steady hyperpolarization removes the inactivation, allowing the channels to be activated by depolarization. (From Dekin and Getting 1987.) B. When a small depolarizing current pulse is injected into a thalamic neuron at rest, only an electrotonic, subthreshold depolarization is generated (1). If the cell is held at a hyperpolarized level, the same current pulse triggers a burst of action potentials (2). The effectiveness of the current pulse is enhanced because the hyperpolarization causes a type of voltage-gated Ca2+ channel to recover from inactivation. The dashed line indicates the level of the resting potential. (From Llinás and Jahnsen 1982.) The data in A and B demonstrate that steady hyperpolarization, such as might be produced by inhibitory synaptic input to a neuron, can profoundly affect the spike train pattern that a neuron generates. This effect varies greatly among cell types. C. In the absence of synaptic input, thalamocortical relay neurons can fire spontaneously in brief bursts of action potentials. These endogenously generated bursts are produced by current flow through two types of voltage-gated ion channels. The gradual depolarization that leads to a burst is driven by inward current flowing through the h-type channels, whose activation gates have the unusual property of opening in response to hyperpolarizing voltage steps. The burst is triggered by inward Ca2+ current through voltage-gated Ca2+ channels that are activated at relatively low levels of depolarization. This Ca2+ influx generates sufficient depolarization to reach threshold and drive a train of Na+-dependent action potentials. The strong depolarization during the burst causes the h-type channels to close and inactivates the Ca2+ channels, allowing the interburst hyperpolarization to develop. This hyperpolarization then opens the h-type channels, initiating the next cycle in the rhythm. (From McCormick and Huguenard 1992.) D. The firing properties of sympathetic neurons in autonomic ganglia are regulated by a neurotransmitter. A prolonged depolarizing current normally results in only a single action potential. This is because depolarization turns on a slowly activated K+ current, the M current. The slow activation kinetics of the M-type channels allow the cell to fire one action potential before the efflux of K+ through the M-type channels becomes sufficient to shift the membrane to more negative voltages and prevent the cell from firing more action potentials (a process termed accommodation). The neurotransmitter acetylcholine (ACh) closes the M-type channels, allowing the cell to fire many action potentials in response to the same stimulus. (From Jones and Adams 1987.)

Opening of Voltage-Gated Channels Is All-or-None The current flow through a single channel cannot be measured in ordinary voltage-clamp experiments for two reasons. First, the voltage clamp acts on a large area of membrane in which thousands of channels are opening P.162 and closing randomly. Second, the background noise caused by the flow of current through passive membrane channels is much larger than the flow of current through any one channel. Both these problems can be circumvented by electrically isolating a tiny piece of membrane in a patch-clamp electrode (see Box 6-1). Patch-clamp experiments demonstrate that voltage-gated channels generally have only two conductance states, open and closed. Each channel opens in an all-or-none fashion and, when open, permits a pulse of current to flow with a variable duration but constant amplitude (Figure 9-12). The conductances of single voltage-gated Na +,

K+, and Ca2+ channels in the open state typically range from 1 to 20 pS, depending on channel type. One class of Ca2+-activated K+ channels has an unusually large conductance of about 200 pS.

Redistribution of Charges Within Voltage-Gated Sodium Channels Controls Channel Gating In their original study of the squid axon, Hodgkin and Huxley suggested that a voltage-gated channel has a net charge, the gating charge, somewhere within its wall. They postulated that a change in membrane potential causes this charged structure to move within the plane of the membrane, resulting in a conformational change that causes the channel to open or close. They further predicted that such a charge movement would be measurable. For example, when the membrane is depolarized a positive gating charge would move from near the inner surface toward the outer surface of the membrane, owing to its interaction with the membrane electric field. Such a displacement of positive charge would reduce the net separation of charge across the membrane and hence tend to hyperpolarize the membrane. To keep the membrane potential constant in a voltage-clamp experiment, a small extra component of outward capacitive current, called gating current, would have to be generated by the voltage clamp. When the membrane current was examined by means of very sensitive techniques, the predicted gating current was found to flow at the beginning and end of a depolarizing voltage-clamp step prior to the opening or closing of the Na+ channels (Figure 9-13). Analysis of the gating current reveals that activation and inactivation of Na+ channels are coupled processes. During a short depolarizing pulse net outward movement of gating charge within the membrane at the beginning of the pulse is balanced by an opposite inward movement of gating charge at the end of the pulse. However, if the pulse lasts long enough for Na+ inactivation to take place, the movement of gating charge back across the membrane at the end of the pulse is delayed. The gating P.163

charge is thus temporarily immobilized; only as the Na+ channels recover from inactivation is the charge free to move back across the membrane. This charge immobilization indicates that the gating charge cannot move while the channel is in the inactivated state, ie, while the inactivation gate is closed (see Figure 9-9).

Figure 9-12 Individual voltage-gated channels open in an all-or-none fashion. A. A small patch of membrane containing only a single voltage-gated Na+ channel is electrically isolated from the rest of the cell by the patch electrode. The Na+ current that enters the cell through these channels is recorded by a current monitor connected to the patch electrode. B. Recordings of single Na+ channels in cultured muscle cells of rats. 1. Time course of a 10 mV depolarizing voltage step applied across the patch of membrane (Vp = potential difference across the patch). 2. The sum of the inward current through the Na+ channels in the patch during 300 trials (Ip = current through the patch of membrane). The trace was obtained by blocking the K+ channels with tetraethylammonium and subtracting the capacitive current electronically. 3. Nine individual trials from the set of 300, showing six individual Na+ channel openings (circles). These data demonstrate that the total Na+ current recorded in a conventional voltage-clamp record (see Figure 9-3C) can be accounted for by the all-or-none opening and closing of individual Na+ channels. (From Sigworth and Neher 1980.)

Figure 9-13 Gating currents directly measure the changes in charge distribution associated with Na+ channel activation. A. When the membrane is depolarized the Na+ current (INa) first activates and then inactivates. The activation of the Na+ current is preceded by a brief outward gating current (Ig), reflecting the outward movement of positive charge within the Na+ channel protein associated with the opening of the activation gate. To detect the small gating current it is necessary to block the flow of ionic current through the Na+ and K+ channels and mathematically subtract the capacitive current due to charging of the lipid bilayer. B. Illustration of the position of the activation and inactivation gates when the channel is at rest (1), when the Na+ channels have been opened (2), and when the channels have been inactivated (3). It is the movement of the positive charge on the activation gate through the membrane electric field that generates the gating current.

To explain this phenomenon, Clay Armstrong and Francisco Bezanilla proposed that Na+ channel inactivation occurs when the open (activated) channel is blocked by a tethered plug (the ball and chain mechanism), thereby preventing the closure of the activation gate. In support of this idea, exposing the inside of the axon to proteolytic enzymes selectively removes inactivation, causing the Na+ channels to remain open during a depolarization, presumably because the enzymes clip off the inactivation “ball.”

The Voltage-Gated Sodium Channel Selects for Sodium on the Basis of Size, Charge, and Energy of Hydration of the Ion After the gates of the Na+ channel have opened, how does the channel discriminate between Na+ and other ions? The channel's selectivity mechanism can be probed by measuring the channel's relative permeability to several types of organic and inorganic cations that differ in size and hydrogen-bonding characteristics. As we learned in Chapter 6, the channel behaves as if it contains a filter or recognition site that selects partly on the basis of size, thus acting as a molecular sieve (see Figure 6-3A,6-3B). The ease with which ions with good hydrogen-bonding characteristics pass through the channel suggests that part of the inner wall of the channel is made up of negatively polarized or charged amino acid residues that can substitute for water. When the pH of the fluid surrounding the cell is lowered, the conductance of the open channel is gradually reduced, consistent with the titration of important negatively charged carboxylic acid residues. The selectivity filter of the Na+ channel is made up of four loops within the molecule (the P region) that are similar in structure (see below). A glutamic acid residue is situated at equivalent points in two of these loops. A lysine and an alanine residue are situated at the equivalent site in the other two loops. The channel is thought to select for Na+ ions by the following mechanism. The negatively charged carboxylic acid groups of the glutamic acid residues, which are located at the outer mouth of the pore, perform the first step in the selection process by attracting cations and repelling anions. The cations then encounter a constricted portion of the pore, the selectivity filter, with rectangular dimensions of 0.3 × 0.5 nm. This cross section is just large enough to accommodate one Na+ ion contacting one water molecule. Cations that are larger in diameter cannot pass through P.164 the pore. Cations smaller than this critical size pass through the pore, but only after losing most of the waters of hydration they normally carry in free solution. The negative carboxylic acid group, as well as other oxygen atoms that line the pore, can substitute for these waters of hydration, but the degree of effectiveness of this substitution varies among ion species. The more effective the substitution, the more readily ions can traverse the Na+ channel. The Na+ channel excludes K+ ions, in part because the larger-diameter K+ ion cannot interact as effectively with the negative carboxylic group. The lysine and alanine residues also contribute to the selectivity of the channel. When these residues are changed to glutamic acid residues by site-directed mutagenesis, the Na+ channels can act as Ca2+-selective channels! (The mechanism whereby K+ selectivity is achieved was discussed in Chapter 6.)

Genes Encoding the Potassium, Sodium, and Calcium Channels Stem From a Common Ancestor Since a change in two amino acid residues can cause a Na+ channel to behave as a Ca2+ channel, it is reasonable to believe that the Na+ and Ca2+ channels may be closely related. Detailed molecular studies have revealed that all voltage-gated ion channels—those for K+, Na+, and Ca2+—share several functionally important domains and are indeed quite similar. In fact, there is now strong evidence from studies of bacteria, plants, invertebrates, and vertebrates that most voltage-sensitive cation channels stem from a common ancestral channel—perhaps a K+ channel—that can be traced to a single-cell organism living over 1.4 billion years ago, before the evolution of separate plant and animal kingdoms. The amino acid sequences conserved through evolution help identify the domains within contemporary cation channels that are critical for function. Molecular studies of the voltage-sensitive cation channels began with the identification of Na+ channel molecules. Three subunits have been isolated: one large glycoprotein (α) and two smaller polypeptides (β1 and β2). The α-subunit is ubiquitous, and insertion of this subunit into an artificial lipid bilayer reconstitutes the basic features of Na+ channel function. Therefore the α-subunit is presumed to form the aqueous pore of the channel. The smaller subunits, whose presence varies in different regions of the nervous system, regulate various aspects of α-subunit function. Examination of the amino acid sequence encoded by the cloned gene for the α-subunit of the Na+ channel reveals two fundamental features of the structure of the Na+ channel. First, the α-subunit is composed of four internal repeats (domains I-IV), with only slight variations, of a sequence that is approximately 150 amino acids in length. Each of the four repeats of this sequence domain is believed to have six membrane-spanning hydrophobic regions (S1-S6) that are primarily α-helical in form. A seventh hydrophobic region the P region that connects the S5 and S6 segments, appears to form a loop that dips into and out of the membrane (Figure 9-14). The four repeated domains are thought to be arranged roughly symmetrically, with the P region and some of the membrane-spanning regions forming the walls of the waterfilled pore (Figure 9-15). The second structural feature of the Na+ channel revealed by amino acid sequence analysis is that one of the six putative membrane-spanning regions, the S4 region, is structurally quite similar in the Na+ channels of many different species. This strict conservation suggests that the S4 region is critical to Na+ channel function. Moreover, the S4 region of the Na+ channel is similar to corresponding regions of the voltage-gated Ca2+ and K+ channels (Figure 9-14) but is lacking in K+ channels that are not activated by voltage (see below). For this reason the S4 region may be the voltage sensor—that part of the protein that transduces depolarization of the cell membrane into a gating transition within the channel, thereby opening the channel. This idea is supported by the observation that the S4 region contains a distinctive pattern of amino acids. Every third amino acid along the S4 helix is positively charged (lysine or arginine) while the intervening two amino acids are hydrophobic. This highly charged structure is therefore likely to be quite sensitive to changes in the electric field across the membrane. Experiments using site-directed mutagenesis show that reducing the net positive charge in one of the S4 regions of the channel lowers the voltage sensitivity of Na+ channel activation. Structure-function studies based on genetic engineering of the α-subunit have led to a hypothesis about how the charges in the S4 region move across the membrane during channel gating. According to the scheme, at rest one of the charged residues on the S4 α-helix is completely buried in the wall of the channel, where its positive charge is stabilized by interaction with a negatively charged amino acid residue in one of the other membrane-spanning segments of the channel (Figure 9-16). The other positive charges are located on parts of the S4 helix that are within a water-filled lacuna in the wall of the channel that is continuous with the cytoplasm. When the membrane is depolarized the change in electrostatic force causes movement of the S4 helix relative to the surrounding channel wall, translocating some of the positively charged residues to the outside of P.165 the membrane. This movement is somehow transduced into opening of the activation gate.

Figure 9-14 The pore-forming subunits of the voltage-gated Na+, Ca2+, and K+ channels are composed of a common repeated domain. The α-subunit of the Na+ and Ca2+ channels consists of a single polypeptide chain with four repeats (I-IV) of a domain that contains six membrane-spanning α-helical regions (S1-S6). A stretch of amino acids, the P region between α-helices 5 and 6, forms a loop that dips into and out of the membrane. The S4 segment is shown in red, representing its net positive charge. The fourfold repetition of the P region is believed to form a major part of the pore lining (see Figure 9-15). The K+ channel, in contrast, has only a single repeat of the six α-helices and the P region. Four K+ channel subunits are assembled to form a complete channel (see Figure 6-12). (Adapted from Catterall 1988, Stevens 1991.)

The genes encoding the major α-subunits of several voltage-gated Ca2+ channels have also been cloned. Their sequences reveal that the Ca2+ channels are also composed of four repeating domains, each with six hydrophobic transmembrane regions and one P loop, which have amino acid sequences homologous to those of the voltage-gated Na+ channel (see Figure 9-14). The K+ channel genes contain only one copy of the domain that is repeated four times in the genes for Na+ and Ca2+ channels. Nevertheless, the basic channel structure is similar for the three channel types, as four α-subunits must aggregate symmetrically around a central pore to form a K+ channel. It is this striking homology among the voltage-gated Na+, Ca2+, and K+ channels that suggests that all three channels belong to the same gene family and have evolved by gene duplication and modification from a common ancestral structure, presumably a K+ channel.

Figure 9-15 The four membrane-spanning domains of the α-subunit in voltage-gated Na+ and Ca2+ channels form the channel pore. The tertiary structure of the channels proposed here is based on the secondary structures shown in Figure 9-14. The central pore is surrounded by the four internally repeated domains (M-I to M-IV). (Only three of the domains are shown here for clarity.) Each quadrant of the channel includes six cylinders, which represent six putative membrane-spanning α-helices. The S4 segment (in red) is thought to be involved in gating because it contains a significant net charge. The protruding loop in each quadrant represents the P region segment that dips into the membrane to form the most narrow region of the wall of the pore.

P.166 The conservative mechanism by which evolution proceeds—creating new structural or functional entities by modifying, shuffling, and recombining existing gene sequences—is illustrated by the modular design of various members of the extended gene family that includes the voltage-gated Na+, K+, and Ca2+ channels. For example, the basic structures of both a Ca2+-activated K+ channel, an h-type cation channel activated by hyperpolarization and intracellular cycle neucleotides, and a voltage-independent cation channel activated by intracellular cyclic nucleotides are the same as the structures of other members of the gene family (six membranespanning α-helices and a P region), with some modifications. The functional differences between these two channels are due primarily to the addition of regulatory domains that bind Ca2+ or cyclic nucleotides, respectively, to the C-terminal ends of the proteins. As we saw in Chapter 6, the subunits that comprise the inwardrectifying K+ channels are truncated versions of the fundamental domain, consisting of the P region and its two flanking membrane-spanning regions. Four such subunits combine to form a functional channel (Figure 9-17). The modular design of this extended gene family is also illustrated by a comparison of activation and inactivation mechanisms of various channels within the family. The S4 membrane-spanning region, which is thought to be the voltage sensor in channels of this family, has a relatively large net charge in the Na+, K+, and Ca2+ channels that open in response to depolarization. In contrast, the S4 regions in cyclic nucleotide-gated channels, which are only weakly sensitive to voltage, have significantly less net charge, and h-type channels lack certain conserved S4 residues. Moreover, inward-rectifying K+ channels, which have essentially no intrinsic voltage sensitivity, completely lack the S4 region. These inward-rectifying channels are activated by the effect of hyperpolarization on freely diffusible, positively charged blocking particles in the cytoplasm. Depending on the subspecies of channel, this blocker may be either Mg2+ or various organic polyamines. These channels open when the cation-blocking particle is electrostatically drawn out of the channel at negative potentials around the resting potential. Inactivation of voltage-gated ion channels is also mediated by different molecular modules. For example, the rapid inactivation of both the A-type K+ channel and the voltage-gated Na+ channel can be attributed to a tethered plug that binds to the inner mouth of the channel when the activation gate opens. In the A-type K+ channel the plug is formed by the cytoplasmic N terminus of the channel, whereas in voltage-gated Na+ channels the cytoplasmic loop connecting domains III and IV of the αsubunit forms the plug.

Various Smaller Subunits Contribute to the Functional Properties of Voltage-Gated Sodium, Calcium, and Potassium Channels Most, perhaps all, voltage-gated Na+, K+, and Ca2+ channels have β- and, in some cases, γ- and δ-subunits that modulate the functional properties of the channelforming α-subunits. The modulatory function of these subunits, which may be either cytoplasmic or membrane-spanning, depends on the type of channel. For example, the subunits may enhance the efficiency of coupling of depolarization to activation or inactivation gating. They may also shift the gating functions to different voltage ranges. In some K+ channels in which the α-subunit lacks a tethered inactivation plug, addition of a set of β-subunits with their own N-terminal tethered plugs can endow the channel with the ability to rapidly inactivate. In contrast to the α-subunits, there is no known homology among the β-, γ-, and δ-subunits from the threemajor subfamilies of voltage-gated channels.

Figure 9-16 Gating of the Na+ channel is thought to rely on redistribution of net charge in the S4 region. A. At rest, the inside-negative electric field across the membrane biases the positively charged S4 helix toward the inside of the membrane. One of the positive charges is stabilized by interaction with a negative charge in another part of the channel. The remainder of the charged region lies in a water-filled cavity in the channel wall that is continuous with the cytoplasm. B. When the cell is depolarized the change in electrical field across the membrane drives the S4 region toward the extracellular face of the membrane. This change in configuration opens the activation gate by a mechanism that is not well understood. (Adapted from Yang et al. 1996.)

P.167

The Diversity of Voltage-Gated Channel Types Is Due to Several Genetic Mechanisms A single ion species can cross the membrane through several distinct types of ion channels, each with its own characteristic kinetics, voltage sensitivity, and sensitivity to different modulators. In voltage-gated channels this diversity may be due to any of five genetic mechanisms: (1) More than one gene may encode related α-subunits within each class of channel. (2) A single gene product may be alternatively spliced in different classes of neurons, resulting in different variants of the mRNA that encodes the α-subunit. (3) The four α-subunits that coalesce to form a K+ channel may be encoded by different genes. After translation the gene products are mixed and matched in various combinations, thus forming different subclasses of heteromultimeric channels. (4) A given α-subunit may be combined with different β-, γ- or δsubunits to form functionally different channel types. (5) The diversity of some β-subunits is increased either by alternative splicing of the pre-mRNA molecule or by the encoding of different variants of a basic β-subunit type on different genes. These various sources of diversity endow the nervous system with tremendous opportunities for regional diversity of functional properties.

Mutations in Voltage-Gated Channels Cause Specific Neurological Diseases Several inherited neurological disorders are now known to be caused by mutations in voltage-gated ion channels. Patients with hyperkalemic periodic paralysis have episodes of muscle stiffness (myotonia) and muscle weakness (paralysis) in response to the elevation of K+ levels in serum after vigorous exercise. Genetic studies have shown that the disease is caused by a point mutation in the α-subunit of the gene for the voltage-gated Na+ channel found in skeletal muscle. Voltage-clamp P.168 P.169 studies of cultured skeletal muscle cells obtained from biopsies of patients with this disorder demonstrate that the voltage-gated Na+ channels fail to completely inactivate. This defect is exacerbated by elevation of external K+. The prolonged opening of the Na+ channels is thought to cause muscles to fire repetitive trains of action potentials, thus producing the muscle stiffness. As the fraction of channels with altered inactivation increases (as a result of continued K+ elevation), the muscle resting potential eventually reaches a new stable depolarized level (around -40 mV), at which point most Na+ channels become inactivated so that the membrane fails to generate further action potentials (paralysis).

Figure 9-17 Ion channels belonging to the extended gene family of voltage-gated channels are variants of a common molecular design. A. Depolarization-activated, noninactivating K+ channels are formed from four copies of an α-subunit, the basic building block of voltage-gated channels. The αsubunit is believed to have six membrane-spanning regions and one membrane-embedded region (the P region). The P region contains a K+- selective sequence (denoted by the rectangle). B. Many K+ channels that are first activated and then inactivated by depolarization have a ball-and-chain segment on their N-terminal ends that inactivates the channel by plugging its inner mouth. C. Potassium channels that are activated by both depolarization and intracellular Ca2+ have a Ca2+-binding sequence attached to the C-terminal end of the channel. D. Cation channels gated by cyclic nucleotides have a cyclic nucleotide-binding domain attached to the C-terminal end. One class of such channels is the voltageindependent, cyclic nucleotide-gated channels important in the transduction of olfactory and visual sensory signals. Another class of channels is the hyperpolarizationactivated h-type channels important for pacemaker activity (see Figure 9-11C). E. Inward-rectifying K+ channels, which are gated by blocking particles available in the cytoplasm, are formed from truncated versions of the basic building block, with only two membrane-spanning regions and the P region.

Patients with episodic ataxia exhibit normal neurological function except during periods of emotional or physical stress, which can trigger a generalized ataxia due to involuntary muscle movements. The disease has been shown to result from one of several point mutations in a delayed-rectifier, voltage-gated K+ channel. These mutations decrease current through the channel, in part by enhancing the rate of inactivation. As a result, because less outward K+ current is available for repolarization, the tendency of nerves and muscle cells to fire repetitively is enhanced. (Remarkably, the first K+ channel gene to be cloned was identified based on a genetic strategy involving a similar mutation in a Drosophila K+ channel gene, which gives rise to the so-called Shaker phenotype.) Muscle diseases involving mutations in Cl- channels (myotonia congenita) and Ca2+ channels (hypokalemic periodic paralysis) have also been identified.

An Overall View An action potential is produced by the movement of ions across the membrane through voltage-gated channels. This ion movement, which occurs only when the channels are open, changes the distribution of charges on either side of the membrane. An influx of Na+, and in some cases Ca2+, depolarizes the membrane, initiating an action potential. An outflow of K+ then repolarizes the membrane by restoring the initial charge distribution. A particularly important subset of voltage-gated ion channels opens primarily when the membrane potential nears the threshold for an action potential; these channels have a profound effect on the firing patterns generated by a neuron. We know something about how channels function from studies using variations on the voltage-clamp technique—these studies let us eavesdrop on a channel at work. And we know something from biochemical and molecular biology studies about the channel's structure—about the primary amino acid sequence of the proteins that form them. Now these two approaches are being combined in a concerted effort to understand the relationship between structure and function in these channels: how they are put together, what their contours and surface map look like, how they interact with other molecules, what the structure of the channel pore is, and how its gate is opened. Thus, we may soon be able to understand the molecular mechanism for the remarkable ability of voltage-gated channels to generate the action potential. These insights have two important implications: they will allow us to understand better the molecular bases of certain genetic diseases that involve mutations in ion channel genes, and they will enable us to design safer and more effective drugs to treat a variety of diseases that involve disturbances in electrical signaling (such as epilepsy, multiple sclerosis, myotonia, and ataxia).

Selected Readings Armstrong CM. 1992. Voltage-dependent ion channels and their gating. Physiol Rev 72:S5–13.

Armstrong CM, Hille B. 1998. Voltage-gated ion channels and electrical excitability. Neuron 20:371–380.

Cannon SC. 1996. Ion-channel defects and aberrant excitability in myotonia and periodic paralysis. Trends Neurosci 19:3–10.

Catterall WA. 1994. Molecular properties of a superfamily of plasma-membrane cation channels. Curr Opin Cell Biol 6:607–615.

Hille B. 1991. Ionic Channels of Excitable Membranes, 2nd ed. Sunderland, MA: Sinauer.

Hodgkin AL. 1992. Chance & Design: Reminiscences of Science in Peace and War. Cambridge: Cambridge Univ. Press.

Isom LL, De Jongh KS, Catterall WA. 1994. Auxiliary subunits of voltage-gated ion channels. Neuron 12:1183–1194.

Jan LY, Jan YN. 1997. Cloned potassium channels from eukaryotes and prokaryotes. Annu Rev Neurosci 20:91–123.

Kukuljan M, Labarca P, Latorre R. 1995. Molecular determinants of ion conduction and inactivation in K+ channels. Am J Physiol 268:C535-C556.

Llinás RR. 1988. The intrinsic electrophysiological properties of mammalian neurons: insights into central nervous system function. Science 242:1654–1664. P.170

References Armstrong CM, Bezanilla F. 1977. Inactivation of the sodium channel. II. Gating current experiments. J Gen Physiol 70:567–590.

Catterall WA. 1988. Structure and function of voltage-sensitive ion channels. Science 242:50–61.

Cole KS, Curtis HJ. 1939. Electric impedance of the squid giant axon during activity. J Gen Physiol 22:649–670.

Dekin MS, Getting PA. 1987. In vitro characterization of neurons in the vertical part of the nucleus tractus solitarius. II. Ionic basis for repetitive firing patterns. J Neurophysiol 58:215–229.

Hartmann HA, Kirsch GE, Drewe JA, Taglialatela M, Joho RH, Brown AM. 1991. Exchange of conduction pathways between two related K+ channels. Science 251:942–944.

Heinemann SH, Terlau H, Stühmer W, Imoto K, Numa S. 1992. Calcium channel characteristics conferred on the sodium channel by single mutations. Nature 356:441–443.

Hodgkin AL, Huxley AF. 1952. A quantitative description of membrane current and its application to conduction and excitation in nerve. J Physiol (Lond) 117:500–544.

Hodgkin AL, Katz B. 1949. The effect of sodium ions on the electrical activity of the giant axon of the squid. J Physiol (Lond) 108:37–77.

Jones SW. 1985. Muscarinic and peptidergic excitation of bull-frog sympathetic neurones. J Physiol 366:63–87.

Llinás R, Jahnsen H. 1982. Electrophysiology of mammalian thalamic neurones in vitro. Nature 297:406–408.

MacKinnon R. 1991. Determination of the subunit stoichiometry of a voltage-activated potassium channel. Nature 350:232–235.

McCormick DA, Huguenard JR. 1992. A model of electrophysiological properties of thalamocortical relay neurons. J Neurophysiol 68:1384–1400.

Noda M, Shimizu S, Tanabe T, Takai T, Kayano T, Ikeda T, Takahashi H, Nakayama H, Kanaoka Y, Minamino N, Kangawa K, Matsuo H, Raferty MA, Hirose T, Inayama S, Hayashida H, Miyata T, Numa S. 1984. Primary structure of Electrophorus electricus sodium channel deduced from cDNA sequence. Nature 312:121–127.

Papazian DM, Schwarz TL, Tempel BL, Jan YN, Jan LY. 1987. Cloning of genomic and complementary DNA from Shaker, a putative potassium channel gene from Drosophila. Science 237:749–753.

Pongs O, Kecskemethy N, Müller R, Krah-Jentgens I, Baumann A, Kiltz HH, Canal I, Llamazares S, Ferrus A. 1988. Shaker encodes a family of putative potassium channel proteins in the nervous system of Drosophila. EMBO J 7:1087–1096.

Rosenberg RL, Tomiko SA, Agnew WS. 1984. Single-channel properties of the reconstituted voltage-regulated Na channel isolated from the electroplax of Electrophorus electricus. Proc Natl Acad Sci U S A 81:5594–5598.

Santoro B, Liu DT, Yao H, Bartsch D, Kandel ER, Siegelbaum SA, Tibbs GR. 1998. Identification of a gene encoding a hyperpolarization-activated pacemaker of brain. Cell 93:717–729.

Sigworth FJ, Neher E. 1980. Single Na+ channel currents observed in cultured rat muscle cells. Nature 287:447–449.

Stühmer W, Conti F, Suzuki H, Wang X, Noda M, Yahagi N, Kubo H, Numa S. 1989. Structural parts involved in activation and inactivation of the sodium channel. Nature 339:597–603.

Takeshima H, Nishimura S, Matsumoto T, Ishida H, Kangawa K, Minamino N, Matsuo H, Ueda M, Hanaoka M, Hirose T, Numa S. 1989. Primary structure and expression from complementary DNA of skeletal muscle ryanodine receptor. Nature 339:439–445.

Vassilev PM, Scheuer T, Catterall WA. 1988. Identification of an intracellular peptide segment involved in sodium channel inactivation. Science 241:1658–1661.

Woodhull AM. 1973. Ionic blockage of sodium channels in nerve. J Gen Physiol 61:687–708.

Yang N, George AL Jr, Horn R. 1996. Molecular basis of charge movement in voltage-gated sodium channels. Neuron 16:113–122.

Yellen G, Jurman ME, Abramson T, MacKinnon R. 1991. Mutations affecting internal TEA blockade identify the probable pore-forming region of a K+ channel. Science 251:939–942.

Yool AJ, Schwarz TL. 1991. Alteration of ionic selectivity of a K+ channel by mutation of the H5 region. Nature 349:700–704. 1.

It may at first seem paradoxical that to depolarize the cell experimentally one passes outward current across the membrane (see Figure 7-2C), while at the same

time attributing the depolarization during the upstroke of the action potential to an inward Na+ current. However, in both cases the current flow across the passive components, the nongated leakage channels (γ1) and the capacitance of the membrane (Cm), is outward because positive charge is injected into the cell in one case

through an intracellular electrode (see Figure 7-2A,7-2B,7-2C,7-2D) and in the other case by the opening of voltage-gated Na+ channels. It is a matter of convention that when we refer to current injected through a microelectrode we refer to the direction in which the current crosses the membrane capacitance and leakage channels, whereas when we refer to current that flows through channels we refer to the direction of movement of charge through the channels.

Back

II Cell and Molecular Biology of the Neuron

Oscilloscope Trace of Current Flow During the Action Potential. A net increase in ionic conductance accompanies the action potential in the squid giant axon. This historic oscilloscope record was obtained by K. C. Cole and H. J. Curtis in 1938. It shows an action potential superimposed on a trace of the simultaneous membrane conductance.

IN ALL BIOLOGICAL SYSTEMS, FROM THE most primitive to the most advanced, the basic building block is the cell. Cells are often organized into functional modules that are repeated in complex biological systems. The vertebrate brain is the most complex example of a modular system. Complex biological systems have another structural feature: they are architectonic—that is, their anatomy, fine structure, and biochemistry all reflect a specific physiological function. Thus, the construction of the brain and the cytology, biophysics, and biochemistry of its component neurons reflect its fundamental function—to mediate behavior. The great diversity of nerve cells—the fundamental units from which the modules of the nervous systems are assembled—is derived from one basic cell plan. Three features of this plan give nerve cells the unique ability to communicate with one another precisely and rapidly over long distances. First, the neuron is polarized, possessing receptive dendrites on one end and axons with synaptic terminals at the other. This polarization of functional properties is commonly used to restrict the flow of impulses to one direction. Second, the neuron is electrically and chemically excitable. Its external membrane contains specialized proteins—ion channels and receptors—that permit the influx and efflux of specific inorganic ions, thus creating electrical currents. Third, the neuron's cell body contains proteins and organelles that endow it with specialized secretory properties. In this part of the book we shall be concerned with the properties of the neuron that give it the ability to generate signals in the form of synaptic and action potentials. The initiation of a signal depends on ion channels in the cell membrane that open in response to changes in potential across the membrane and to neurotransmitters released by other nerve cells. Neurons use two classes of channels for signaling: (1) resting channels generate the resting potential and underlie the passive properties of neurons that determine the time course of synaptic potentials and the speed of conduction of the action potential and (2) voltage-gated channels are responsible for the active currents that generate the action potential.

Back

10 Overview of Synaptic Transmission Eric R. Kandel Steven A. Siegelbaum WHAT GIVES NERVE CELLS their special ability to communicate with one another so rapidly, over such great distances, and with such tremendous precision? We have already seen how signals are propagated within a neuron, from its dendrites and cell body to its axonal terminal. Beginning with this chapter we consider the cellular mechanisms for signaling between neurons. The point at which one neuron communicates with another is called a synapse, and synaptic transmission is fundamental to many of the processes we consider later in the book, such as perception, voluntary movement, and learning. The average neuron forms about 1000 synaptic connections and receives even more, perhaps as many as 10,000 connections. The Purkinje cell of the cerebellum receives up to 100,000 inputs. Although many of these connections are highly specialized, all neurons make use of one of two basic forms of synaptic transmission: electrical or chemical. Moreover, the strength of both forms of synaptic transmission can be enhanced or diminished by cellular activity. This plasticity in nerve cells is crucial to memory and other higher brain functions. In the brain, electrical synaptic transmission is rapid and rather stereotyped. Electrical synapses are used primarily to send simple depolarizing signals; they do not lend themselves to producing inhibitory actions or making long-lasting changes in the electrical properties of postsynaptic cells. In contrast, chemical synapses are capable of more variable signaling and thus can produce more complex behaviors. They can mediate either excitatory or inhibitory actions in postsynaptic cells and produce electrical changes in the postsynaptic cell that last from milliseconds to many minutes. Chemical synapses also serve to amplify neuronal signals, so that even a small presynaptic nerve terminal can alter the response of a large postsynaptic cell. Because chemical synaptic transmission is so central to understanding brain and behavior, it is examined in detail in Chapters 11, 12, and 13.

Synapses Are Either Electrical or Chemical The term synapse was introduced at the turn of the century by Charles Sherrington to describe the specialized zone of contact at which one neuron communicates with another; this site had first been described histologically (at the level of light microscopy) by Ramón y Cajal. Initially, all synapses were thought to operate by means of electrical transmission. In the 1920s, however, Otto Loewi showed that acetylcholine (ACh), a chemical compound, conveys signals from the vagus nerve to the P.176 heart. Loewi's discovery in the heart provoked considerable debate in the 1930s over how chemical signals could generate electrical activities at other synapses, including nerve-muscle synapses and synapses in the brain. Table 10-1 Distinguishing Properties of Electrical and Chemical Synapses

Type of synapse Electrical Chemical

Cytoplasmic Distance between pre- continuity between and postsynaptic cell pre- and postsynaptic cells membranes 3.5 nm 20-40 nm

Yes No

Ultrastructural components Gap-junction channels Presynaptic vesicles and active zones; postsynaptic receptors

Agent of transmission Ion current Chemical transmitter

Synaptic delay Virtually absent Significant: at least 0.3 ms, usually 1-5

Direction of transmission Usually bidirectional Unidirectional

ms or longer

Two schools of thought emerged, one physiological and the other pharmacological. Each championed a single mechanism for all synaptic transmission. The physiologists, led by John Eccles (Sherrington's student), argued that all synaptic transmission is electrical, that the action potential in the presynaptic neuron generates a current that flows passively into the postsynaptic cell. The pharmacologists, led by Henry Dale, argued that transmission is chemical, that the action potential in the presynaptic neuron leads to the release of a chemical substance that in turn initiates current flow in the postsynaptic cell.

Figure 10-1 Current flows differently at electrical and chemical synapses. A. At an electrical synapse some of the current injected into a presynaptic cell escapes through resting ion channels in the cell membrane. However, some current also flows into the postsynaptic cell through specialized ion channels, called gap-junction channels, that connect the cytoplasm of the pre- and postsynaptic cells. B. At chemical synapses all of the injected current escapes through ion channels in the presynaptic cell. However, the resulting depolarization of the cell activates the release of neurotransmitter molecules packaged in synaptic vesicles (open circles), which then bind to receptors on the postsynaptic cell. This binding opens ion channels, thus initiating a change in membrane potential in the postsynaptic cell.

When physiological techniques improved in the 1950s and 1960s it became clear that both forms of transmission exist. Although most synapses use a chemical transmitter, some operate purely by electrical means. Once the fine structure of synapses was made visible with the electron microscope, chemical and electrical synapses were found to have different morphologies. At chemical synapses neurons are separated completely by a small space, the synaptic cleft. There is no continuity between the cytoplasm of one cell and the next. In contrast, at electrical synapses the pre- and postsynaptic cells communicate through special channels, the gapjunction channels, that serve as conduits between the cytoplasm of the two cells. The main functional properties of the two types of synapses are summarized in Table 10-1. The most important differences can be observed by injecting current P.177 into the presynaptic cell to elicit a signal (Figure 10-1). At both types of synapses the current flows outward across the presynaptic cell membrane. This current deposits a positive charge on the inside of the presynaptic cell membrane, reducing its negative charge and thereby depolarizing the cell (see Chapter 8).

Figure 10-2 Electrical synaptic transmission was first demonstrated to occur at the giant motor synapse in the crayfish. (Adapted from Furshpan and Potter 1957 and 1959.) A. The presynaptic neuron is the lateral giant fiber running down the nerve cord. The postsynaptic neuron is the motor fiber, which projects from the cell body in the ganglion to the periphery. The electrodes for passing current and for recording voltage are placed within both the pre- and postsynaptic cells. B. Transmission at an electrical synapse is virtually instantaneous—the postsynaptic response follows presynaptic stimulation in a fraction of a millisecond. The dashed line shows how the responses of the two cells correspond in time. In contrast, at chemical synapses there ia a delay between the pre- and postsynaptic potentials (see Figure 10-7).

At electrical synapses the gap-junction channels that connect the pre- and postsynaptic cells provide a low-resistance (high conductance) pathway for electrical current to flow between the two cells. Thus, some of the current injected in the presynaptic cell flows through these channels into the postsynaptic cell. This current deposits a positive charge on the inside of the membrane of the postsynaptic cell and depolarizes it. The current then flows out through resting ion channels in the postsynaptic cell (Figure 10-1A). If the depolarization exceeds threshold, voltage-gated ion channels in the postsynaptic cell will open and generate an action potential. At chemical synapses there is no direct low-resistance pathway between the pre- and postsynaptic cells. Thus, current injected into a presynaptic cell flows out of the cell's resting channels into the synaptic cleft, the path of least resistance. Little or no current crosses the external membrane of the postsynaptic cell, which has a high resistance (Figure 10-1B). Instead, the action potential in the presynaptic neuron initiates the release of a chemical transmitter, which diffuses across the synaptic cleft to interact with receptors on the membrane of the postsynaptic cell. Receptor activation causes the cell either to depolarize or to hyperpolarize.

Electrical Synapses Provide Instantaneous Signal Transmission At electrical synapses the current that depolarizes the postsynaptic cell is generated directly by the voltage-gated ion channels of the presynaptic cell. Thus these channels not only have to depolarize the presynaptic cell above the threshold for an action potential, they must also generate sufficient ionic current to produce a change in potential in the postsynaptic cell. To generate such a large current, the presynaptic terminal has to be large enough for its membrane to contain a large number of ion channels. At the same time, the postsynaptic cell has to be relatively small. This is because a small cell has a higher input resistance (Rin) than a large cell and, P.178 according to Ohm's law (∆V = ∆I × Rin), will undergo a greater voltage change (∆V) in response to a given presynaptic current (∆I).

Figure 10-3 Electrical transmission is graded and occurs even when the currents in the presynaptic cell are below the threshold for an action potential. This can be demonstrated by depolarizing the presynaptic cell with a small outward current pulse. Current is passed by one electrode while the membrane potential is recorded with a second electrode. A subthreshold depolarizing stimulus causes a passive depolarization in the presynaptic and postsynaptic cells. (Outward, depolarizing current is indicated by upward deflection.)

Electrical synaptic transmission was first described in the giant motor synapse of the crayfish, where the presynaptic fiber is much larger than the postsynaptic fiber (Figure 10-2A). An action potential generated in the presynaptic fiber produces a depolarizing post- synaptic potential that is often large enough to discharge an action potential. The latency—the time between the presynaptic spike and the postsynaptic potential—is remarkably short (Figure 10-2B). Such a short latency is incompatible with chemical transmission, which requires several biochemical steps: release of a transmitter from the presynaptic neuron, diffusion of the transmitter to the postsynaptic cell, binding of the transmitter to a specific receptor, and subsequent gating of ion channels (all described later in this chapter). Only current flowing directly from one cell to another can produce the near-instantaneous transmission observed at the giant motor synapse. Further evidence for electrical transmission is that the change in potential of the postsynaptic cell is directly related to the size and shape of the change in potential of the presynaptic cell. At an electrical synapse any amount of current in the presynaptic cell triggers a response in the postsynaptic cell. Even when a subthreshold depolarizing current is injected into the pre- synaptic neuron, current flows into the postsynaptic cell and depolarizes it (Figure 10-3). In contrast, at a chemical synapse the presynaptic current must reach the threshold for an action potential before the cell can release transmitter. Most electrical synapses will transmit both depolarizing and hyperpolarizing currents. A presynaptic action potential that has a large hyperpolarizing afterpotential will produce a biphasic (depolarizing-hyperpolarizing) change in potential in the postsynaptic cell. Transmission at electrical synapses is similar to the passive electrotonic propagation of subthreshold electrical signals along axons (see Chapter 8) and therefore is often referred to as electrotonic transmission. Electrotonic transmission has been observed even at junctions where, unlike the giant motor synapse of the crayfish, the pre- and postsynaptic elements are similar in size. Because signaling between neurons at electrical synapses depends on the passive electrical properties at the synapse, such electrical synapses can be bidirectional, transmitting a depolarization signal equally well from either cell.

Gap-Junction Channels Connect Communicating Cells at an Electrical Synapse Electrical transmission takes place at a specialized region of contact between two neurons termed the gap junction. At electrical synapses the separation between two neurons is much less (3.5 nm) than the normal, nonsynaptic space between neurons (20 nm). This narrow gap is bridged by the gap-junction channels, specialized protein structures that conduct the flow of ionic current from the presynaptic to the postsynaptic cell (Figure 10-4). All gap-junction channels consist of a pair of hemichannels, one in the presynaptic and the other in the postsynaptic cell. These hemichannels make contact in the gap between the two cell membranes, forming a continuous bridge between the cytoplasm of the two cells (Figure 10-4A). The pore of the channel has a large diameter of around 1.5 nm, and this large size permits small intracellular metabolites and experimental markers such as fluorescent dyes to pass between the two cells. Each hemichannel is called a connexon. A connexon is made up of six identical protein subunits, called connexins (Figure 10-4B). Each connexin is involved in two sets of interactions. First, each connexin recognizes the other five connexins to form a hemichannel. Second, each connexin of a hemichannel in one cell recognizes the extracellular domains of the apposing connexin of the hemichannel of the other cell to form the conducting channel that connects the two cells.

Figure 10-4 A three-dimensional model of the gap-junction channel, based on X-ray and electron diffraction studies. A. At electrical synapses two cells are structurally connected by gap-junction channels. A gap-junction channel is actually a pair of hemichannels, one in each apposite cell, that match up in the gap junction through homophilic interactions. The channel thus connects the cytoplasm of the two cells and provides a direct means of ion flow between the cells. This bridging of the cells is facilitated by a narrowing of the normal intercellular space (20 nm) to only 3.5 nm at the gap junction. (Adapted from Makowski et al. 1977.) Electron micrograph: The array of channels shown here was isolated from the membrane of a rat liver. The tissue has been negatively stained, a technique that darkens the area around the channels and in the pores. Each channel appears hexagonal in outline. Magnification × 307,800. (Courtesy of N. Gilula.) B. Each hemichannel, or connexon, is made up of six identical protein subunits called connexins. Each connexin is about 7.5 nm long and spans the cell membrane. A single connexin is thought to have four membrane-spanning regions. The amino acid sequences of gap- junction proteins from many different kinds of tissue all show regions of similarity. In particular, four hydrophobic domains with a high degree of similarity among different tissues are presumed to be the regions of the protein structure that traverse the cell membrane. In addition, two extracellular regions that are also highly conserved in different tissues are thought to be involved in the homophilic matching of apposite hemichannels. C. The connexins are arranged in such a way that a pore is formed in the center of the structure. The resulting connexon, with an overall diameter of approximately 1.5-2 nm, has a characteristic hexagonal outline, as shown in the electron micrograph in A. The pore is opened when the subunits rotate about 0.9 nm at the cytoplasmic base in a clockwise direction. (From Unwin and Zampighi 1980.)

P.179 P.180 Connexins from different tissues all belong to one large gene family. Each connexin subunit has four hydrophobic domains thought to span the cell membrane. These membrane-spanning domains in the gap-junction channels of different tissues are quite similar, as are the two extracellular domains thought to be involved in the homophilic recognition of the hemichannels of apposite cells (Figure 10-4C). On the other hand, the cytoplasmic regions of different connexins vary greatly, and this variation may explain why gap junctions in different tissues are sensitive to different modulatory factors that control their opening and closing. For example, most gap-junction channels close in response to lowered cytoplasmic pH or elevated cytoplasmic Ca2+. These two properties serve to decouple damaged cells from other cells, since damaged cells contain elevated Ca2+ and proton concentrations. At some specialized gap junctions the channels have voltage-dependent gates that permit them to conduct depolarizing current in only one direction, from the presynaptic cell to the postsynaptic cell. These junctions are called rectifying synapses. (The crayfish giant motor synapse is an example.) Finally, neurotransmitters released from nearby chemical synapses can modulate the opening of gapjunction channels through intracellular metabolic reactions (see Chapter 13). How do the channels open and close? One suggestion is that, to expose the channel's pore, the six connexins in a hemichannel rotate slightly with respect to one another, much like the shutter in a camera. The concerted tilting of each connexin by a few Ångstroms at one end leads to a somewhat larger displacement at the other end (Figure 10-4B). As we saw in Chapter 7, conformational changes in ion channels may be a common mechanism for opening and closing the channels.

Electrical Transmission Allows the Rapid and Synchronous Firing of Interconnected Cells Why is it useful to have electrical synapses? As we have seen, transmission across electrical synapses is extremely rapid because it results from the direct flow of current from the presynaptic neuron to the postsynaptic cell. And speed is important for certain escape responses. For example, the tail-flip response of goldfish is mediated by a giant neuron (known as Mauthner's cell) in the brain stem, which receives input from sensory neurons at electrical synapses. These electrical synapses rapidly depolarize the Mauthner's cell, which in turn activates the motor neurons of the tail, allowing the fish to escape quickly from danger. Electrical transmission is also useful for connecting large groups of neurons. Because current flows across the membranes of all electrically coupled cells at the same time, several small cells can act coordinately as one large cell. Moreover, because of the electrical coupling between the cells, the effective resistance of the coupled network of neurons is smaller than the resistance of an individual cell. As we have seen from Ohm's law (∆V = ∆I × R), the lower the resistance of a neuron, the smaller the depolarization produced by an excitatory synaptic current. Thus, electrically coupled cells require a larger synaptic current to depolarize them to threshold, compared with the current that would be necessary to fire an individual cell. This property makes it difficult to cause them to fire action potentials. Once this high threshold is surpassed, however, electrically coupled cells tend to fire synchronously because active Na+ currents generated in one cell are rapidly transmitted to the other cells.

Thus, a behavior controlled by a group of electrically coupled cells has an important adaptive advantage: It is triggered explosively in an all-or-none manner. For example, when seriously perturbed, the marine snail Aplysia releases massive clouds of purple ink that provide a protective screen. This stereotypic behavior is mediated by three electrically coupled, high-threshold motor cells that innervate the ink gland. Once the threshold for firing is exceeded in these cells, they fire synchronously (Figure 10-5). In certain fish, rapid eye movements (called saccades) are also mediated by electrically coupled motor neurons acting synchronously. In addition to providing speed or synchrony in neuronal signaling, electrical synapses also may transmit metabolic signals between cells. Because gap-junction channels are relatively large and nonselective, they readily allow inorganic cations and anions to flow through. In fact, gap-junction channels are large enough to allow moderatesized organic compounds (less than 1000 molecular weight)—such as the second messengers IP3 (inositol triphosphate), cAMP, and even small peptides—to pass from one cell to the next.

Gap Junctions Have a Role in Glial Function and Disease Gap junctions are found between glial cells as well as between neurons. In glia the gap junctions seem to mediate both intercellular and intracellular communication. The role of gap junctions in signaling between glial cells is best observed in the brain, where individual astrocytes are connected to each other through gap junctions, forming a glial cell network. Electrical stimulation of neuronal pathways in brain slices can trigger a rise of intracellular Ca2+ in certain astrocytes. This produces a wave of intracellular Ca2+ throughout the astrocyte network, P.181 P.182 traveling at a rate of around 1 µm/ms. These Ca2+ waves are believed to propagate by diffusion through gap-junction channels. Although the precise function of such Ca2+ waves is not known, their existence clearly suggests that glia may play an active role in signaling in the brain.

Figure 10-5 Electrically coupled motor neurons firing together can produce instantaneous behaviors. The behavior illustrated here is the release of a protective cloud of ink by the marine snail Aplysia. (Adapted from Carew and Kandel 1976.) A. Sensory neurons from the tail ganglion form synapses with three motor neurons that project to the ink gland. The motor neurons are interconnected by means of electrical synapses. B. A train of stimuli applied to the tail produces a synchronized discharge in all three motor neurons. 1. When the motor neurons are at rest the stimulus triggers a train of identical action potentials in all three cells. This synchronous activity in the motor neurons results in the release of ink. 2. When the cells are hyperpolarized the stimulus cannot trigger action potentials, because the cells are too far from their threshold level. Under these conditions the inking response is blocked.

Evidence that gap junctions enhance communication within a single glial cell is found in Schwann cells of the myelin sheath. As we have seen in Chapter 4, successive layers of myelin are connected by gap junctions, which may serve to hold the layers of myelin together. However, they may also be important for passing small metabolites and ions across the many intervening layers of myelin, from the outer perinuclear region of the Schwann cell down to the inner periaxonal region. The importance of these gap-junction channels is underscored by certain neurological genetic diseases. For example, the X chromosome-linked form of Charcot-Marie-Tooth disease, which causes demyelination, results from single mutations in one of the connexin genes (connexin32) expressed in the Schwann cell. Such mutations prevent this connexin from forming functional gap-junction channels essential for the normal flow of metabolites in the Schwann cell.

Chemical Synapses Can Amplify Signals In contrast to the situation at electrical synapses, there is no structural continuity between pre- and postsynaptic neurons at chemical synapses. In fact, at chemical synapses the region separating the pre- and postsynaptic cells—the synaptic cleft—is usually slightly wider (20-40 nm), sometimes substantially wider, than the adjacent nonsynaptic intercellular space (20 nm). As a result, chemical synaptic transmission depends on the release of a neurotransmitter from the presynaptic neuron. A neurotransmitter is a chemical substance that will bind to specific receptors in the postsynaptic cell membrane. At most chemical synapses transmitter release occurs from presynaptic terminals, specialized swellings of the axon. The presynaptic terminals contain discrete collections of synaptic vesicles, each of which is filled with several thousand molecules of a specific transmitter (Figure 10-6). The synaptic vesicles cluster at regions of the membrane specialized for releasing transmitter called active zones. During discharge of a presynaptic action potential Ca2 +

enters the presynaptic terminal through voltage-gated Ca2+ channels at the active zone. The rise in intracellular Ca2+ concentration causes the vesicles to fuse with

the presynaptic membrane and thereby release their neurotransmitter into the synaptic cleft, a process termed exocytosis. The transmitter molecules then diffuse across the synaptic cleft and bind to their receptors on the postsyn-aptic cell membrane. This in turn activates the receptors, leading to the opening or closing of ion channels. The resulting ionic flux alters the membrane conductance and potential of the postsynaptic cell (Figure 10-7). These several steps account for the synaptic delay at chemical synapses, a delay that can be as short as 0.3 ms but often lasts several milliseconds or longer. Although chemical transmission lacks the speed of electrical synapses, it has the important property of amplification. With the discharge of just one synaptic vesicle, several thousand molecules of transmitter stored in that vesicle are released. Typically, only two molecules of transmitter are required to open a single postsynaptic ion channel. Consequently, the action of one synaptic vesicle can open thousands of ion channels in the postsynaptic cell. In this way a small presynaptic nerve terminal, which generates only a weak electrical current, can release thousands of transmitter molecules that can depolarize even a large postsynaptic cell.

Figure 10-6 The synaptic cleft separates the presynaptic and postsynaptic cell membranes at chemical synapses. This electron micrograph shows the fine structure of a presynaptic terminal in the cerebellum. The large dark structures are mitochondria. The many round bodies are vesicles that contain neurotransmitter. The fuzzy dark thickenings along the presynaptic side of the cleft (arrows) are specialized areas, called active zones, that are thought to be docking and release sites for vesicles. (Courtesy of J. E. Heuser and T. S. Reese.)

Figure 10-7 Synaptic transmission at chemical synapses involves several steps. An action potential arriving at the terminal of a presynaptic axon causes voltage-gated Ca2+ channels at the active zone to open. The influx of Ca2+ produces a high concentration of Ca2+ near the active zone, which in turn causes vesicles containing neurotransmitter to fuse with the presynaptic cell membrane and release their contents into the synaptic cleft (a process termed exocytosis). The released neurotransmitter molecules then diffuse across the synaptic cleft and bind to specific receptors on the post-synaptic membrane. These receptors cause ion channels to open (or close), thereby changing the membrane conductance and membrane potential of the postsynaptic cell. The complex process of chemical synaptic transmission is responsible for the delay between action potentials in the pre- and post-synaptic cells compared with the virtually instantaneous transmission of signals at electrical synapses (see Figure 10-2B). The gray filaments represent the docking and release sites of the active zone.

P.183

Chemical Transmitters Bind to Postsynaptic Receptors Chemical synaptic transmission can be divided into two steps: a transmitting step, in which the presynaptic cell releases a chemical messenger, and a receptive step, in which the transmitter binds to the receptor molecules in the postsynaptic cell. The transmitting process resembles the release process of an endocrine gland, and chemical synaptic transmission can be seen as a modified form of hormone secretion. Both endocrine glands and presynaptic terminals release a chemical agent with a signaling function, and both are examples of regulated secretion (Chapter 4). Similarly, both endocrine glands and neurons are usually some distance from their target cells. There is one important difference, however. The hormone released by the gland travels through the blood stream until it interacts with all cells that contain an appropriate receptor. A neuron, on the other hand, usually communicates only with specific cells, the cells with which it forms synapses. Communication consists of a presynaptic neuron sending an action potential down its axon to the axon terminal, where the electrical signal triggers the focused release of the chemical transmitter onto a target cell. Thus the chemical signal travels only a small distance to its target. Neuronal signaling, therefore, has two special features: It is fast and precisely directed. To accomplish this highly directed or focused release, most neurons have specialized secretory machinery, the active zones. In neurons without active zones the distinction between neuronal and hormonal transmission becomes blurred. For example, the neurons in the autonomic nervous system that innervate smooth muscle reside at some distance from their postsynaptic cells and do not have specialized release sites in their terminals. Synaptic transmission between these cells is slower and more diffuse. Furthermore, at one set of terminals a transmitter can be released at an active zone, as a conventional transmitter acting directly on neighboring cells; at another locus it can be released in a less focused way as a modulator, producing a more diffuse action; and at a third locus it can be released into the blood stream as a neurohormone. Although a variety of chemicals serve as neurotransmitters, including both small molecules and peptides (see Chapter 15), the action of a transmitter in the P.184 postsynaptic cell does not depend on the chemical properties of the transmitter but rather on the properties of the receptors that recognize and bind the transmitter. For example, acetylcholine (ACh) can excite some postsynaptic cells and inhibit others, and at still other cells it can produce both excitation and inhibition. It is the receptor that determines whether a cholinergic synapse is excitatory or inhibitory and whether an ion channel will be activated directly by the transmitter or indirectly through a second messenger.

Figure 10-8 Neurotransmitters act either directly or indirectly on ion channels that regulate current flow in neurons. A. Direct gating of ion channels is mediated by ionotropic receptors. This type of receptor is an integral part of the same macromolecule that forms the channel it regulates and thus is sometimes referred to as a receptor-channel or ligand-gated channel. Many ionotropic receptors are composed of five subunits, each of which is thought to contain four membrane-spanning α-helical regions (see Chapters 11, 12). B. Indirect gating is mediated by activation of metabotropic receptors. This type of receptor is distinct from the ion channels it regulates. The receptor activates a GTPbinding protein (G protein), which in turn activates a second-messenger cascade that modulates channel activity. Here the G protein stimulates adenylyl cyclase, which converts ATP to cAMP. The cAMP activates the cAMP-dependent protein kinase (cAMP-kinase), which phosphorylates the channel (P), leading to a change in function. (The action of second messengers in regulating ion channels is described in detail in Chapter 13.) The typical metabotropic receptor is composed of a single subunit with seven membrane-spanning α-helical regions that bind the ligand within the plane of the membrane.

Within a group of closely related animals a given transmitter substance binds to conserved families of receptors and is associated with specific physiological functions. For example, in vertebrates ACh produces synaptic excitation at the neuromuscular junction by acting on a special type of excitatory ACh receptor. It also slows the heart by acting on a special type of inhibitory ACh receptor. The notion of a receptor was introduced in the late nineteenth century by the German bacteriologist Paul Ehrlich to explain the selective action of toxins and other pharmacological agents and the great specificity of immunological reactions. In 1900 Ehrlich wrote, “Chemical substances are only able to exercise an action on the tissue elements with which they are able to establish an intimate chemical relationship.… [This relationship] must be specific. The [chemical] groups must be adapted to one another… as lock and key.” In 1906 the English pharmacologist John Langley postulated that the sensitivity of skeletal muscle to curare and nicotine was caused by a “receptive molecule.” A theory of receptor function was later developed by Langley's students (in particular, Eliot Smith and Henry Dale), a development that was based on concurrent studies of enzyme kinetics and cooperative interactions between small molecules and proteins. As we shall see in the next chapter, Langley's “receptive molecule” has been isolated and characterized as the ACh receptor of the neuromuscular junction P.185 All receptors for chemical transmitters have two biochemical features in common:

●

They are membrane-spanning proteins. The region exposed to the external environment of the cell recognizes and binds the transmitter from the pre-synaptic cell. ●

They carry out an effector function within the target cell. The receptors typically influence the opening or closing of ion channels.

Postsynaptic Receptors Gate Ion Channels Either Directly or Indirectly Chemical neurotransmitters act either directly or indirectly in controlling the opening of ion channels in the postsynaptic cell. The two classes of transmitter actions are mediated by receptor proteins derived from different gene families. Receptors that gate ion channels directly, such as the nicotinic ACh receptor at the neuromuscular junction, are integral membrane proteins. Several subunits comprise a single macromolecule that contains both an extracellular domain that forms the receptor for transmitter and a membrane-spanning domain that forms an ion channel (Figure 10-8A). Such receptors are often referred to as ionotropic receptors. Upon binding neurotransmitter the receptor undergoes a conformational change that results in the opening of the channel. The actions of ionotropic receptors, also called receptor-channels or ligand-gated channels, are discussed in greater detail in Chapter 11. Receptors that gate ion channels indirectly, like the several types of norepinephrine or serotonin receptors at synapses in the cerebral cortex, are macromolecules that are distinct from the ion channels they affect. These receptors act by altering intracellular metabolic reactions and are often referred to as metabotropic receptors. Activation of these receptors very often stimulates the production of second messengers, small freely diffusible intracellular metabolites such as cAMP and diacylglycerol. Many such second messengers activate protein kinases, enzymes that phosphorylate different substrate proteins. In many instances the protein kinases directly phosphorylate ion channels, leading to their opening or closing. The actions of the metabotropic receptor are examined in detail in Chapter 13. Ionotropic and metabotropic receptors have different functions. The ionotropic receptors produce relatively fast synaptic actions lasting only milliseconds. These are commonly found in neural circuits that mediate rapid behaviors, such as the stretch receptor reflex. The metabotropic receptors produce slower synaptic actions lasting seconds to minutes. These slower actions can modulate behavior by altering the excitability of neurons and the strength of the synaptic connections of the neural circuitry mediating behavior. Such modulatory synaptic pathways often act as crucial reinforcing pathways in the process of learning.

Selected Readings

Bennett MV. 1997. Gap junctions as electrical synapses. J Neurocytol 26:349–366.

Eccles JC. 1976. From electrical to chemical transmission in the central nervous system. The closing address of the Sir Henry Dale Centennial Symposium. Notes Rec R Soc Lond 30:219–230.

Furshpan EJ, Potter DD. 1959. Transmission at the giant motor synapses of the crayfish. J Physiol (Lond) 145:289–325.

Goodenough DA, Goliger JA, Paul DL. 1996. Connexins, connexons, and intercellular communication. Ann Rev Biochem 65:475–502.

Jessell TM, Kandel ER. 1993. Synaptic transmission: a bidirectional and a self-modifiable form of cell-cell communication. Cell 72(Suppl):1–30.

Unwin N. 1993. Neurotransmitter action: opening of ligand-gated ion channels. Cell 72(Suppl):31–41.

References Beyer EC, Paul DL, Goodenough DA. 1987. Connexin43: a protein from rat heart homologous to a gap junction protein from liver. J Cell Biol 105:2621–2629.

Bruzzone R, White TW, Scherer SS, Fischbeck KH, Paul DL. 1994. Null mutations of connexin 32 in patients with x-linked Charcot-Marie-Tooth disease. Neuron 13:1253–1260.

Carew TJ, Kandel ER. 1976. Two functional effects of decreased conductance EPSP's: synaptic augmentation and increased electrotonic coupling. Science 192:150–153.

Cornell-Bell AH, Finkbeiner SM, Cooper MS, Smith SJ. 1990. Glutamate induces calcium waves in cultured astrocytes: long-range glial signaling. Science 247:470–473.

Dale H. 1935. Pharmacology and nerve-endings. Proc R Soc Med (Lond) 28:319–332.

Eckert R. 1988. Propagation and transmission of signals. In: Animal Physiology: Mechanisms and Adaptations, 3rd ed, pp. 134-176. New York: Freeman.

Ehrlich P. 1900. On immunity with special reference to cell life. Croonian Lect Proc R Soc Lond 66:424–448. P.186

Furshpan EJ, Potter DD. 1957. Mechanism of nerve-impulse transmission at a crayfish synapse. Nature 180:342–343.

Heuser JE, Reese TS. 1977. Structure of the synapse. In: ER Kandel (ed), Handbook of Physiology: A Critical, Comprehensive Presentation of Physiological Knowledge and Concepts, Sect. 1, The Nervous System. Vol. 1, Cellular Biology of Neurons, Part 1, pp. 261-294. Bethesda, MD: American Physiological Society.

Jaslove SW, Brink PR. 1986. The mechanism of rectification at the electrotonic motor giant synapse of the crayfish. Nature 323:63–65.

Langley JN. 1906. On nerve endings and on special excitable substances in cells. Proc R Soc Lond B Biol Sci 78:170–194.

Loewi O, Navratil E. 1926. Über humorale Übertragbarkeit der Herznervenwirkung. X. Mitteilung: über das Schicksal des Vagusstoffs. Pflügers Arch. 214:678-688; 1972. Translated in: On the humoral propagation of cardiac nerve action. Communication X. The fate of the vagus substance. In: I Cooke, M Lipkin Jr (eds). Cellular Neurophysiology: A Source Book, pp. 478-485. New York: Holt, Rinehart and Winston.

Makowski L, Caspar DLD, Phillips WC, Baker TS, Goodenough DA. 1984. Gap junction structures. VI. Variation and conservation in connexon conformation and packing. Biophys J 45:208–218.

Pappas GD, Waxman SG. 1972. Synaptic fine structure—morphological correlates of chemical and electrotonic transmission. In: GD Pappas, DP Purpura (eds). Structure and Function of Synapses, pp. 1-43. New York: Raven.

Ramón y Cajal S. 1894. La fine structure des centres nerveux. Proc R Soc Lond 55:444–468.

Ramón y Cajal S. 1911. Histologie du Systéme Nerveux de l'Homme & des Vertébrés, Vol. 2. L Azoulay (transl). Paris: Maloine; 1955. Reprint. Madrid: Instituto Ramón y Cajal.

Sherrington C. 1947. The Integrative Action of the Nervous System, 2nd ed. New Haven: Yale Univ. Press.

Unwin PNT, Zampighi G. 1980. Structure of the junction between communicating cells. Nature 283:545–549.

Back

11 Signaling at the Nerve-Muscle Synapse: Directly Gated Transmission Eric R. Kandel Steven A. Siegelbaum SYNAPTIC COMMUNICATION in the brain relies mainly on chemical mechanisms. Before we examine the complexities of chemical synaptic transmission in the brain, however, it will be helpful to examine the basic features of chemical synaptic transmission at the site where they were first studied and remain best understood—the nerve-muscle synapse, the junction between a motor neuron and a skeletal muscle fiber. The nerve-muscle synapse is an ideal site for studying chemical signaling because it is relatively simple and also very accessible to experimentation. The muscle cell is large enough to accommodate the two or more microelectrodes needed to make electrical measurements. Also, the postsynaptic muscle cell is normally innervated by just one presynaptic axon, in contrast to the convergent connections on central nerve cells. Most importantly, chemical signaling at the nerve-muscle synapse involves a relatively simple mechanism. Release of neurotransmitter from the presynaptic nerve directly opens a single type of ion channel in the postsynaptic membrane.

The Neuromuscular Junction Is a Well-Studied Example of Directly Gated Synaptic Transmission The axon of the motor neuron innervates the muscle at a specialized region of the muscle membrane called the end-plate (see Figure 11-1). At the region where the motor axon approaches the muscle fiber, the axon loses its myelin sheath and splits into several fine branches. The ends of the fine branches form multiple expansions or varicosities, called synaptic boutons, from which the motor neuron releases its transmitter (Figure 11-1). Each bouton is positioned over a junctional fold, a deep depression in the surface of the postsynaptic muscle fiber that contains the transmitter receptors (Figure 11-2). The transmitter released by the axon terminal is acetylcholine (ACh), and the receptor on the muscle membrane P.188 P.189 is the nicotinic type of ACh receptor (Figure 11-3).1

Figure 11-1 The neuromuscular junction is readily visible with the light microscope. At the muscle the motor axon ramifies into several fine branches approximately 2 µm thick. Each branch forms multiple swellings called presynaptic boutons, which are covered by a thin layer of Schwann cells. The boutons lie over a specialized region of the muscle fiber membrane, the end-plate, and are separated from the muscle membrane by a 100 nm synaptic cleft. Each presynaptic bouton contains mitochondria and synaptic vesicles clustered around active zones, where the acetylcholine (ACh) transmitter is released. Immediately under each bouton in the end-plate are several junctional folds, which contain a high density of ACh receptors at their crests. The muscle fiber is covered by a layer of connective tissue, the basement membrane (or basal lamina), consisting of collagen and glycoproteins. Both the presynaptic terminal and the muscle fiber secrete proteins into the basement membrane, including the enzyme acetylcholinesterase, which inactivates the ACh released from the presynaptic terminal by breaking it down into acetate and choline. The basement membrane also organizes the synapse by aligning the presynaptic boutons with the postsynaptic junctional folds. (Adapted in part from McMahan and Kuffler 1971.)

Figure 11-2 Electron microscope autoradiograph of the vertebrate neuromuscular junction, showing localization of ACh receptors (black developed grains) at the top one-third of the postsynaptic junctional folds. This receptor-rich region is characterized by an increased density of the postjunctional membrane (arrow). The membrane was incubated with radiolabeled α-bungarotoxin, which binds to the ACh receptor. Radioactive decay results in the emittance of a radioactive particle, causing silver grains to become fixed (dark grains). Magnification × 18,000.

The presynaptic and postsynaptic membranes are separated by a synaptic cleft around 100 nm wide. Within the cleft is a basement membrane composed of collagen and other extracellular matrix proteins. The enzyme acetylcholinesterase, which rapidly hydrolyzes ACh, is anchored to the collagen fibrils of the basement membranes. In the muscle cell, in the region below the crest of the junctional fold and extending into the fold, the membrane is rich in voltage-gated Na+ channels. Each presynaptic bouton contains all the machinery required to release neurotransmitter. This includes the synaptic vesicles, which contain the transmitter ACh, and the active zone, a part of the membrane specialized for vesicular release of transmitter (see Figure 11-1). Every active zone in the presynaptic membrane is positioned opposite a junctional fold in the postsynaptic cell. At the crest of each fold the receptors for ACh are clustered in a lattice, with a density of about 10,000 receptors per square micrometer (Figures 11-2 and 11-3). In addition, each active zone contains voltage-gated Ca2+ channels that permit Ca2+ to enter the terminal with each action potential (see Figure 11-1). This influx of Ca2+ triggers fusion of the synaptic vesicles in the active zones with the plasma membrane, and fusion leads to release of the vesicle's content into the synaptic cleft.

Figure 11-3 Reconstructed electron microscope image of the ACh receptor-channel complex in the fish Torpedo californica. The image was obtained by computer processing of negatively stained images of ACh receptors. The resolution is 1.7 nm, fine enough to see overall structures but too coarse to resolve individual atoms. The overall diameter of the receptor and its channel is about 8.5 nm. The pore is wide at the external and internal surfaces of the membrane but narrows considerably within the lipid bilayer. The channel extends some distance into the extracellular space. (Adapted from Toyoshima and Unwin 1988.)

Figure 11-4 The end-plate potential can be isolated pharmacologically for study. A. Under normal circumstances stimulation of the motor axon produces an action potential in a skeletal muscle cell. The dashed line shows the inferred time course of the end-plate potential that triggers the action potential. B. The end-plate potential can be isolated in the presence of curare, which blocks the binding of ACh to its receptor and so prevents the end-plate potential from reaching the threshold for an action potential (dashed line). In this way the currents and channels that contribute to the end-plate potential, which are different from those producing an action potential, can be studied. The values for the resting potential (-90 mV), end-plate potential, and action potential shown in these intracellular recordings are typical of a vertebrate skeletal muscle.

P.190

The Motor Neuron Excites the Muscle by Opening Ion Channels at the End-Plate Upon release of ACh from the motor nerve terminal, the membrane at the end-plate depolarizes rapidly. The excitatory postsynaptic potential in the muscle cell is called the end-plate potential. The amplitude of the end-plate potential is very large; stimulation of a single motor cell produces a synaptic potential of about 70 mV. This change in potential usually is large enough to rapidly activate the voltage-gated Na+ channels in the junctional folds. This converts the end-plate potential into an action potential, which propagates along the muscle fiber. (In contrast, in the central nervous system most presynaptic neurons produce postsynaptic potentials less than 1 mV in amplitude, so that input from many presynaptic neurons is needed to generate an action potential there.)

The Synaptic Potential at the End-Plate Is Produced by Ionic Current Flowing Through Acetylcholine-Gated Channels The end-plate potential was first studied in detail in the 1950s by Paul Fatt and Bernard Katz using intracellular voltage recordings. Fatt and Katz were able to isolate the end-plate potential using the drug curare2 to reduce the amplitude of the end-plate potential below the threshold for the action potential (Figure 11-4). They found that the synaptic potential in muscle cells was largest at the end-plate, decreasing progressively with distance from the end-plate region (Figure 11-5). They concluded that the synaptic potential is generated by an inward ionic current confined to the end-plate region, which then spreads passively away from the end-plate. (Remember, an inward current corresponds to an influx of positive charge, which will depolarize the inside of the membrane.) Current flow is confined to the end-plate because the ACh-activated ion channels are localized there, opposite the presynaptic terminal from which transmitter is released. The synaptic potential at the end-plate rises rapidly but decays more slowly. The rapid rise is due to the sudden release of ACh into the synaptic cleft by an action potential in the presynaptic nerve terminal. Once released, ACh diffuses rapidly to the receptors at the end-plate. Not all the ACh reaches postsynaptic receptors, however, because it is quickly removed from the synaptic cleft by two processes: hydrolysis and diffusion out of the synaptic cleft. The current that generates the end-plate potential was first studied in voltage-clamp experiments (see Box 9-1). These studies revealed that the end-plate current rises and decays more rapidly than the resultant end-plate potential (Figure 11-6). The time course of the end-plate current is directly determined by the rapid opening and closing of the ACh-gated ion channels. Because it takes time for an ionic current to charge or discharge the muscle membrane capacitance, and thus alter the membrane voltage, the end-plate potential lags behind the synaptic current (see Figure 8-3 and the Postscript at the end of this chapter).

Figure 11-5 The synaptic potential in muscle is largest at the end-plate region and passively propagates away from it. (Adapted from Miles 1969.) A. The amplitude of the synaptic potential decays and the time course of the potential slows with distance from the site of initiation in the end-plate. B. The decay results from leakiness of the muscle fiber membrane. Since current flow must complete a circuit, the inward synaptic current at the end-plate gives rise to a return flow of outward current through resting channels and across the membrane (the capacitor). It is this return flow of outward current that produces the depolarization. Since current leaks out all along the membrane, the current flow decreases with distance from the end-plate. Thus, unlike the regenerative action potential, the local depolarization produced by the synaptic potential of the membrane decreases with distance.

P.191

The Ion Channel at the End-Plate Is Permeable to Both Sodium and Potassium Why does the opening of the ACh-gated ion channels lead to an inward current flow that produces the depolarizing end-plate potential? And which ions move through the ACh-gated ion channels to produce this inward current? One important clue to the identity of the ion (or ions) responsible for the synaptic current can be obtained from experiments that measure the value of the chemical driving force propelling ions through the channel. Remember, from Chapter 7, the current flow through a membrane conductance is given by the product of the membrane conductance and the electrochemical driving force on the ions conducted through the channels. The end-plate current that underlies the excitatory postsynaptic potential (EPSP) is defined as

where IEPSP is the end-plate current, gEPSP is the conductance of the ACh-gated channels, Vm is the membrane potential, and EEPSP is the chemical driving force, or battery, that results from the concentration gradients of the ions conducted through the ACh-gated channels. The fact that current flowing through the end-plate is inward at the normal resting potential of a muscle cell (-90 mV) indicates that there is an inward (negative) electrochemical driving force on the ions that carry current through the ACh-gated channels at this potential. Thus, EEPSP must be positive to -90 mV. From Equation 11-1 we see that the value of EEPSP can be determined by altering the membrane potential in a voltage-clamp experiment and determining its effect on the synaptic current. Depolarizing the membrane reduces the net inward electrochemical driving force, causing a decrease in the magnitude of the inward endplate current. If the membrane potential is set equal to the value of the battery representing the chemical driving force (EEPSP), no net synaptic current will flow through the end-plate because the electrical driving force (due to Vm) will exactly balance the chemical driving force (due to EEPSP). The potential at which the net ionic current is zero is the reversal potential for current flow through the synaptic channels. By determining the reversal potential we can experimentally measure the value of EEPSP, the chemical force driving ions through the ACh-gated channels at the end-plate. If the membrane potential is made more positive than EEPSP, there will be a net outward driving force. In this case stimulation of the motor nerve leads to an outward ionic current, by opening the ACh-gated channels, and this outward ionic current hyperpolarizes the membrane. If an influx of Na+ were solely responsible for the end-plate potential, the reversal potential for the excitatory postsynaptic potential would be the same as the equilibrium potential for Na+, or +55 mV. Thus, if the membrane potential is experimentally altered from -100 to +55 mV, the end-plate current should diminish progressively because the electrochemical driving force P.192 on Na+ (Vm - ENa) is reduced. At +55 mV the inward current flow should be abolished, and at potentials more positive than +55 mV the end-plate current should reverse in direction and flow outward.

Figure 11-6 The end-plate current rises and decays more rapidly than the end-plate potential. A. The membrane at the end-plate is voltage-clamped by inserting two microelectrodes into the muscle at the end-plate. One electrode measures membrane voltage (Vm) and the second passes current (Im). Both electrodes are connected to a feedback amplifier, which ensures that the proper amount of current (Im) is delivered so that Vm will be clamped at the command potential Vc. The synaptic current evoked by stimulating the motor nerve can then be measured at a constant membrane potential, for example -90 mV (see Box 9-1). B. The end-plate potential, measured when the voltage clamp is not active, changes relatively slowly, following in time the inward synaptic current measured under voltage-clamp conditions. This is because synaptic current must first alter the charge on the membrane capacitance of the muscle before the muscle membrane is depolarized (see Chapter 8 and Postscript in this chapter).

Instead experiments at the end-plate showed that as the membrane potential is reduced, the inward current rapidly becomes smaller and is abolished at 0 mV! At values more positive than 0 mV the end-plate current reverses direction and begins to flow outward (Figure 11-7). This particular value of membrane potential is not equal to the equilibrium potential for Na+, or for that matter any of the major cations or anions. In fact, this potential is produced not by a single ion species but by a combination of ions. The synaptic channels at the end-plate are almost equally permeable to both major cations, Na+ and K+. Thus, during the end-plate potential Na+ flows into the cell and K+ flows out. The reversal potential is at 0 mV because this is a weighted average of the equilibrium potentials for Na+ and K+ (Box 11-1). At the reversal potential the influx of Na+ is balanced by an equal efflux of K+. Why are the ACh-gated channels at the end-plate not selective for a single ion species like the voltage-gated channels selective for either Na+ or K+? The pore diameter of the ACh-gated channel is thought to be substantially larger than that of the voltage-gated channels. Electrophysiological measurements suggest that the pore may be up to 0.8 nm in diameter in mammals. This estimate is based on the size of the largest organic cation that can permeate the channel. For example, the permeant cation tetramethylammonium (TMA) is around 0.6 nm in diameter. In contrast, the voltage-gated Na+ channel is only permeant to organic cations that are smaller than 0.5 × 0.3 nm in cross section, and voltage-gated K+ channels will only conduct ions less than 0.3 nm in diameter. The relatively large diameter of the ACh pore is thought to provide a water-filled environment that allows cations to diffuse through the channel, much as they would in free solution. This explains why the pore does not discriminate between Na+ and K+. It also explains why even divalent cations, such as Ca2+, can permeate the channel. Anions are excluded, however, by the presence of fixed negative charges in the channel, as described later in this chapter.

The Current Flow Through Single Ion Channels Can Be Measured by the Patch Clamp The current for an end-plate potential flows through several hundred thousand channels. Recordings of the current flow through single ACh-gated ion channels, using the patch clamp technique (see Box 6-1), have provided us with insight into the molecular events underlying the end-plate potential. Before the introduction of the patch clamp physiologists held two opposing views as to what the time course of the single-channel current should look like. Some thought that the singlechannel currents were a microscopic version of the end-plate current recorded with the voltage clamp, having a rapid P.193 rising phase and a more slowly decaying falling phase. Others thought that the channels opened in an all-or-none manner, producing step-like currents similar to that seen with gramicidin (see Chapter 6).

Figure 11-7 The end-plate potential is produced by the simultaneous flow of Na+ and K+ through the same ACh-gated channels. A. The ionic currents responsible for the end-plate potential can be determined by measuring the reversal potential of the end-plate current. The voltage of the muscle membrane is clamped at different potentials, and the synaptic current is measured when the nerve is stimulated. If Na+ flux alone were responsible for the end-plate current, the reversal potential would occur at +55 mV, the equilibrium potential for Na+ (ENa). The arrow next to each current record reflects the magnitude of the net Na+ flux at that membrane potential. B. The end-plate current actually reverses at 0 mV because the ion channel is permeable to both Na+ and K+, which are able to move into and out of the cell simultaneously (see Box 11-1). The net current is the sum of the Na+ and K+ fluxes through the end-plate channels. At the reversal potential (EEPSP) the inward Na+ flux is balanced by an outward K+ flux so that no net current flows.

Individual Acetylcholine-Gated Channels Conduct a Unitary Current The first successful recordings of single ACh-gated channels from skeletal muscle cells, by Erwin Neher and Bert Sakmann in 1976, showed that the channels open and close in a step-like manner, generating very small rectangular steps of ionic current (Figure 11-8). At a constant membrane potential a channel generates a similar-size current pulse each time it opens. At a resting potential of -90 mV the current steps are around -2.7 pA in amplitude. Although this is a very small current, it corresponds to a flow through an open channel of around 17 million ions per second! The unitary current steps change in size with membrane potential. This is because the single-channel current depends on the electrochemical driving force (Vm EEPSP). Recall that Ohm's law applied to synaptic current is

For single ion channels the equivalent expression is

where iEPSP is the amplitude of current flow through one channel and γEPSP is the conductance of a single channel. The relationship between iEPSP and membrane voltage is linear, indicating that the single-channel conductance is constant and does not depend on membrane voltage; that is, the channel behaves as a simple resistor. From the slope of this relation the channel is found to have a conductance of 30 pS. The reversal potential of 0 mV, obtained from the intercept of the voltage axis, is identical to that for the end-plate current (Figure 11-9). Although the amplitude of the current flowing through a single ACh channel is constant from opening P.194 to opening, the duration of openings and the time between openings of an individual channel vary considerably. These variations occur because channel openings and closings are stochastic. They obey the same statistical law that describes radioactive decay. Because of the random thermal motions and fluctuations that a channel experiences, it is impossible to predict exactly how long it will take any one channel to encounter ACh or how long that channel will stay open before the ACh dissociates and the channel closes. However, the average length of time a particular type of channel stays open is a well-defined property of that channel, just as the half-life of radioactive decay is an invariant property of a particular isotope. The mean open time for ACh-gated channels is around 1 ms. Thus each channel opening is associated with the movement of about 17,000 ions.

Box 11-1 Reversal Potential of the End-Plate Potential The reversal potential of a membrane current carried by more than one ion species, such as the end-plate current through the ACh-gated channel, is determined by two factors: (1) the relative conductance for the permeant ions (gNa and gK in the case of the end-plate current) and (2) the equilibrium potentials of the ions (ENa and EK). At the reversal potential for the ACh-gated current, inward current carried by Na+ is balanced by outward current carried by K+: The individual Na+ and K+ currents can be obtained from and Remember that these currents do not result from Na+ and K+ flowing through separate channels (as occurs during the action potential) but represent Na+ and K+ movement through the same ACh-gated channel. Since at the reversal potential Vm = EEPSP, we can substitute Equations 11-3a and 11-3b for INa and IK in Equation 11-2:

Solving this equation for EEPSP yields

If we divide the top and bottom of the right side of this equation by gK, we obtain

Thus, if gNa = gK, then EEPSP = (ENa + EK)/2. These equations can also be used to solve for the ratio gNa/gK if one knows EEPSP, EK, and ENa. Thus, rearranging Equation 11-4 yields

At the neuromuscular junction EEPSP = 0 mV, EK = -100 mV, and ENa = +55 mV. Thus, from Equation 4, gNa/gK has a value of approximately 1.8, indicating that the conductance of the ACh-gated channel for Na+ is slightly higher than for K+. A comparable approach can be used to analyze the reversal potential and the movement of ions during excitatory and inhibitory synaptic potentials in central neurons (Chapter 12).

Unlike the voltage-gated channels, the ACh-gated channels are not opened by membrane depolarization. Instead a ligand (ACh) causes the channels to open. Each channel is thought to have two binding sites for ACh; to open, a channel must bind two molecules of ACh. Once a channel closes, the ACh molecules dissociate and the channel remains closed until it binds ACh again.

Four Factors Determine the End-Plate Current

Stimulation of a motor nerve releases a large quantity of ACh into the synaptic cleft. The ACh rapidly diffuses across the cleft and binds to the ACh receptors, causing more than 200,000 ACh receptor-channels to open almost simultaneously. (This number is obtained by comparing the total end-plate current, around -500 nA, with the current through a single ACh-gated channel, around -2.7 pA). How do small step-like changes in current flowing through 200,000 individual AChgated channels produce the smooth waveform of the end-plate current? The rapid and large rise in ACh concentration upon stimulation of the motor nerve causes a large increase in the total conductance of the end-plate membrane, gEPSP, and produces the rapid rise in end-plate current (Figure 11-10). The ACh in the cleft falls to zero rapidly (in less than 1 ms) because of enzymatic hydrolysis and diffusion. After the fall in ACh concentration, the channels begin to close in the random manner described above. Each closure produces a small step-like decrease in end-plate current because of the all-or-none nature of single-channel currents. However, since each unitary current step is P.195 P.196 tiny relative to the large current carried by many thousands of channels, the random closing of a large number of small unitary currents causes the total end-plate current to appear to decay smoothly (Figure 11-10).

Figure 11-8 Individual ACh-gated channels open in an all-or-none fashion. A. The patch-clamp technique is used to record currents from single ACh-gated channels. The patch electrode is filled with salt solution that contains a low concentration of ACh and is then brought into close contact with the surface of the muscle membrane (see Box 6-1). B. Single-channel currents from a patch of membrane on a frog muscle fiber were recorded in the presence of 100 nM ACh at a resting membrane potential of -90 mV. 1. The opening of a channel results in the flow of inward current (recorded as a downward step). The patch contained a large number of ACh-gated channels so that successive openings in the record probably arise from distinct channels. 2. A histogram of the amplitudes of these rectangular pulses has a single peak. This distribution indicates that the patch of membrane contains only a single type of active channel and that the size of the elementary current through this channel varies randomly around a mean of -2.7 pA (1 pA = 10-12 A). This mean, the elementary current, is equivalent to an elementary conductance of about 30 pS. (Courtesy of B. Sakmann.) C. When the membrane potential is increased to -130 mV, the individual channel currents give rise to all-or-none increments of -3.9 pA, equivalent to 30 pS. Sometimes more than one channel opens simultaneously. In this case, the individual current pulses add linearly. The record shows one, two, or three channels open at different times in response to transmitter. (Courtesy of B. Sakmann.)

Figure 11-9 Single open ACh-gated channels behave as simple resistors. A. The voltage across a patch of membrane was systematically varied during exposure to 2 µM ACh. The current recorded at the patch is inward at voltages negative to 0 mV and outward at voltages positive to 0 mV, defining the reversal potential for the channels. B. The current flow through a single ACh-activated channel depends on membrane voltage. The linear relation shows that the channel behaves as a simple resistor with a conductance of about 30 pS.

The summed conductance of all open channels in a large population of ACh channels is the total synaptic conductance, gEPSP = n × γ, where n is the average number of channels opened by the ACh transmitter and γ is the conductance of a single channel. For a large number of ACh channels, n = N × po, where N is the total number of ACh channels in the end-plate membrane and po is the probability that any given ACh channel is open. The probability that a channel is open depends largely on the concentration of the transmitter at the receptor, not on the value of the membrane potential, because the channels are opened by the binding of ACh, not by voltage. The total end-plate current is therefore given by

or

This equation shows that the current for the end-plate potential depends on four factors: (1) the total number of end-plate channels (N); (2) the probability that a channel is open (po); (3) the conductance of each open channel (γ); and (4) the driving force that acts on the ions (Vm - EEPSP). The relationships between single-channel current, total end-plate current, and end-plate potential are shown in Figure 11-11 for a wide range of membrane potentials.

The Molecular Properties of the Acetylcholine-Gated Channel at the Nerve-Muscle Synapse Are Known Ligand-Gated Channels for Acetylcholine Differ From Voltage-Gated Channels Ligand-gated channels such as the ACh-gated channels that produce the end-plate potential differ in two important ways from the voltage-gated channels that generate the action potential at the neuromuscular junction. First, two distinct classes of voltage-gated channels are activated sequentially to generate the action potential, one selective for Na+ and the other for K+. In contrast, the ACh-gated channel alone generates end-plate potentials, and it allows both Na+ and K+ to pass with nearly equal permeability. P.197 A second difference between ACh-gated and voltage-gated channels is that Na+ flux through voltage-gated channels is regenerative: the increased depolarization of the cell caused by the Na+ influx opens more voltage-gated Na+ channels. This regenerative feature is responsible for the all-or-none property of the action potential. In contrast, the number of ACh-activated channels opened during the synaptic potential varies according to the amount of ACh available. The depolarization produced by Na+ influx through these channels does not lead to the opening of more transmitter-gated channels; it is therefore limited and by itself cannot produce an action potential. To trigger an action potential, a synaptic potential must recruit neighboring voltage-gated channels (Figure 11-12). As might be expected from these two differences in physiological properties, the ACh-gated and voltage-gated channels are formed by distinct macromolecules

that exhibit different sensitivities to drugs and toxins. Tetrodotoxin, which blocks the voltage-gated Na+ channel, does not block the influx of Na+ through the nicotinic ACh-gated channels. Similarly, α-bungarotoxin, a snake venom protein that binds tightly to the nicotinic receptors and blocks the action of ACh, does not interfere with voltage-gated Na+ or K+ channels (α-bungarotoxin has proved useful in the biochemical characterization of the ACh receptor). In Chapter 12 we shall learn about still another type of ligand-gated channel, the N-methyl-D-aspartate or NMDA-type glutamate receptor, which is found in most neurons of the brain. This channel is doubly gated, responding both to voltage and to a chemical transmitter.

A Single Macromolecule Forms the Nicotinic Acetylcholine Receptor and Channel The nicotinic ACh-gated channel at the nerve-muscle synapse is a directly gated or ionotropic channel: the pore in the membrane through which ions flow and the binding site for the chemical transmitter (ACh) that regulates the opening of the pore are all formed by a single macromolecule. Where in the molecule is the binding site located? How is the pore formed? What are its properties? Insights into these questions have been obtained from molecular studies of the ACh-gated receptor-channel proteins and their genes. Biochemical studies by Arthur Karlin and Jean-Pierre Changeux indicate that the mature nicotinic ACh receptor is a membrane glycoprotein formed from five subunits: two α-subunits and one β-, one γ-, and one δ-subunit (Figure 11-13). The amino terminus of each of the subunits is exposed on the extracellular surface of the membrane. The amino terminus of the α-subunit contains a site that binds ACh with high affinity. Karlin and his colleagues have demonstrated the presence of two extracellular binding sites for ACh on each channel. Those sites are formed in a cleft between each α-subunit and its neighboring γ- or δ-subunits. One molecule of ACh must bind to each of the two α-subunits for the channel to open efficiently (Figure 11-13). The inhibitory snake venom α-bungarotoxin also binds to the α- subunit.

Figure 11-10 The time course of the total current at the end-plate results from the summed contributions of many individual ACh-gated channels. (Adapted from D. Colquhoun 1981.) A. Individual ACh-gated channels open in response to a brief pulse of ACh. All channels (1-6) open rapidly and nearly simultaneously. The channels then remain open for varying durations and close at different times. B. The stepped trace shows the sum of the six records in A. It reflects the sequential closing of each channel (the number indicates which channel has closed) at a hypothetical end-plate containing only six channels. In the final period of net current flow only channel 1 is open. In a current record from a whole muscle fiber, with thousands of channels, the individual channel closings are not visible because the total end-plate current (hundreds of nanoamperes) is so much larger than the single-channel current amplitude (-2.7 pA). As a result, the total end-plate current appears to decay smoothly.

Figure 11-11 Membrane potential affects the end-plate potential, total end-plate current, and ACh-gated single-channel current in a similar way. A. At the normal muscle resting potential of -90 mV the single-channel currents and total end-plate current (made up of currents from more than 200,0000 channels) are large and inward because of the large inward driving force on current flow through the ACh-gated channels. This large inward current produces a large depolarizing end-plate potential. At more positive levels of membrane potential (increased depolarization), the inward driving force on Na+ is less and the outward driving force on K+ is greater. This results in a decrease in the size of the single-channel currents and in the magnitude of the end-plate currents, thus reducing the size of the end-plate potential. At the reversal potential (0 mV) the inward Na+ flux is balanced by the outward K+ flux, so there is no net current flow at the end-plate and no change in Vm. Further depolarization to +30 mV inverts the direction of the end-plate current, as there is now a large outward driving force on K+ and a small inward driving force on Na+. As a result, the outward flow of K+ hyperpolarizes the membrane. On either side of the reversal potential the end-plate current drives the membrane potential toward the reversal potential. B. The direction of Na+ and K+ fluxes in individual channels is altered by changing Vm. The algebraic sum of the Na+ and K+ currents, INa and IK, gives the net current that flows through the ACh-gated channels. This net synaptic current is equal in size, and opposite in direction, to that of the net extrasynaptic current flowing in the return pathway of the resting channels and membrane capacitance. (The length of each arrow represents the relative magnitude of a current.)

P.198 Insight into the structure of the channel pore has come from analysis of the primary amino acid sequences of the receptor-channel subunits as well as from biophysical studies. The work of Shosaku Numa and his colleagues demonstrated that the four subunit types are encoded by distinct but related genes. Sequence comparison of the subunits shows a high degree of similarity among them: half of the amino acid residues are identical or conservatively substituted. This similarity suggests that all subunits have a similar P.199 structure. Furthermore, all four of the genes for the subunits are homologous; that is, they are derived from a common ancestral gene. The distribution of the polar and nonpolar amino acids of the subunits provides important clues as to how the subunits are threaded through the membrane bilayer. Each subunit contains four hydrophobic regions of about 20 amino acids called M1-M4, each of which is thought to form an α-helix traversing the membrane. The amino acid sequences of the subunits suggest that the subunits are symmetrically arranged to create the pore through the membrane (Figure 1114). The walls of the channel pore are thought to be formed by the M2 region and by the segment connecting M2 to M3 (Figure 11-14B). Certain drugs that bind to one ring of serine residues and two rings of hydrophobic residues on the M2 region within the channel pore are able to inhibit current flow through the pore. Moreover, three rings of negative charge that flank the M2 region (Figure 11-15B) contribute to the channel's selectivity for cations. Each ring is made up of three or four aligned negatively charged residues contributed by different subunits. A three-dimensional model of the ACh receptor has been proposed by Arthur Karlin and Nigel Unwin based on neutron scattering and electron diffraction images respectively (see Figure 11-3). The receptor-channel complex is divided into three regions: a large vestibule at the external membrane surface, a narrow transmembrane pore that determines cation selectivity, and a larger exit region at the internal membrane surface (Figure 11-15A). The region that extends into the extracellular space is surprisingly large, about 6 nm in length. At the external surface of the membrane the channel has a wide mouth about 2.5 nm in diameter. Within the bilayer of the membrane the channel gradually narrows. This narrow region is quite short, only about 3 nm in length, corresponding to the length of both the M2 segment and the hydrophobic core of the bilayer (Figure 11-15B). In the open channel, the M2 segment appears to slope inward toward the central axis of the channel, so that the pore narrows continuously from the outside of the membrane to the inside (Figure 11-15C). Near the inner surface of the membrane the pore reaches its narrowest diameter, around 0.8 nm, in reasonable agreement with estimates from electrophysiological measurements. This site may correspond to the selectivity filter of the channel. At the selectivity filter, polar threonine residues extend their side chains into the lumen of the pore. The electronegative oxygen atom of the hydroxyl group may interact with the

permeant cation to compensate for loss of waters of hydration. At the inner surface of the membrane, the pore suddenly widens again

Figure 11-12 The binding of ACh in a postsynaptic muscle cell opens channels permeable to both Na+ and K+. The flow of these ions into and out of the cell depolarizes the cell membrane, producing the end-plate potential. This depolarization opens neighboring voltage-gated Na+ channels in the muscle cell. To trigger an action potential, the depolarization produced by the end-plate potential must open a sufficient number of Na+ channels to exceed the cell's threshold. (After Alberts et al. 1989.)

Figure 11-13 Three-dimensional model of the nicotinic ACh-gated ion channel. The receptor-channel complex consists of five subunits, all of which contribute to forming the pore. When two molecules of ACh bind to portions of the α-subunits exposed to the membrane surface, the receptor-channel changes conformation. This opens a pore in the portion of the channel embedded in the lipid bilayer, and both K+ and Na+ flow through the open channel down their electrochemical gradients.

P.200 On the basis of images of ACh receptors in the presence and absence of transmitter, Unwin has proposed that the M2 helix may be important for channel gating, as well as for ion permeation. His studies indicate that the M2 helix is not straight but rather has a bend or kink in its middle (Figure 11-15C). When the channel is closed, this kink projects inward toward the central axis of the pore, thereby occluding it. When the channel opens, the M2 helix rotates so that the kink lies along the wall of the channel. A somewhat different view of the pore and gate has been provided by Karlin, who studied the reactions of small, charged reagents with amino acid side chains in the M2 segment. By comparing the ability of these compounds to react in the open and closed states of the P.201 channel, Karlin concluded that the gate was at the cytoplasmic end of M2.

Figure 11-14 A molecular model of the transmembrane subunits of the nicotinic ACh receptor-channel. A. Each subunit is composed of four membrane-spanning α-helices (labeled M1 through M4). B. The five subunits are arranged such that they form an aqueous channel, with the M2 segment of each subunit facing inside and forming the lining of the pore (see turquoise cylinders, Figure 11-15A). Note that the γ-subunit lies between the two α-subunits.

Figure 11-15 A functional model of the nicotinic ACh receptor-channel. A. According to this model negatively charged amino acids on each subunit form three rings of charge around the pore (see part B). As an ion traverses the channel it encounters this series of negatively charged rings. The rings at the external (1) and internal (3) surfaces of the cell membrane may serve as prefilters and divalent blocking sites. The central ring (2) within the bilayer may contribute to the selectivity filter for cations, along with a ring of threonine and serine residues that contribute an electronegative oxygen. (Dimensions are not to scale.) B. The amino acid sequences of the M2 and flanking regions of each of the five subunits. The horizontal series of amino acids numbered 1, 2, and 3 identify the three rings of negative charge (see part A). The position of the aligned serine and threonine residues within M2, which help form the selectivity filter, is indicated. C. A model for gating of the ACh receptor-channel. Three of the five M2 transmembrane segments are shown. Each M2 segment is split into two cylinders, one on top of the other. Left: In the closed state each M2 cylinder points inward toward the central axis of the channel. A ring of five hydrophobic leucine residues (large spheres, one from each M2 segment) occludes the pore. Right: In the open state the cylinders tilt, thus enlarging the ring of leucines. A ring of hydrophilic threonine residues (small spheres) may form the selectivity filter near the inner mouth of the channel. (Based on Unwin 1995).

An Overall View The terminals of motor neurons form synapses with muscle fibers at specialized regions in the muscle membrane called end-plates. When an action potential reaches the terminals of a presynaptic motor neuron, it causes release of ACh. The transmitter diffuses across the synaptic cleft and binds to nicotinic ACh receptors in the end-plate, thus opening channels that allow Na+, K+, and Ca2+ to flow across the postsynaptic muscle. A net influx of Na+ ions produces a depolarizing synaptic potential called the end-plate potential. P.202 Because the ACh-activated channels are localized to the end-plate, the opening of these channels produces only a local depolarization that spreads passively along the muscle fibers. But by depolarizing the postsynaptic cell past threshold, the transmitter-gated channels activate voltage-dependent Na+ channels near the endplate region. As the postsynaptic cell becomes progressively depolarized, more and more voltage-gated Na+ channels open. In this way the Na+ channels can quickly generate enough current to produce an actively propagated action potential. The protein that forms the nicotinic ACh-activated channel has been purified, its genes cloned, and its amino acids sequenced. It is composed of five subunits, two of which—the α-subunits that recognize and bind ACh—are identical. Each subunit has four hydrophobic regions that are thought to form membrane-spanning αhelices. The protein that forms the nicotinic ACh-gated channel also contains a site for recognizing and binding the ACh. This channel is thus gated directly by a chemical transmitter. The functional molecular domains of the ACh-gated channel have been identified, and the steps that link ACh-binding to the opening of the channel are now being investigated. Thus, we may soon be able to see in atomic detail the molecular dynamics of this channel's various physiological functions. The large number of ACh-gated channels at the end-plate normally ensures that synaptic transmission will proceed with a high safety factor. In the autoimmune disease myasthenia gravis, antibodies to the ACh receptor decrease the number of ACh-gated channels, thus seriously compromising transmission at the neuromuscular junction (see Chapter 16). Acetylcholine is only one of many neurotransmitters in the nervous system, and the end-plate potential is just one example of chemical signaling. Do transmitters in the central nervous system act in the same fashion, or are other mechanisms involved? In the past such questions were virtually unanswerable because of the small size and great variety of nerve cells in the central nervous system. However, advances in experimental technique—in particular, patch clamp-ing—have made synaptic transmission at central synapses easier to study. Already it is clear that many neurotransmitters operate in the central nervous sys-tem much as ACh operates at the end-plate, while other transmitters produce their effects in quite differ-ent ways. In the next two chapters we shall explore some of the many variations of synaptic transmission that characterize the central and peripheral nervous systems.

Postscript: The End-Plate Current Can Be Calculated From an Equivalent Circuit Although the flow of current through a population of ACh-activated end-plate channels can be described by Ohm's law, to understand fully how the flow of electrical current generates the end-plate potential we also need to consider all the resting channels in the surrounding membrane. Since channels are proteins that span the bilayer of the membrane, we must also take into consideration the capacitive properties of the membrane and the ionic batteries determined by the distribution of Na+ and K+ inside and outside the cell. The dynamic relationship of these various components can be explained using the same rules we used in Chapter 8 to analyze the flow of current in passive electrical devices that consist only of resistors, capacitors, and batteries. We can represent the end-plate region with an equivalent circuit that has three parallel branches: (1) a branch representing the flow of synaptic current through the transmitter-gated channels; (2) a branch representing the return current flow through resting channels (the nonsynaptic membrane); and (3) a branch representing current flow across the lipid bilayer, which acts as a capacitor (Figure 11-16). Since the end-plate current is carried by both Na+ and K+, we could represent the synaptic branch of the equivalent circuit as two parallel branches, each representing the flow of a different ion species. At the end-plate, however, Na+ and K+ flow through the same ion channel. It is therefore more convenient (and correct) to combine the Na+ and K+ current pathways into a single conductance, representing the channel gated by ACh. The conductance of this pathway depends on the number of channels opened, which in turn depends on the concentration of transmitter. In the absence of transmitter no channels are open and the conductance is zero. When a presynaptic action potential causes the release of transmitter, the conductance of this pathway rises to a value of around 5 × 10-6 S (or a resistance of 2 × 105 ω). This is about five times the conductance of the parallel branch representing the resting or leakage channels (gl). The end-plate conductance is in series with a battery (EEPSP), whose value is given by the reversal potential for synaptic current flow (0 mV) (Figure 11-16). This value is the weighted algebraic sum of the Na+ and K+ equilibrium potentials (see Box 11-1). The current flowing during the excitatory postsynaptic potential (IEPSP) is given by

Using this equation and the equivalent circuit of Figure 11-17 we can now analyze the end-plate potential in P.203 terms of the flow of ionic current. At the onset of the excitatory synaptic action (the dynamic phase), an inward current (IEPSP) flows through the ACh-activated channels because of the increased conductance to Na+ and K+ and the large inward driving force on Na+ at the initial resting potential (-90 mV). Since current flows in a closed loop, the inward synaptic current must leave the cell as outward current. From the equivalent circuit we see that there are two parallel pathways for outward current flow: a conductance pathway (Il) representing current flow through the resting (or leakage) channels and a capacitive pathway (Ic) representing current flow across the membrane capacitance. Thus,

Figure 11-16 The equivalent circuit of the end-plate with two parallel current pathways. One pathway representing the synapse consists of a battery, EEPSP, in series with a conductance through ACh-gated channels, gEPSP. The other pathway consists of the battery representing the resting potential (El) in series with the conductance of the resting channels (gl). In parallel with both of these conductance pathways is the membrane capacitance (Cm). The voltmeter (V) measures the potential difference between the inside and the outside of the cell. When no ACh is present, the gated channels are closed and no current flows through them. This state is depicted as an open electrical circuit in which the synaptic conductance is not connected to the rest of the circuit. The binding of ACh opens the synaptic channel. This event is electrically equivalent to throwing the switch that connects the gated conductance pathway (gEPSP) with the resting pathway (gl). In the steady state current flows inward through the gated channels and outward through the resting channels. With the indicated values of conductances and batteries, the membrane will depolarize from -90 mV (its resting potential) to -15 mV (the peak of the end-plate potential).

During the earliest phase of the end-plate potential the membrane potential, Vm, is still close to its resting value, El. As a result, the outward driving force on current flow through the resting channels (Vm - El) is small. Therefore, most of the current leaves the cell as capacitive current and the membrane depolarizes rapidly (phase 2 in Figure 11-17). As the cell depolarizes, the outward driving force on current flow through the resting channels increases, while the inward driving force on synaptic current flow through the ACh-gated channels decreases. Concomitantly, as the concentration of ACh in the synapse falls, the ACh-gated channels begin to close, and eventually the flow of inward current through the gated channels is exactly balanced by outward current flow through the resting channels (IEPSP = -Il). At this point no current flows into or out of the capacitor, that is, Ic = 0. Since the rate of change of membrane potential is directly proportional to Ic,

the membrane potential will have reached a peak steady-state value, ∆V/∆t = 0 (phase 3 in Figure 11-17). As the gated channels close, IEPSP decreases further. Now IEPSP and Il are no longer in balance and the membrane potential starts to repolarize, because the outward current flow due to Il becomes larger than the inward synaptic current. During most of the declining phase of the synaptic action, current no longer flows through the ACh-gated channels since all these channels are closed. Instead, current flows out only through the resting channels and in across the capacitor (phase 4 in Figure 11-17). When the end-plate potential is at its peak or steady-state value, Ic = 0 and therefore the value of Vm can be easily calculated. The inward current flow through

the gated channels (IEPSP) must be exactly balanced by outward current flow through the resting channels (Il):

The current flowing through the active ACh-gated channels (IEPSP) and through the resting channels (Il) is given by Ohm's law:

and

By substituting these two expressions into Equation 11-8, we obtain

To solve for Vm we need only expand the two products in P.204 P.205 the equation and rearrange them so that all terms in voltage (Vm) appear on the left side:

By factoring out Vm on the left side, we finally obtain

Figure 11-17 Both the ACh-gated synaptic conductance and the passive membrane properties of the muscle cell determine the time course of the end-plate potential. A. Comparison of the time course of the end-plate potential (top trace) with the time courses of the component currents through the ACh-gated channels (IEPSP), the resting (or leakage) channels (Il), and the capacitor (Ic). Capacitive current flows only when the membrane potential is changing. In the steady state, such as at the peak of the end-plate potential, the inward flow of ionic current through the ACh-gated channels is exactly balanced by the outward flow of ionic current across the resting channels, and there is no flow of capacitive current. B. Equivalent circuits for the current at times 1, 2, 3, and 4 shown in part A. (The relative magnitude of a current is represented by the length of the arrows.)

This equation is similar to that used to calculate the resting and action potentials (Chapter 7). According to Equation 11-9, the peak voltage of the end-plate potential is a weighted average of the electromotive forces of the two batteries for gated and resting currents. The weighting factors are given by the relative magnitude of the two conductances. If the gated conductance is much smaller than the resting membrane conductance (gEPSP 45°C)

Cold nociceptors

C

IV

Nociceptors

Cold temperatures (12 Hz) electrical activity called desynchronized. During deep sleep the EEG is dominated by high-voltage, slow ( leg); Left posterior frontal cortex, patient aware of defect and and underlying structures may be depressed No motor signs; patient may be Left posterior, superior, and

articulated, melodic

anxious, agitated, euphoric, or

middle temporal cortex

Fluent with some

paranoid Often none; patient may have

Left superior temporal and

articulatory defects

corticalsensory loss or

supramarginal gyri

Global Transcortical Motor

Scant, nonfluent Nonfluent, explosive

Impaired Intact or largely preserved

Impaired Intact or largely preserved

weakness in right arm Right hemiplegia Massive left perisylvian lesion Sometimes right-sided weaknessAnterior or superior to Broca's

Transcortical Sensory

Fluent; scant

Impaired

Intact or largely preserved

No motor signs

Conduction

Intact or largely preserved

Impaired

area Posterior or inferior to Wernicke's area,

Figure 59-2 Broca aphasia. Left: A three-dimensional magnetic resonance imaging (MRI) reconstruction of a lesion (an infarction in the left frontal operculum, dark gray area) in a patient with Broca aphasia. Right: Coronal section of the same brain taken along the plane defined by the blue slab. The brain is viewed from the front, with the left hemisphere on the right half of the image. The infarct is visible in black.

When damage is restricted to Broca's area alone, or to its subjacent white matter, a condition now known as Broca area aphasia, the patient develops a milder and transient aphasia rather than true Broca aphasia.

People With Broca Aphasia Have Trouble Understanding Grammatically Complex Sentences Broca aphasia was initially thought to be a deficit of production only, because most patients give the impression of understanding casual speech. Modern psycholinguistic studies have shown that people who have Broca aphasia comprehend sentences whose meaning can be pieced together from the individual meanings of content words and prior knowledge of how the world works. For example, these patients can understand The apple that the boy is eating is red. Boys eat apples, but apples do not eat boys; apples are red, but boys are not. But they cannot comprehend sentences in which meaning depends on complex grammar. They cannot understand The boy that the girl is chasing is tall. Aphasic patients can understand the first sentence, as well as much casual conversation in general, based on vocabulary and general knowledge, without exercising grammatical abilities. But they have difficulty with the second sentence because either boys or girls can be tall and either one can chase the other. The only way to understand the second sentence is to recover its phrase structure, look up the lexical entry of chase to find the positions of the chaser and the person being chased, and link the gap after chasing to the boy. People with Broca aphasia are tripped up by this demand, showing that their aphasia is not just a disorder of speech output but embraces deficits in syntactic processing. Is Broca aphasia, then, a deficit of grammar, implying that Broca's area is the center for grammar? Not really. First, the speech of patients with Broca aphasia is not altogether devoid of grammatical structure. Their speech retains the phrase order of their particular language (eg, subject-verb-object in English, subject-object-verb in Turkish). Moreover, although grammatical suffixes such as -ed, -ing, and -s are often omitted in the speech of English-speaking aphasic patients, suffixes may be preserved in the speech of aphasic patients speaking other languages in which suffixes are obligatory to conform with the phonological structure of words. Second, people with Broca aphasia often can make surprisingly fine grammatical judgments, discriminating the grammatical and ungrammatical versions of sentences such as the following:

John was finally kissed by Louise. John was finally kissed Louise. I want you to go to the store now. I want you will go to the store now.

For a sentence to be grammatically well formed, it needs certain functional morphemes —the smallest meaningful unit of a word. The ability of patients to recognize that a sentence needs these morphemes—combined with an inability to analyze those morphemes when understanding complex sentences—has been called the “syntax-there-but-not-there” paradox. A possible resolution is that the major syntactic difficulty in Broca aphasia is linking up elements in different parts of the sentence that must refer to the same entity (anaphora and gap-filling). In John was finally kissed by P.1178 P.1179 Louise, the failure to link John to the empty object position after was kissed would make the sentence incomprehensible. The aphasic person is able to detect the ungrammaticality of John was finally kissed Louise by simply noting that a passive verb (was kissed) appears illicitly with a direct object. This recognition does not depend on linking a gap with its filler. Indeed, people who have Broca aphasia cannot recognize that a sentence is ungrammatical if the ungrammaticality comes from an incorrect linkage between two separated elements in a sentence. That is, they are poor at discriminating between sentences such as the following pairs: Table 59-2 Examples of Spontaneous Speech Production, Auditory Comprehension, and Repetition for the Primary Types of Aphasia Type of aphasia

Broca

Spontaneous speech Stimulus (Western Aphasia Battery picnic picture): What do you see in this picture? “O, yea. Det's a boy an' a girl… an'… a… car… house… light po' (pole). Dog an' a… boat. ‘N det's a… mm… a… cofee, an' reading. Det's a… mm… a… det's a boy… fishin'.” (Elapsed time: 1 min 30 s)

Auditory comprehension

Repetition

Stimulus: What seems to be the trouble?

Stimulus: The pastry cook was elated.

“Yea, but, ah, notes an', ah… an', ah… I don' know.”

“Elated.”

Wernicke

“Ah, yes, it's, ah… several things. It's a girl… uncurl… on a boat. A dog…'S is another dog… uh-oh… long's…

“Well, I jus' lost a lot a time”

“/I/… no… In a fog.”

“T: see if I can't talk straight, where I can have… not havin'trouble to say words an' sentences.”

“The baker was… What was that last word?” (“Let me repeat it: The pastry cook was

on a boat. The lady, it's a young lady. An' a man a They were eatin'. ‘S be place there. This… a tree! A boat. No, this is a… It's a house. Over in here… a cake. An' it's, it's a lot of water. Ah, all right. I think I mentioned about that boat. I noticed a boat being there. I did mention that before.… Several things down,

Conduction

different things down… a bat… a cake… you have a…” (Elapsed time: 1 min 20 s) “Kay. I see a guy readin' a book. See a women / ka… he… /pourin' drink or somethin'. An' they're sittin' under a tree. An' there's a… car behind that an' then there's a house behind th' car. An' on the other side, the guy's flyn' a / fait… fait /(kite). See a dog there an'

elated.”)“The baker-er was/vaskerin/… uh…”

a guy down on the bank. See a flag blowin' in the wind. Bunch of/hi… a…/trees in behind. An a sailboat on th' river, river… lake. 'N guess that's about all… ‘Basket Global

there.” (Elapsed time: 1 min 5 s) (Grunt)

(Gesturing)

(No response)

Figure 59-3 Wernicke aphasia. Left:A three-dimensional magnetic resonance imaging (MRI) reconstruction of a lesion in a patient with Wernicke aphasia. The infarction affected a large area of temporal lobe cortex as well as underlying white matter. Large, deep lesions are typically seen in severe cases. Right: Coronal section of the same brain taken along the plane defined by the blue slab. The brain is viewed from the front, with the left hemisphere on the right half of the image. The infarct is visible in black.

The woman is outside, isn't she? The woman is outside, isn't it? The girl fixed herself a sandwich. The girl fixed themselves a sandwich.

Linking two elements (filler to gap, or antecedent to pronoun) requires keeping the first element in one's working memory (Chapters 19 and 62) until the second is encountered and the two can be joined. This suggests that Broca's area and associated regions may participate in the verbal short-term memory required for sentence comprehension. Recent functional brain imaging studies using PET show that the level of activation in a subregion of Broca's area increases when a subject has to understand a sentence in which there is a long gap in the middle compared with the level when the subject must understand similar sentences with shorter gaps in the middle The idea that Broca's area is related to short-term working memory fits with other findings. Working memory is thought to have a phonological loop consisting of a transient memory store for phonological information and a rehearsal process—a covert articulatory process in which commands are sent to the vocal tract muscles but not carried out—which repeatedly refreshes the memory. Broca's area may participate in the rehearsal component of the loop, something that accords with the well-documented role of Broca's area in articulation. The structures usually damaged in true Broca aphasia and in Broca area aphasia may be part of a neural network involved in both the assembly of phonemes into words and the assembly of words into sentences. This network is thought to be concerned with relational aspects of language, which include the grammatical structure of sentences and the proper use of grammatical vocabulary and verbs. The other cortical components of the network are located in external areas of the left frontal cortex (Brodmann's areas 47, 46, and 9), the left parietal cortex (areas 40, and 39), and sensorimotor areas above the sylvian fissure between Broca's and Wernicke's areas (the lower sector of areas 3, 1, 2, and 4) and the insula.

Wernicke Aphasia Results From Damage to Left Temporal Lobe Structures Wernicke aphasia is usually caused by damage to the posterior sector of the left auditory association cortex (Brodmann's area 22), although in severe and persisting cases there is involvement of the middle temporal gyrus and deep white matter (Figure 59-3). The speech of patients with Wernicke aphasia is effortless, melodic, and produced at a normal rate and is thus quite unlike that of patients with true Broca aphasia. The content, however, is often unintelligible because of frequent errors in the choice of words and phonemes, the individual sound units that make up morphemes (Table 59-2). Patients with Wernicke aphasia often shift the order of individual sounds and sound clusters and add or subtract them to a word in a manner that distorts the intended phonemic plan. These errors are called phonemic paraphasias (paraphasia refers to any substitution of an erroneous phoneme or entire word for the intended, correct P.1180 one). When phoneme shifts occur frequently and close together, words become unintelligible and constitute neologisms. Even when words are put together with the proper individual sounds, patients with Wernicke aphasia have great difficulty selecting words that accurately represent their intended meaning (known as a verbal or semantic paraphasia). For example, a patient may say headman for president. These patients also have difficulty comprehending sentences uttered by others. Although this deficit is suggested by the Wernicke-Geschwind model,

Wernicke's area is no longer seen as the center of auditory comprehension. The modern view is that Wernicke's area is part of a processor of speech sounds that associates the sounds with concepts. This processing involves, in addition to Wernicke's area, the many parts of the brain that subserve grammar, attention, social knowledge, and knowledge of the concepts corresponding to the meanings of the words in the sentences.

Conduction Aphasia Results From Damage to Structures That Interact With Major Language Areas of the Brain Patients with conduction aphasia comprehend simple sentences and produce intelligible speech but, like those with Broca and Wernicke aphasias, they cannot repeat sentences verbatim, cannot assemble phonemes effectively (and thus produce many phonemic paraphasias), and cannot easily name pictures and objects (the task called confrontation naming). Speech production and auditory comprehension are less compromised in conduction aphasia than in the two other major aphasias (Table 59-2). Persistent conduction aphasia is caused by damage to the left superior temporal gyrus and the inferior parietal lobe (Brodmann's areas 39 and 40). The damage may extend to the left primary auditory cortex (Brodmann's areas 41 and 42), the insula, and the underlying white matter. There is no evidence that conduction aphasia is caused by a simple interruption or disconnection of the arcuate fasciculus alone, although the damage does destroy feed-forward and feedback projections that interconnect temporal, parietal, insular, and frontal cortices. This connectional system seems to be part of the network required to assemble phonemes into words and coordinate speech articulation. Even though the exact anatomical correlates of conduction aphasia are being revised and the mechanism of the defect now appears not to be as proposed in the Wernicke-Geschwind model, Wernicke correctly predicted the main signs of the syndrome. This is a testimony to the considerable power of the early clinical observations in aphasia.

Transcortical Motor and Sensory Aphasias Result From Damage to Areas Near Broca's and Wernicke's Areas The Wernicke-Geschwind model predicts that aphasias can be caused by damage not only to components of the language system but also to areas and pathways that connect those components to the rest of the brain. Patients with transcortical motor aphasia speak nonfluently but they can repeat even very long sentences. According to the Wernicke-Geschwind model, the aphasia is caused by a disconnection of the language areas from those that initiate and control spontaneous speech; repetition is preserved because the connection to Wernicke's area is intact. The aphasia has been linked to damage to the left dorsolateral frontal area, a patch of association cortex anterior and superior to Broca's area, although there may be substantial damage to Broca's area itself. Dorsolateral frontal cortex is involved in the allocation of attention and the maintenance of higher executive abilities, including the selection of words. For example, part of the area is activated in PET studies when subjects have to produce the names of actions associated with particular objects (eg, saying kick in response to ball). Damage to this area leaves patients unable to perform such a task, although they can produce words in ordinary conversation. The aphasia can also be caused by damage to the left supplementary motor area, located high in the frontal lobe, directly in front of the primary motor cortex and buried mesially between the hemispheres. Electrical stimulation of the area in nonaphasic surgery patients causes the patients to make involuntary vocalizations or be unable to speak, and neuroimaging studies have shown this area to be activated in tasks of speech production. Thus the supplementary motor area appears to contribute to the initiation of speech, whereas the dorsolateral frontal regions contribute to its ongoing control, particularly when the task is difficult. People with transcortical sensory aphasia have fluent speech with impaired comprehension, and they also have great trouble naming things. This aphasia differs from Wernicke aphasia in the same way that transcortical motor aphasia differs from Broca aphasia: repetition is spared. In fact, patients with transcortical sensory aphasia may repeat and even make grammatical corrections in phrases and sentences they do not understand, and they can repeat words in foreign languages. The aphasia thus appears to be a deficit in semantic retrieval, with syntactic and phonological abilities still relatively intact Transcortical motor and sensory aphasias are believed to be caused by damage outside of the perisylvian area, in particular, outside the superior temporal and P.1181 inferior parietal lobes, which explains the sparing of repetition skills. Transcortical aphasias are thus the complement of conduction aphasia, behaviorally and anatomically. Transcortical sensory aphasia itself appears to be caused by damage to parts of the junction of the temporal, parietal, and occipital lobes, which connect the perisylvian language areas with the parts of the brain underlying word meaning.

Figure 59-4 Positron emission tomography images compare the adjusted mean activity in the brain during separate tasks: naming of unique persons, animals, and tools. All sections are axial (horizontal) with left hemisphere structures on the right half of each image. The search volume (the section of the brain sampled in the analysis) includes inferotemporal and temporal pole regions (enclosed by the dotted lines). Red areas are statistically significant activity after correction for multiple comparisons. There are distinct patterns of activation in the left inferotemporal and temporal pole regions for each task. (Courtesy of H. Damasio.)

Global Aphasia Is a Combination of Broca, Wernicke, and Conduction Aphasias Global aphasics have completely lost the ability to comprehend language, formulate speech, and repeat sentences, thus combining the features of Broca, Wernicke, and conduction aphasias. Speech is reduced to a few words at best. The same word may be used repeatedly, appropriately or not, in a vain attempt to communicate an idea. However, other abilities may be preserved: nondeliberate (“automatic”) speech such as stock expletives (used appropriately and with normal phonemic, phonetic, and inflectional structures), routines such as counting or reciting the days of the week, and the ability to sing previously learned melodies and their lyrics. Auditory comprehension is limited to a few words and idiomatic expressions. Classic global aphasia is accompanied by weakness in the right side of the face and paralysis of the right limbs and is caused by damage in the anterior language region and the basal ganglia and insula (as in Broca's area), the superior temporal gyrus (as in conduction aphasia), and the posterior language regions (as in Wernicke aphasia). So much damage can only be caused by a large infarct in the region supplied by the middle cerebral artery.

Beyond the Classic Language Areas: Other Brain Areas Are Important for Language The anatomical correlates of the classical aphasias comprise only a restricted map of language-related areas in the brain. The past decade of research on aphasia has uncovered numerous other language-related centers in the cerebral cortex and in subcortical structures. Some are located in the left temporal region. For example, until recently the anterior temporal and inferotemporal cortices, in either the left or the right P.1182 hemisphere, had not been associated with language. Recent studies reveal that damage to left temporal cortices (Brodmann's areas 21, 20, and 38) causes severe and pure naming defects—impairments of word retrieval without any accompanying grammatical, phonemic, or phonetic difficulty. When the damage is confined to the left temporal pole (Brodmann's area 38) the patient has difficulty recalling the names of unique places and persons but not names for common things. When the lesions involve the left midtemporal sector (areas 21 and 20) the patient has difficulty recalling both unique and common names. Finally, damage to the left posterior inferotemporal sector causes a deficit in recalling words for particular types of items—tools and utensils—but not words for natural things or unique entities. Recall of words for actions or spatial relationships is not compromised. These findings suggest that the left temporal cortices contain neural systems that access words denoting various categories of things but not words denoting the actions of the things or their relationships to other entities. Localization of a brain region that mediates word-finding for classes of things has been inferred from two types of studies: examination of patients with lesions in their brain from stroke, head injuries, herpes encephalitis, and degenerative processes such as Alzheimer disease and Pick disease, and functional imaging studies of normal individuals and electrical stimulation of these same temporal cortices during surgical interventions (Figure 59-4). Another area not included in the classical model is a small section of the insula, the island of cortex buried deep inside the cerebral hemispheres (Figure 595). Recent evidence suggests that this area is important for planning or coordinating the articulatory movements necessary for speech. Patients who have lesions in this area have difficulty pronouncing phonemes in their proper order; they usually produce combinations of sounds that are very close to the target word. These patients have no difficulty in perceiving speech sounds or recognizing their own errors and do not have trouble in finding the word, only in producing it. This area is also damaged in patients with true Broca aphasia and accounts for much of their articulatory deficits.

The frontal cortices in the mesial surface of the left hemisphere, which includes the supplementary motor area and the anterior cingulate region (also known as Brodmann's area 24), play an important role in the initiation and maintenance of speech. They are also important to attention and emotion and thus can influence many higher functions. Damage to these areas does not cause an aphasia in the proper sense but impairs the initiation of movement (akinesia) and causes mutism, the complete absence of speech. Mutism is a rarity in aphasic patients and is seen only during the very early stages of the condition. Patients with akinesia and mutism fail to communicate by words, gestures, or facial expression. They have an impairment of the drive to communicate, rather than aphasia.

The Right Cerebral Hemisphere Is Important for Prosody and Pragmatics In almost all right-handers, and in a smaller majority of left-handers, linguistic abilities—phonology, the lexicon, and grammar—are concentrated in the left hemisphere. This conclusion is supported by numerous studies of patients with brain lesions and studies of electrical and metabolic activity in the cerebral hemispheres of normal people. In “split-brain” patients, whose corpus callosum has been sectioned to control epilepsy, the right hemisphere occasionally has rudimentary abilities to comprehend or read words, but syntactic abilities are poor, and in many cases the right hemisphere has no lexical or grammatical abilities at all. Nonetheless, the right cerebral hemisphere does play a role in language. In particular, it is important for communicative and emotional prosody (stress, timing, and intonation). Patients with right anterior lesions may produce inappropriate intonation in their speech; those with right posterior lesions have difficulty interpreting the emotional tone of others' speech. In addition, the right hemisphere plays a role in the pragmatics of language. Patients with damage in the right hemisphere have difficulty incorporating sentences into a coherent narrative or conversation and using appropriate language in particular social settings. They often do not understand jokes. These impairments make it difficult for patients with right hemisphere damage to function effectively in social situations, and these patients are sometimes shunned because of their odd behavior. When adults with severe neurological disease have the entire left hemisphere removed, they suffer a permanent and catastrophic loss of language. In contrast, when the left hemisphere of an infant is removed the child learns to speak fluently. Adults do not have this plasticity of function, and this age difference is consistent with other findings that suggest there is a critical period for language development in childhood. Children can acquire several languages perfectly, whereas most adults who take up a new language are saddled with a foreign accent and permanent grammatical errors. When children are deprived of language input because their parents are deaf or depraved, they can catch up fully if exposed to language before puberty, but they are strikingly inept if the first exposure comes later.

Figure 59-5 A. Lesions of 25 patients with deficits in planning articulatory movements were computer-reconstructed and overlapped. All patients had lesions that included a small section of the insula, an area of cortex underneath the frontal, temporal, and parietal lobes. The area of infarction shared by all patients is depicted here in dark purple. B. The lesions of 19 patients without a deficit in planning articulatory movements were also reconstructed and overlapped. Their lesions completely spare the precise area that was infarcted in the patients with the articulatory deficit. (For this figure, left hemisphere lesions were reconstructed on the left side of the image.)

P.1183 Despite the remarkable ability of the right hemisphere to take on responsibility for language in young children, it appears to be less suited for the task than the left hemisphere. One study of a small number of children in whom one hemisphere had been removed revealed that the children with only a right hemisphere were impaired in language (and other aspects of intellectual functioning), compared with children who had only a left hemisphere (these children were less impaired overall). Like people with Broca aphasia, children with only a right hemisphere comprehend most sentences in conversation but have trouble interpreting more complex constructions, such as sentences in the passive voice. A child with only a left hemisphere, in contrast, has no difficulty even with complex sentences.

Alexia and Agraphia Are Acquired Disorders of Reading and Writing Certain brain lesions in adults can cause alexia (also known as word blindness), a disruption of the ability to read, or agraphia, a disruption of the ability to write. The two disorders may appear combined or separately, and they may or may not be associated with aphasia, depending on the site of the causative lesion. Reading emerged only recently in history (less than 5000 years ago), and universal literacy is even more recent (less than a century ago). Therefore, pure alexia without aphasia cannot be attributed to impairment of a special “reading system” in the brain but must be caused by a disconnection between the visual and language systems. Because vision is bilateral and language is lateralized, pure alexia results from disruptions in the transfer of visual information to the language areas of the

left hemisphere. In 1892 the French neurologist Jules Dejerine studied an intelligent and highly articulate man who had recently lost the ability to read, even though he could spell, understand words spelled to him, copy written words, and recognize words after writing the individual letters. The patient could not see color in his right visual field, but his vision was otherwise intact in both visual fields. Postmortem examination revealed damage in a critical area of the left occipital region that P.1184 disrupted the transfer of visually related signals from both the left and right visual cortices to language areas in the left hemisphere. The postmortem examination also revealed some damage to the splenium, the posterior portion of the corpus callosum that interconnects left and right visual association cortices. This lesion is no longer believed to be involved in pure alexia, however. When the splenium is cut for surgical reasons without damaging visual cortices, the patient can read words normally in the right visual field but not those in the left.

Figure 59-6 Areas of significant change in activity, indexed by perfusion, when subjects performed two language tests. The activated areas are superimposed on a lateral projection of the dominant left hemisphere with the frontal lobe to the left. The two pictures on the left are the results from normal subjects and the pictures on the right demonstrate results from patients with developmental dyslexia. Memory task: The upper two images demonstrate activity associated with remembering short lists of letters. In the normal subject an extensive area involving the inferior left frontal cortex, the superior temporal cortex, and the inferior parietal cortex is activated. In dyslexic patients only the inferior parietal and superior temporal cortex are activated. Rhyming task: During a rhyming task (lower images) that engages inner speech almost exclusively without taxing phonological memory, the inferior frontal and superior temporal cortex are activated in normal subjects, but only the inferior frontal cortex is activated in dyslexic subjects. Thus, dyslexic patients are able to activate each component of the verbal working memory system separately, but, unlike normal subjects, integrated activity between the precentral and postcentral structures appears defective. (Courtesy of R. Frackowiack.)

PET studies have shown that reading words and word-like shapes selectively activates extrastriate left cortical areas anterior to the visual cortex. This suggests that the processing of word shapes, like other complex visual qualities, requires that general region.

Developmental Dyslexia Is a Difficulty in Learning to Read A more prevalent form of reading disorder is seen in children who have difficulty in learning to read and spell despite normal eyesight and hearing, adequate education, and normal IQ. This syndrome, called developmental dyslexia, has been estimated to affect between 10 and 30% of the population. As mentioned earlier, reading is a complex and historically recent skill, and it is unlikely that P.1185 there is a well-defined system in the brain dedicated to it. Many disorders of visual and language processing could disrupt reading, and dyslexia is probably a condition with several possible causes rather than a single syndrome. Most children with dyslexia have not developed phonological awareness: the ability to attend to individual sounds, particularly phonemes, in the continuous speech wave and to associate them with letters. However, they understand other communicative symbols—such as traffic signs or words—that have a unique visual appearance, such as the Coca Cola trademark. Indeed, studies in the United States have shown that some dyslexic children can learn to read English when entire words are represented by single characters rather than a sequence of characters. Defects in visual processing can also lead to developmental dyslexia. Similarities between dyslexia and alexia caused by stroke suggest that developmental dyslexia might sometimes result from abnormalities in connections between visual and language areas. Some dyslexic children also exhibit a tendency to read words backward (eg, confusing saw and was) and have difficulty distinguishing letters that are mirror images of each other—such as b and d —both in reading and writing. These errors, together with the disproportionate number of left-handers among dyslexics, suggest that dyslexia might involve a deficit in the development of hemispheric specialization. In fact, in dyslexic males, unlike in normal males, the left planum temporale is not much larger than the right one, and it shows cytoarchitectonic abnormalities, including an incomplete segregation of cell layers and clusters of inappropriately connected neurons. Thus the migration of neurons to the left temporal cortex during development may have been

slowed in some dyslexic patients. Another possible problem in dyslexia is an inability to process transient sensory input quickly. The normally rapid conduction in the magnocellular pathway of the visual system (Chapter 27) is below average in people with dyslexia, whereas conduction in the parvocellular pathway is normal. In particular, dyslexic patients have difficulty processing fast, high-contrast, visual stimuli. A plausible anatomical correlate of this disorder is seen in some dyslexic patients examined at autopsy: the cells in the magnocellular layers of the lateral geniculate nucleus are abnormally small compared to parvocellular layers and compared to magnocellular layers in control subjects. A similar defect is sometimes evident in the fast-conducting component of the auditory pathways (Chapter 30). In addition to these processing impairments, patients who have developmental difficulties with reading can have other neuropsychological deficits (Figure 596). Such linkages must be considered tentative, however, until there is finer delineation of the disorders currently lumped together as dyslexia.

An Overall View The study of language processing in the brain has come a long way in a century, but the challenges to understanding it are formidable. Great progress has been made since Broca's and Wernicke's seminal discoveries, and that progress has brought a more complete understanding of linguistic processes and an appreciation of the complex ways in which they interconnect with systems for perception, motor control, conceptual knowledge, and attention. Several developments offer the hope of even greater progress in the near future. Improvements in anatomical imaging will allow more precise and consistent delineation of lesions that affect specific features of language ability, and greater involvement by linguists and experimental psychologists will allow more precise and consistent delineation of the deficits in functioning. Measurement of brain activity in normal subjects, using PET, functional MRI, and magnetoencephalography (MEG), will become more important in the next few years as the spatial and temporal resolution of these techniques improves and the most sophisticated experimental paradigms and linguistic analyses are systematically applied. Neurosurgical candidates, whose brain functions must be mapped by stimulation during surgery or recording from implanted electrode grids that remain in the skull during everyday activities, will be an important source of fine-grained information, especially if the language tasks administered to them are carefully constructed to isolate functions. Progress in the understanding of language is important for the advancement of fundamental neuroscience and indispensable for the treatment of patients with aphasia, which is by far the most frequent impairment of higher function caused by stroke and head injury. The astonishing feat of language is too complex to be understood with the tools of any single academic or medical specialty, but as several disciplines come together to study the underlying neural processes, we can expect significant breakthroughs. P.1186

Selected Readings Damasio AR, Damasio H. 1992. Brain and language. Sci Am 267:88–95.

Dronkers NF. 1999. The neural basis of language. In: R Wilson, F Keil (eds). The MIT Encyclopedia of the Cognitive Sciences. Cambridge: MIT Press.

Fromkin V, Rodman R. 1997. An Introduction to Language, 6th ed. New York: Harcourt Brace Jovanovich.

Goodglass H. 1993. Understanding Aphasia. San Diego: Academic.

Pinker S. 1994. The Language Instinct. New York: William Morrow.

References Baddeley AD, Hitch GJ. 1994. Developments in the concept of working memory. Neuropsychology 8:485–493.

Basso A, Lecours AR, Moraschini S, Vanier M. 1985. Anatomoclinical correlations of the aphasias as defined through computerized tomography: exceptions. Brain Lang 26:201–229.

Bates E, Wulfeck B, MacWhinney B. 1991. Cross-linguistic research in aphasia: an overview. Brain Lang 41:123–148.

Baynes K. 1990. Language and reading in the right hemisphere: highways or byways of the brain? J Cogn Neurosci 2:159–179.

Bishop DV. 1983. Linguistic impairment after left hemidecortication for infantile hemiplegia? A reappraisal. Q J Exp Psychol [A]35:199–207.

Broca P. 1861. Remarques sur le siegè de la faculté du langage articulé, suivies d'une observation d'aphemie (perte de la parole). Bulletin Société Anatomique de Paris 6:330–357.

Caplan D. 1987. Neurolinguistics and Linguistic Aphasiology: An Introduction. Cambridge: Cambridge Univ. Press.

Caramazza A, Zurif EB. 1976. Dissociation of algorithmic and heuristic processes in language comprehension: evidence from aphasia. Brain Lang 3:572–582.

Chomsky N. 1991. Linguistics and cognitive science: problems and mysteries. In: A Kasher (ed). The Chomskyan Turn. Cambridge, MA: Blackwell.

Cornell TL, Fromkin VA, Mauner G. 1993. A linguistic approach to language processing in Broca's aphasia: a paradox resolved. Curr Direct Psychol Sci 2:47–52.

Damasio AR. 1992. Aphasia. N Engl J Med 326:531–539.

Damasio AR. 1990. Category-related recognition defects as a clue to the neural substrates of knowledge. Trends Neurosci 13:95–98.

Damasio AR, Geschwind N. 1984. The neural basis of language. Annu Rev Neurosci 7:127–147.

Damasio AR, Tranel D. 1993. Nouns and verbs are retrieved with differently distributed neural systems. Proc Natl Acad Sci U S A 90:4957–4960.

Damasio H, Damasio AR. 1989. Lesion Analysis in Neuropsychology. New York: Oxford Univ. Press.

Damasio H, Grabowski TJ, Tranel D, Hichwa RD, Damasio AR. 1996. A neural basis for lexical retrieval. Nature 380:499–505.

Darwin CR. 1874. The Descent of Man and Selection in Relation to Sex, 2nd ed, pp. 101-102. New York: Hurst.

Deacon TW. 1997. The Symbolic Species: The Co-Evolution of Language and the Brain. New York: Norton.

Dejerine J. 1892. Contribution a l'étude anatomopathologique et clinique des differentes varietés de cecité verbale. Memoires Societé Biologique 4:61–90.

Demonet JF, Chollet F, Ramsay S, Cardebat D, Nespoulous JL, Wise R, Rascol A, Frackowiak R. 1992. The anatomy of phonological and semantic processing in normal subjects. Brain 115:1753–1768.

Dennis M, Whitaker HA. 1976. Language acquisition following hemidecortication: linguistic superiority of the left over the right hemisphere. Brain Lang 3:404–433.

Dronkers NF. 1996. A new brain region for coordinating speech articulation. Nature 384:159–161.

Etcoff NL. 1989. Asymmetries in recognition of emotion. In: F Boller, J Grafman (eds). Handbook of Neuropsychology, 3:363-382. New York: Elsevier.

Etcoff NL. 1986. The neuropsychology of emotional expression. In: G Goldstein, RE Tarter (eds). Advances in Clinical Neuropsychology, 3:127-179. New York: Plenum.

Galaburda AM. 1994. Developmental dyslexia and animal studies: at the interface between cognition and neurology. Cognition 50:133–149.

Gardner H, Brownell H, Wapner W, Michelow D. 1983. Missing the point: the role of the right hemisphere in the processing of complex linguistic materials. In: E Perecman (ed). Cognitive Processes in the Right Hemisphere. New York: Academic.

Gardner RA, Gardner BT. 1969. Teaching sign language to a chimpanzee. Science 165:664–672.

Gazzaniga MS. 1983. Right hemisphere language following brain bisection: a 20-year perspective. Am Psychologist 38:525–549.

Geschwind N. 1965. Disconnexion syndromes in animals and man II. Brain 88:585–644.

Geschwind N. 1970. The organization of language and the brain. Science 170:940–944.

Grodzinsky Y. 1990. Theoretical Perspectives on Language Deficits. Cambridge, MA: MIT Press.

Hauser M. 1996. The Evolution of Communication. Cambridge, MA: MIT Press.

Jackendoff R. 1994. Patterns in the Mind. New York: Basic Books.

Lesser RP, Arroyo S, Hart J, Gordon B. 1994. Use of subdural electrodes for the study of language functions. In: A Kertesz (ed). Localization and Neuroimaging in Neuropsychology, pp. 57-72. San Diego: Academic.

Linebarger MC, Schwartz MF, Saffran EM. 1983. Sensitivity to grammatical structure in so-called agrammatic aphasics. Cognition 13:361–392.

Mazoyer BM, Tzourio N, Frak V, Syrota A, Murayama N, Levrier O, Salamon G, Dehaene S, Cohen L, Mehler J. 1993. The cortical representation of speech. J Cogn Neurosci 5:467–479. P.1187

Mazzocchi F, Vignolo LA. 1979. Localization of lesions in aphasia: clinical CT scan correlations in stroke patients. Cortex 15:627–653.

Naeser MA, Hayward RW. 1978. Lesion localization in aphasia with cranial computed tomography and the Boston Diagnostic Aphasia Exam. Neurology 28:545–551.

Ojemann G. 1994. Cortical stimulation and recording in language. In: A Kertesz (ed). Localization and Neuroimaging in Neuropsychology, pp. 35-55. San Diego: Academic.

Paulesu E, Frith CD, Frackowiak RJ. 1993. The neural correlates of the verbal component of working memory. Nature 362:342–345.

Penfield W, Roberts L. 1959. Speech and Brain Mechanisms. Princeton, NJ: Princeton Univ. Press.

Petersen SE, Fox PT, Posner MI, Mintun M, Raichle ME. 1988. Positron emission tomographic studies of the cortical anatomy of single-word processing. Nature 331:585–589.

Pinker S, Bloom P. 1990. Natural language and natural selection. Behav Brain Sci 13:707–784.

Rapp BC, Caramazza A. 1995. Disorders of lexical processing and the lexicon. In: M Gazzaniga (ed). The Cognitive Neurosciences. Cambridge, MA: MIT Press.

Seidenberg MS. 1986. Evidence from the great apes concerning the biological basis of language. In: W Demopoulos, A Marras (eds). Language Learning and Concept Acquisition: Foundational Issues. Norwood, NJ: Ablex.

Seidenberg MS, Petitto LA. 1979. Signing behavior in apes: a critical review. Cognition 7: 177–215.

Shaywitz SE. 1998. Dyslexia. New Engl J Med 338:307–312.

Stromswold K, Caplan D, Alpert N, Rauch S. 1996. Localization syntactic comprehension by using positron emission tomography. Brain Lang 52:452–473.

Terrace HS, Petitto LA, Sanders RJ, Bever TG. 1979. Can an ape create a sentence? Science 206:891–902.

Ullman M, Corkin S, Coppola M, Hickok G, Growdon JH, Koroshetz WJ, Pinker S. 1997. A neural dissociation within language: evidence that the mental dictionary is part of declarative memory, and that grammatical rules are processed by the procedural system. J Cogn Neurosci 9:289–299.

Wallman J. 1992. Aping Language. New York: Cambridge Univ. Press.

Wernicke C. 1874. Der Aphasische Symptomencomplex. Breslau: Kohn and Weigert.

Wertz RT, LaPointe LL, Rosenbek JC. 1984. Apraxia of Speech in Adults: The Disorder and Its Management. Orlando, FL: Grune & Stratton.

Zaidel E. 1990. Language functions in the two hemispheres following complete commissurotomy and hemispherectomy. In: F Boller, J Grafman (eds). Handbook of Neuropsychology. New York: Elsevier.

Zurif EB, Caramazza A, Myerson R. 1972. Grammatical judgments of agrammatic aphasics. Neuropsychologia 10:405–417.

Back

60 Disorders of Thought and Volition: Schizophrenia Eric R. Kandel THE SUCCESS OF NEUROBIOLOGY in providing insights into perception and language has inspired biological investigation into thought and mood and their disorders. In this chapter and the next we examine the four most serious disorders of thinking and mood: schizophrenia, depression, mania, and the anxiety states. These disorders involve disturbances in thought, self-awareness, perception, affect, volition, and social interaction. In addition to being scientifically challenging, mental illness is of great social importance. Fully 10% of people with schizophrenia commit suicide. Many more are homeless. Before the advent of psychopharmacologic agents, schizophrenia and the affective disorders accounted for more than half of all hospital admissions in the United States. Even now schizophrenia accounts for about 30% of all hospitalizations.

Mental Illnesses Can Be Diagnosed Using Classical Medical Criteria In medicine the term disease refers to a cluster of symptoms and signs that results from a specific cause and leads through a defined course to a specific outcome. As with other diseases of the brain, the analysis of a mental disease requires good delineation of the symptoms and signs. Ideally, a diagnosis is based on two additional factors: (1) a clear and evident causative agent (whether the illness results from a genetic abnormality, a viral or bacterial infection, toxins, tumors, or stress) and (2) a plausible pathogenesis (a clear idea of the mechanism by which the causative agent produces the disease). Unfortunately, unlike most other medical illnesses, the causes and pathogenesis of most mental illnesses have not, as yet, been determined with certainty. As a result, psychiatric disorders are to a large extent still grouped today as they were in other areas of medicine at the beginning of the twentieth century. In other areas of medicine diseases were once grouped according to organ systems: lung, heart, gastrointestinal system, etc. P.1189 Likewise, in psychiatry diseases were grouped according to which of the four major mental systems was affected: cognition, affect, intelligence, or social behavior. Thus the diseases are categorized as follows: (1) disorders of cognition (schizophrenia and delirium); (2) disorders of mood (affective disorders and anxiety states); (3) disorders of learning, memory, and intelligence (mental retardation and dementia); and (4) disorders of social behavior (personality disorders). This classification derives importantly from the work at the turn of the century by Emil Kraepelin, the director of the Psychiatry Clinic at the University of Heidelberg in Germany. Before Kraepelin's initiative psychiatrists did not think of mental illnesses as diseases with a specific onset, progression, and outcome. They classified symptoms along arbitrary lines that had no medical significance. Influenced by Rudolf Virchow, the German pioneer of cellular pathology, and Thomas Sydenham, the English clinician who focused attention on the course of disease, Kraepelin began to study the disorders of mental faculties as specific disease processes. Kraepelin argued that even in the absence of empirical knowledge about etiology and pathogenesis, diseases of the mind could be distinguished descriptively on the basis of two classical approaches that had been followed in other areas of medicine. First, mental disorders can be classified on the basis of signs (what the examiner sees) and symptoms (what the patient reports). Of course, the presentation of a single sign or symptom is not in itself evidence for disease, since it may occur in healthy people. But when certain signs and symptoms occur together in several patients, they are said to form a syndrome, a condition that can be distinguished from normal behavior or from other clusters of signs and symptoms. Second, a mental disorder can be characterized on the basis of its natural history, by tracing the emergence of signs and symptoms at specific times in the patient's life and the evolution of these symptoms over time. Thus, a syndrome may be present at a characteristic age or be associated with a specific event, or it may follow a characteristic clinical course. For example, at least 33% of patients with schizophrenia deteriorate progressively, whereas most patients with the major affective disorders show cycles of relapse and recovery. Since Kraepelin's pioneering work both approaches have been used to delineate a mental disease. The delineation of a mental disease can, in principle, be refined further by one of three measures:

●

Response to specific treatment. A disease may respond specifically to a class of drugs that are not effective against other diseases. For example, manicdepressive illness responds to lithium, but other mental illnesses do not. ●

Pathologic condition. The clinical diagnosis of diseases of the heart, lung, kidney, and intestines, and even many neurological diseases, can be confirmed by examining the structural and functional changes in the diseased tissue, and this examination in turn provides information about the pathogenesis of disease. The absence of anatomically demonstrable pathologic conditions distinguishes diseases of the mind from those of other areas of medicine, including neurology. Huntington disease, for example, is associated with a lesion in the head of the caudate nucleus. ●

Causality. To conclude that a syndrome is the manifestation of a specific disease, specific causative agents must be identified. A syndrome need not have a single cause and therefore need not be a unitary disease. For example, the syndrome of pneumonia can be caused by different bacteria or different viruses giving rise to different specific diseases. The discovery of a specific molecular abnormality can provide particularly powerful insight into the cause of a disease. For example, in Duchenne muscular dystrophy the membrane-associated protein dystrophin is always absent or abnormal because of abnormalities in the gene encoding the protein.

Unfortunately, the pathogenesis of most psychiatric disorders has yet to be demonstrated. The defects underlying most psychiatric disorders are thought to involve subtle genetic, molecular, and anatomical changes, and these changes have remained elusive. Psychiatric diagnosis therefore must rely heavily on the individual patient's history and the patient's response to treatment. Yet these clinical features can be hard to determine and even harder to quantify. In the past these limitations made it difficult to achieve consensus in the evaluation of psychiatric symptoms and to investigate psychiatric illness systematically. Today, however, substantial progress has been made in diagnosing mental illness and, as we shall see later, there is reason to hope that a genuine neuropathology of mental illness may emerge soon.

Schizophrenia Is Likely to Be Several Related Disorders Schizophrenia is perhaps the most devastating disorder of humankind. Fairly common, it strikes about 1% of the population worldwide, and it seems to affect men P.1190 slightly more frequently and severely than it does women. In addition to the 1% with schizophrenia, another 2-3% of the general population have schizotypal personality disorder, which is often considered to be a milder form of the disease because patients do not manifest overtly psychotic behavior.

Box 60-1 The Functional Neuroanatomy of Hallucinations in Schizophrenia Imaging studies are beginning to shed light on the functional anatomy of hallucinations in schizophrenia. Frank Middleton and Peter Strick found that the basal ganglia, which are known to receive input from widespread areas of the cerebral cortex, including the frontal, parietal, and temporal lobes, project to both the frontal and the inferotemporal cortex. The inferotemporal cortex is critically involved in the recognition and discrimination of visual objects and is the area disturbed in prosopagnosia, a disorder concerned with the recognition of faces (Chapters 25 and 28). The output nuclei of the basal ganglia—the substantia nigra pars reticulata— project via the thalamus to the inferotemporal cortex. Thus, the inferotemporal cortex is not only a source of input to the basal ganglia but also a target of basal ganglia output (Figure 60-1). This result implies that the basal ganglia can influence higher-order visual processing, and that the basal ganglia loop may lead to alterations in visual perception, including visual hallucinations characteristic of schizophrenia. In fact, visual hallucinations are a major side effect of L-DOPA and other dopaminergic agents used in the treatment of Parkinson disease. Approximately 30% of patients with Parkinson disease treated in this manner experience this peculiar side effect. The hallucinations in these patients may be due to excessive stimulation of the dopamine receptors in the visual striatum, which leads to a net increase in activity in the nucleus pars reticulata and thus abnormal increases in thalamic input to the inferotemporal cortex. Brain images of schizophrenic patients experiencing hallucinations support this hypothesis; the subjects display significant changes in blood flow at several brain sites that are part of the inferotemporal system (Figure 60-2).

Figure 60-1 Proposed loop between the basal ganglia and the inferotemporal cortex. In a series of PET studies five patients with classical auditoryverbal hallucinations received medication yet still hallucinated. PET scans taken during hallucinations demonstrated activation of thalamic and striatal nuclei as well as of the hippocampus, the paralimbic region, the cingulate cortex, and the orbitofrontal cortex. One patient who had never received drugs had visual as well as auditory hallucinations. That patient showed activation in visual and auditory language association cortices near Wernicke's area, part of a distributed cortical network involved in the hallucinations. The interaction of these distributed neural systems may provide a neuroanatomical basis for the bizarre behavior of patients with schizophrenia. The prominent feature in this group of patients is involvement of the thalamus and the lack of activation of Broca's area. Shading indicates the portion of each structure that contributes to the circuit. (Based on Silbersweig et al. 1995.)

Figure 60-2 A. Increased activity in the brain during auditory-verbal hallucinations. Functional PET results (yellow and orange) are superimposed on a magnetic resonance image for anatomical reference. Section numbers refer to the distance from the anterior commissure-posterior commissure line, with positive numbers being superior to the line. Activation (yellow) extends into the amygdala bilaterally and the right orbitofrontal cortex. These regions are consistent with activation of limbic, paralimbic, and inferotemporal system during hallucinations. B.1. Two surface projections (left lateral and ventral) show brain areas with significantly increased activity during visual and auditory-verbal hallucinations. 2. Functional PET results (yellow and orange) are superimposed on the structural T

1

weighted MRI scan, illustrating several areas of activation.

In 1990 the annual cost of caring for patients with schizophrenia in the United States was estimated to be $33 billion. This cost accounts for about 2.5% of the total annual expenditures for health care in the United States. Even more disturbing is the estimate that about 30% of all the homeless people in the United States have schizophrenia, P.1191 and the homeless are not likely to be beneficiaries of the health care system. Thus the substantial funds being spent on the treatment of schizophrenia reach only a fraction of those afflicted with the disease. The increase in the incidence of schizophrenia among the homeless in the United States dates to 1960, with the movement away from institutional treatment for schizophrenia. (Before 1960 patients with schizophrenia were almost routinely committed for long-term in-hospital care.) At the same time, adequate community outpatient facilities have not been developed to handle the social problems of patients with chronic schizophrenia. P.1192 Because of the prevalence and social cost of schizophrenia, a major effort has been expended to develop better criteria for diagnosing the illness. More precise criteria have emerged only recently. In the early 1900s two majors types of mental disorders had been well delineated: senile dementia, the loss of cognitive capacities in certain elderly people (a disease we now recognize as Alzheimer disease), and personality disorders, disorders of social behavior. Based on a review of the signs and symptoms as well as long-term progress of hundreds of patients with a variety of mental disorders, Kraepelin defined two new syndromes. One new syndrome he called dementia praecox (early deterioration of the intellect) because of its early age of onset (typically in adolescence as compared to senile dementia). Kraepelin observed that this syndrome often follows a progressive course without remission, leading ultimately to a dramatic deterioration of intellect. Kraepelin called the second newly defined syndrome manic - depressive psychosis. This condition usually has different symptoms—disturbances of mood rather than intellect—but most important it also has a very different course. Characteristically, the onset is later and is marked by remissions and relapses without progressive deterioration

Eugen Bleuler objected to the term dementia praecox because he saw some patients who became sick in adulthood rather than adolescence and other patients who occasionally experienced remission. He concluded that the symptoms described by Kraepelin did not reflect a single disease, but a group of closely related illnesses characterized by a specific disorder of cognition rather than a general deterioration of intellect (dementia). He proposed that the disorder was a fragmentation of the mind, with the result that cognitive processes were split off from volition, behavior, and emotion. Therefore Bleuler called this group of illnesses schizophrenia, a splitting of the mind. (This condition is not to be confused with multiple or split personalities, an uncommon disease in which a person alternately assumes two or more identities.) People with schizophrenia may show evidence of this splitting of the mind by having inappropriate affect (emotion). They may laugh while recounting a tragic event or may show no emotion (a flat affect) while describing a joyous occasion. Schizophrenia is characterized by psychotic episodes— discrete, often reversible, mental states in which some of the patient's thought processes are not able to test reality correctly. During a psychotic episode patients are unable to examine their beliefs and perceptions realistically and to compare them to what is actually happening in the world. This loss of reality testing is accompanied by other disturbances of higher mental functioning, especially delusions (aberrant beliefs that fly in the face of facts and are not changed by evidence that the beliefs are unreasonable), hallucinations (Box 60-1), incoherent thinking, disordered memory, and sometimes confusion. For example, people with schizophrenia often hear internal voices (auditory hallucinations) that tell them things that are not true, for example that their parents are trying to poison them. Psychotic episodes are not unique to schizophrenia and often also occur in affective disorders, brief reactive states, and states of toxic delirium (for example, psychosis resulting from the use of phencyclidine, also known as PCP or angel dust, which we shall learn about later). Using modern descriptive approaches, as given in the revised fourth edition of the Diagnostic and Statistical Manual of the American Psychiatric Association (DSM-IV), psychiatrists are now able to differentiate schizophrenia more clearly from other psychotic disorders with similar features that were formerly lumped with schizophrenia into a common diagnostic category. Modern diagnostic criteria include not only those features required to make the diagnosis (inclusive criteria) but also those that would cause one to reject it (exclusive criteria). Moreover, in actual clinical contexts independent observers agree on the usefulness of DSM-IV criteria in achieving accurate diagnoses.

Psychotic Episodes Are Preceded by Prodromal Signs and Followed by Residual Symptoms The first psychotic episode of schizophrenia is often preceded by prodromal signs. These include social isolation and withdrawal, impairment in the normal fulfillment of expected roles, odd behavior and ideas, neglect of personal hygiene, and blunted affect. The prodromal period is then followed by one or more psychotic episodes that may include loss of reality testing, memory disturbances, delusions, and hallucinations. These episodes are sometimes separated by long periods in which the patient is not overtly psychotic but nonetheless behaves eccentrically, is socially isolated, and has a low level of emotional arousal (a flat affect), an impoverished social drive, poverty of speech, a poor attention span, and lack of motivation. These symptoms of the nonpsychotic period are called negative symptoms because they reflect the absence of certain normal social and interpersonal behaviors. In contrast, the striking abnormalities of psychotic episodes are called positive symptoms because they reflect the presence of distinctively abnormal behaviors. The negative symptoms are chronic features of the illness and are the most difficult to manage. Modern criteria for the diagnosis of schizophrenia require that a patient be continuously ill for at least six P.1193 months and that there be at least one psychotic phase followed by a residual phase. During the psychotic episode one or more of the following three groups of positive symptoms must be present:

●

Delusions (for example, the belief that one is being persecuted or that one's feelings, thoughts, and actions are controlled by an outside force). ●

Prominent hallucinations, usually auditory (for example, hearing voices commenting on one's actions). ●

Disordered thoughts, incoherence, loss of the normal association between ideas, or marked poverty of speech accompanied by a loss of emotional expression (flattening of affect).

During psychotic episodes patients with schizophrenia may also exhibit unusual postures, mannerisms, or rigidity. On the basis of these criteria and other differences, schizophrenia is often divided into subtypes, of which three are most readily distinguished: paranoid schizophrenia, a form more often found in men, in which systematic delusions of persecution predominate; disorganized schizophrenia (hebephrenia), a form characterized by early age of onset, a wide range of symptoms, and a profound deterioration of personality; and catatonic schizophrenia, a rare form in which mutism and abnormal postures dominate. In diagnosing schizophrenia it is important to exclude a disorder of mood, especially manic-depressive illness or a drug-induced psychosis resulting from the use of amphetamine, PCP, or other psychostimulants. The prognosis for schizophrenia is generally (but not always) poor. There are frequent relapses into psychotic behavior, and each relapse in turn results in greater deterioration. Some students of schizophrenia view the psychotic episodes (positive symptoms) and nonpsychotic episodes (negative symptoms) as different phases of the same disease, with the negative symptoms representing the long-term outcome of positive symptoms. However, other students of schizophrenia view the two types of symptoms as independent, arguing that negative and positive symptoms reflect two distinctive courses and underlying psychopathologies. According to this second view, patients in whom the negative symptoms predominate have a more severe illness, one in which the prognosis is poorer and in which, as we shall see later, there is more of a disturbance in the anatomy of the brain, especially more prominently enlarged ventricles, and more loss of cortical tissue. Negative symptoms are often associated with a history of poor social development before the onset of the disease, and this history of social withdrawal is perhaps the strongest predictor of a poor prognosis.

Genetic Predisposition Is an Important Factor Identifying the causes of schizophrenia is one of the most challenging goals of psychiatric research. The only reliable clue as to cause comes from the finding that schizophrenia is due in part to a genetic abnormality. The first direct evidence that genes are important in the development of schizophrenia was provided in the 1930s by Franz Kallmann. Kallmann was impressed when he discovered that the incidence of schizophrenia throughout the world is uniformly about 1%, even though social and environmental factors vary dramatically. He found, however, that the incidence of schizophrenia among parents, children, and siblings of patients with the disease is about 15%, strong evidence that the disease runs in families. A genetic basis for schizophrenia cannot simply be inferred from the increased incidence in families, however. Not all conditions that run in families are necessarily genetic—wealth and poverty and habits and values also run in families. In earlier times even the nutritional deficiency pellagra ran in families. To distinguish genetic from environmental factors, Kallmann and other investigators developed several research strategies. One strategy was to compare the rates of illness in monozygotic (identical) and dizygotic (fraternal) twins. Monozygotic twins have essentially identical genomes; they share almost 100% of each other's genes. In contrast, dizygotic twins share only 50% of their genes and are genetically equivalent to siblings. If schizophrenia were caused entirely by genetic factors, monozygotic twins would have an identical tendency to have the disease develop. Even if genetic factors were necessary but not sufficient for the development of schizophrenia, because environmental factors were also involved, the monozygotic twin of a patient with schizophrenia would still be at

significantly higher risk than a dizygotic twin. The tendency for twins to have the same illness is called concordance. Studies of twins have established that the concordance for schizophrenia in monozygotic twins is about 45%, but in dizygotic twins only about 15%, about the same as for other siblings. However, the high concordance in identical twins is still insufficient evidence for a genetic basis for schizophrenia, which can be explained as being acquired by learning from the disturbed behavior of the parents. To address this issue, and to disentangle further the effects of nature and nurture, Leonard Heston studied the rate of schizophrenia among adoptees in the United States, and Seymour Kety, David Rosenthal, and Paul Wender P.1194 studied adoptees in Denmark. In both sets of studies the rate of schizophrenia was higher among the biological relatives of schizophrenic adoptees than among relatives of normal adoptees. The difference in rate, about 10-15%, was the same observed earlier by Kallmann (Table 60-1). In addition to documenting the importance of genetic factors in schizophrenia, these studies of adoptees in whom schizophrenia developed showed that rearing does not play a major role in the disease. Table 60-1 Evidence for the Importance of Genetic Factors in Schizophreniaa Biological relatives With schizophrenia Control Chronic schizophrenia Latent schizophrenia Schizophrenia, uncertain subtype Total aAdapted b

Adoptive relatives With schizophrenia Control

0%

1.4%

1.1%

7.5a

1.7 1.7

0 1.4

1.1 3.3

14.0a

3.4

2.7

5.5

2.9%b 3.5

from Kety et al. 1975.

Statistically significant.

Studies of adoptees further revealed that some of the blood relatives of adoptees with schizophrenia show odd behavior even if they do not manifest signs of schizophrenia—they are socially isolated, have poor rapport with people, ramble in their speech, tend to be suspicious, have eccentric beliefs, and engage in magical thinking. This group of symptoms, called schizotypal personality disorder, is thought to be a mild form of the disease, a nonpsychotic condition related to schizophrenia. The familial pattern of schizophrenia is most dramatically illustrated in an analysis by Irving Gottesman, who ranked the relatives of Danish schizophrenics by the percentage of genes shared with the patient. He found a higher incidence of schizophrenia among first-order relatives (those who share 50% of the patient's genes, including siblings, parents, and children) than among second-order relatives (those who share 25% of the patient's genes, including aunts, uncles, nieces, nephews, and grandchildren). Even the third-degree relatives, who share only 12.5% of the patient's genes, had a higher incidence of schizophrenia than the 1% found in the population at large (Figure 60-3). These data strongly support a genetic contribution to schizophrenia. If schizophrenia were caused entirely by genetic abnormalities, then the concordance rate for monozygotic twins, who share almost 100% of each other's genes, would be nearly 100%. The finding that the concordance rate in monozygotic twins is only about 45% indicates that the genetic transmission is unusual and that genetic factors are not the only cause. Relatively routine studies of pedigrees often are sufficient to decide whether the mode of transmission of a disease is the classical dominant or recessive Mendelian inheritance of a single gene controlling the critical trait that is disordered. For example, Huntington disease is expressed in nearly 100% of those who carry the gene mutations associated with the disease at a single allele of the gene, and there are only minor nongenetic influences in the expression of this disease. Thus it could be said from pedigree inspection of Huntington disease, even before the mutant gene was discovered, that the disease is rare and fully penetrant and that all the symptoms are due to the transmission of a single dominant gene. Schizophrenia clearly does not have this mode of transmission. Nor does it have the simple recessive node of such diseases as phenylketonuria, in which both alleles of a single gene have to be defective for the clinical phenotype to be evident. In simple recessive disease neither parent may have the disease but one in four children will. The most likely explanation for the unusual genetic transmission of schizophrenia—its high frequency of 1% and its partial penetrance—is that the illness is polygenic, involving in any given case perhaps as many as 3 to 10 genes. As with other polygenic diseases, such as diabetes and hypertension, it is possible that one or all of the critical genes are simply allelic variations—polymorphisms—of genes, each one of which by itself would not cause disease. Rather it is the combination of allelic polymorphisms in the context of a specific genetic background that is critical for the disease. As this argument makes clear, in the case of polygenic diseases the distinction between mutations and allelic variations is not black and white. This is perhaps P.1195 not surprising. With the exception of the genes that determine gender identity, people in the population at large do not differ from one another because they have different genes. We all have mainly the same genes. What distinguishes each of us from one another are a number of different alleles of the same genes.

Figure 60-3 The lifetime risk for schizophrenia is correlated with genetic relatedness to a person with schizophrenia. (From Gottesman 1991.)

The idea that schizophrenia is a polygenic disease is consistent with the evidence from other areas of behavioral genetics, which suggests that the normal range of variation for a given behavior or character type usually reflects the combined actions of many genes, each with only a small effect. Acting alone, most alleles alter behavior only subtly if at all. In fact, as we have learned, an allele that contributes to schizophrenia is not necessarily a mutation. A search for particular allelic variations is now under way, applying genetic linkage analysis that makes use of both restriction fragment length polymorphisms and short tandem repeat polymorphisms that might contribute to schizophrenia. Recent studies of schizophrenia have uncovered two possible loci that correlate with schizophrenia. One locus is on the long arm of chromosome 22 (22q). The other is on chromosome 6 (6p). In each case the locus has been narrowed to a region containing about 50-100 genes.

Prominent Anatomical Abnormalities in the Brain Occur in Some Cases of Schizophrenia Computerized tomography, magnetic resonance imaging, and cerebral blood flow studies have revealed that some patients with schizophrenia have one or more of four major anatomical abnormalities. First, early in the disease there is a reduction in the blood flow to the left globus pallidus (Figure 60-4), suggestive of a disturbance in the system that connects the basal ganglia to the frontal lobes. Second, there appears to be a disturbance in the frontal lobes themselves since blood flow does not increase during tests of frontal lobe function involving working memory, as it does in normal subjects. Third, the cortex of the medial temporal lobe is thinner and the anterior portion of the hippocampus is smaller than in normal people, especially on the left side, consistent with a defect in memory. Finally, the lateral and third ventricles are enlarged and there is widening of the sulci, especially in the thinner temporal lobe and in the frontal lobe, reflecting a reduction in the volume of this lobe as well. The reduction in blood flow in the caudate nucleus and the frontal lobe, the reduced size of the hippocampus, the slightly enlarged ventricles, and the other structural changes of the brain are most commonly seen in patients who have prominent negative symptoms. These patients have a history of a prolonged prodromal period with poor social functioning before the onset of psychotic symptoms, suggesting that the disease starts early in life. What is the relationship of these anatomical abnormalities to the genetic predisposition for schizophrenia? This question has been examined in a study of monozygotic twin pairs of which only one twin had schizophrenia. In 12 of 15 cases examined, the twin with P.1196 schizophrenia had larger ventricles compared to the normal twin (Figure 60-5). The twin with schizophrenia almost invariably also had a smaller anterior hippocampus on the left side, and this reduction in hippocampal mass correlated highly with the reduction in blood flow in the left prefrontal cortex. Moreover, the smaller the hippocampal volume of the affected twin, the less the left prefrontal cortex was activated during a cognitive task. These several anatomical findings therefore suggest that the hippocampus, the prefrontal cortex, and the globus pallidus are part of a cognitive system that is impaired in schizophrenia.

Figure 60-4 Reduced blood flow in the left globus pallidus is one of the first anatomical abnormalities to appear in brain scans of patients with schizophrenia. This defect is thought to reflect a disturbance in an attentional system that involves both the basal ganglia and the frontal lobes.

Indeed, the negative symptoms of schizophrenia, which include a loss of executive functions such as planning and working memory, involve activities that normally require the prefrontal association areas (Chapter 19). In monkeys, for example, activation of these executive functions is correlated with increased metabolism in a distributed network that includes the anterior hippocampus, parietal cortex, and dorsolateral prefrontal cortex. A disturbance in this network could contribute to the negative symptoms of schizophrenia.

A Two-Step Model Seems Most Consistent With the Pathogenesis of Schizophrenia The fact that twins who share identical genes have anatomical differences in their brains suggests that genes alone do not account for these structural changes. Rather, the structural changes presumably result from the combined actions of genes and some factors other than a genetic defect, perhaps a viral infection, a developmental abnormality, or a perinatal injury. Thus the development of schizophrenia may be a two-step process in which genetic predisposition is necessary but insufficient to produce the disease. The possibility that developmental injury may be a causative agent in a two-step process that leads to schizophrenia is currently receiving much attention. Indeed, among the several anatomical defects that have been associated with schizophrenia, one developmental abnormality observed in a small group of patients by Edward Jones and his colleagues seems particularly interesting. This abnormality occurs in a population of neurons characterized histochemically by staining for the enzyme nicotinamide adenine dinucleotide phosphate diaphorase.1 In normal people these neurons are found in white matter immediately below layer VI of the cortex. These neurons are part of the cortical subplate, a transitional structure that plays a key role in the formation of connections in the cerebral cortex (Chapter 53). In patients with schizophrenia the number of these neurons in the superficial white matter of both the prefrontal and temporal lobe cortices is significantly reduced, whereas their number in the white matter deeper than 3 mm from the cortex is significantly greater compared to normal subjects. These differences suggest that, rather than remaining in the subplate region as they normally do, these neurons underwent abnormal migration during development. Since the subplate neurons are required for cortical development (Chapter 55), such a defect could lead to the establishment of abnormal patterns of cortical connections in the frontal and temporal lobes, the association areas thought to underlie the negative symptoms commonly observed in schizophrenia, and could contribute to their potential dysfunction. What accounts for this disturbance in development? Some studies suggest that infants exposed to influenza during the second and third trimesters of gestation may have an increased risk for developing schizophrenia when they become adults, so that a viral infection during the mother's pregnancy might be responsible for the anatomical abnormalities. Alternatively, the migratory defect might reflect a premature switching off of genes involved in cell migration, genes that may respond to growth factors or their receptors. Thus, the genetic defects P.1197 in schizophrenia may reflect an underlying failure to maintain the expression of one or another gene required to complete the process of cortical neuronal migration

Figure 60-5 Magnetic resonance images of monozygotic twins show marked enlargement of the lateral ventricle in the twin with schizophrenia. Enlargement of the ventricles has been found to correlate strongly with the presence of schizophrenia. (Adapted from Suddath et al. 1990.)

It is likely, however, that these particular anatomical abnormalities in cortical development represent only one of a variety of basic anatomical defects that characterize the disease.

Antipsychotic Drugs Effective in the Treatment of Schizophrenia Act on Dopaminergic Systems Until 1950 there was no effective treatment for schizophrenia. The first useful treatment was chlorpromazine, a drug that has a fascinating history. The French neurosurgeon Henri Laborit thought that anxiety experienced by patients before surgery led to the release of massive amounts of histamine from mast cells and that the histamines might contribute to the undesirable side effects of anesthesia, including sudden death. To block the release of histamine, Laborit examined various antihistaminics in an attempt to find one that would calm patients. Through trial and error he found chlorpromazine particularly effective. Laborit was so impressed with the calming action of chlorpromazine that he began to think the drug might have a wider range of uses and soon appreciated that it might calm agitated patients with psychiatric conditions. In 1951 this idea was tested by John Delay and Pierre Deniker, who found that a high dosage of chlorpromazine calmed highly agitated and aggressive patients who had either schizophrenic or manic depressive symptoms. Chlorpromazine was originally thought to act as a tranquilizer, calming patients without sedating them unduly. However, by 1964 it became clear that chlorpromazine and other related drugs of the phenothiazine class had specific effects on the psychotic symptoms of schizophrenia. The drugs mitigate or abolish delusions, hallucinations, and some types of disordered thinking (Table 60-2). Also, when patients who experience remission keep taking the antipsychotic medication throughout the period of remission, the rate of relapse is reduced. These findings led to the delineation of a group of drugs, now called the typical antipsychotics, which include the phenothiazines (beginning with chlorpromazine), the P.1198 butyrophenones (haloperidol), and the thioxanthenes (Figure 60-6). More recently a second group of drugs, the atypical antipsychotics (clozapine, risperidone, olanzapine), have also proved useful in the treatment of schizophrenia. Atypical antipsychotics are better than typical antipsychotics in treating negative symptoms (and cognitive defects) in schizophrenia, and they produce fewer side effects on the extrapyramidal systems. Table 60-2 Response of Schizophrenic Symptoms to Phenothiazines1 Response to Symptoms

Phenothiazines2

Schizophrenic symptoms Thought disorder

+++

Blunted affect Withdrawal

+++ +++

Autistic behavior Hallucinations Paranoid ideation Grandiosity Hostility, belligerence Nonschizophrenic symptoms Anxiety, tension, agitation

0

Guilt, depression

0

1Adapted 2

+++ ++ + + 0

from Klein and Davis 1969.

0, no response; +++, best response.

Figure 60-6 The four major groups of antipsychotic drugs used to treat schizophrenia. The typical antipsychotic drugs—the phenothiazines (A), butyrophenones (B), and thioxanthenes (C)—bind to the dopaminergic D2 receptors and have side effects in the extrapyramidal system, such as dry mouth and disorders of movement and gait. The atypical antipsychotic drugs, such as the dibenzodiazepine clozapine (D), bind primarily to dopaminergic D3 and D4 receptors and do not have extrapyramidal side effects.

How do the typical and atypical antipsychotic agents produce their actions? Paradoxically, the first clue to the cellular action of the typical antipsychotic drugs came from analysis of their side effects. The drugs often produce a syndrome resembling parkinsonism, a group of disorders that result from a deficiency in dopamine (Chapter 43). Following a suggestion by Arvid Carlsson, a number of studies soon found that many antipsychotic agents block dopamine receptors (Figure 60-7). This finding in turn suggested that perhaps excess dopamine transmission could be an important part of the pathogenesis of schizophrenia. To determine whether dopaminergic transmission was excessive, it was important to identify the receptor sites at which the drugs exert their effect. At least six major types of dopamine receptors have now been cloned in humans: D1, D2, D3, D4, and D5 (Figure 60-8). The amino acid sequences of each receptor subtype encode the seven membrane-spanning regions characteristic of G protein-coupled receptors (Table 60-3).

Figure 60-7 Chlorpromazine acts on dopamine receptors because it has a similar shape and therefore fits the receptor. However, because of differences in structure, chlorpromazine simply sits on the receptor, blocking it without triggering a response. (Adapted from Snyder 1986.)

P.1199 The D1 and D5 (also called D1b) receptors are coupled to a G protein (Gs) that activates adenylyl cyclase, the enzyme that converts adenosine triphosphate (ATP) to cyclic adenosine monophosphate (cAMP) (Chapter 13). These receptors are expressed primarily in neurons of the cerebral cortex and hippocampus (although D1 is also expressed in the caudate nucleus) and have a low affinity for most types of antipsychotic drugs. The typical antipsychotic drugs have a high affinity for D2 receptors, which are therefore thought to be one of the major sites of the therapeutic action of these drugs. Indeed, the clinical potency of the typical antipsychotic agents in patients with schizophrenia is closely correlated with the affinity of these drugs for the D2 receptors (Figure 60-9).

Table 60-3 Five Major Types of Known Postsynaptic Dopamine Receptors D1

D2

D3

D4

D5

Molecular structure

Seven membrane-spanning regions

Seven membrane-spanning regions

Seven membrane-spanning

Seven membrane-spanning

Seven membrane-spanning

Effect on cyclicAMP

Increases

Decreases

regions Decreases

regions Decreases

regions Increases

Agonists Antagonists

SKF 38393 SCH 23390 Phenothiazines

Bromocriptitine Sulpiride Phenothiazines

7-OH-DPAT UH232

?

SKF 38393 SCH 23390

Thioxanthenes Butyrophenones

Thioxanthenes Butyrophenones Clozapine

Clozapine

Clozapine

AMP = adenosine monophosphate. SKF 38393 = Smith Kline French compound no. 38393. 7-OH-DPAT = 7-hydroxy-dipropylaminotetralin. SCH 23390 = Scherring A. G. compound no. 23390. UH232 = U. Hacksell compound no. 232.

The D2 receptor is part of a family of related receptors (the D2 group), which include D3, and D4. All three of these receptors are able to inhibit adenylyl cyclase (Figure 60-8). These receptors are expressed at particularly higher levels in neurons of the caudate nucleus, the P.1200 putamen, and the nucleus accumbens, but D2 receptors are also present in the amygdala, hippocampus, and parts of the cerebral cortex. Since the D2 group is expressed in the caudate and putamen, these receptors presumably contribute to the side effects of the antipsychotic drugs on the extrapyramidal systems (Chapter 43). The amygdala, hippocampus, and neocortex, however, are possible sites of therapeutic action.

Figure 60-8 There are at least six types of dopamine receptors, four of which are illustrated here. The postsynaptic receptor D2 inhibits adenylyl cyclase (AC) by an inhibitory G protein (Gi). The presynaptic inhibitory autoreceptor, thought to be D3, regulates the amount of dopamine released in response to an action potential via a phosphoinositide second-messenger system (DAG = diacylglycerol; IP3 = inositol triphosphate; PIP

2

= phosphoinositide diphosphate;

PKC = protein kinase C). Both the presynaptic D3 receptor and the postsynaptic receptor D2 have a high affinity for the typical antipsychotic drugs (the phenothiazine, butyrophenone, and thioxanthene classes) and are thought to be key targets for the therapeutic actions of these drugs. The receptors D1 and D5 stimulate AC by a stimulatory G protein (Gs). These have a low affinity for the typical antipsychotic drugs and are therefore not thought to be involved in mediating the effects of these drugs on schizophrenic symptoms. The receptors D3 and D4 bind the atypical antipsychotic drugs.

The atypical antipsychotic agents, such as clozapine, bind to D3 and even more effectively to D4 receptors. These two subtypes of the D2 group are expressed primarily in the limbic system (Chapter 50) and cortex; they are only weakly expressed in the basal ganglia. This selective distribution may explain why the atypical antipsychotic agents do not give rise to side effects in the extrapyramidal systems. Both the D2 and D3 receptors are of further interest because they are present on dopaminergic neurons themselves, on both the cell body and the terminals. Here they act as inhibitory autoreceptors (Chapter 14) to control both the rate of firing of the neuron and the release of dopamine by the action potential at the terminals (see Figure 60-8).

Abnormalities in Dopaminergic Synaptic Transmission Are Thought to Be Associated With Schizophrenic Symptoms Excess Synaptic Transmission of Dopamine May Contribute to the Expression of Schizophrenia The idea that excessive release of dopamine during synaptic transmission underlies at least some aspects of the pathogenesis of schizophrenia has received its primary P.1201 support from pharmacologic studies. Drugs that increase the level of dopamine, such as L-dihydroxyphenylalanine (L-DOPA), cocaine, and amphetamine (Figure 60-10), can induce psychotic episodes resembling paranoid schizophrenia. Some of these drugs, such as amphetamine, also cause bizarre, repetitive, stereotyped behavioral acts in monkeys. Antipsychotic drugs reverse not only amphetamine psychosis in humans but also the bizarre behavioral syndrome in monkeys. There is still no direct evidence, however, that excessive activity in dopaminergic neurons actually contributes to schizophrenia. The challenge in the study of schizophrenia, as with the depressive disorders that we shall consider in Chapter 61, is to advance from initial pharmacologic clues to precise physiological explanations of the pathogenesis of the disease. To explore further the role of dopaminergic transmission in schizophrenia we need to know which components of the dopamine system are altered in the disease and which of these alterations are related to specific neuroanatomic defects and clinical symptoms.

Distinct Anatomical Components of the Dopaminergic System Are Implicated in Schizophrenia How are the dopaminergic neurons organized? Which particular grouping might contribute to schizophrenia? As we saw in Chapter 45, the dopaminergic neurons are not randomly distributed in the brain but are organized into four major systems: the tuberoinfundibular, nigrostriatal, mesolimbic, and mesocortical systems (Figure 60-11). The dopaminergic nigrostriatal system contributes to the symptoms of Parkinson disease (Chapter 43). This system may also be involved in the short-term side

effects of antipsychotic medication on the pyramidal system, such as hand tremor and rigidity of muscles, as well as the long-term side effect called tardive dyskinesia, a disorder involving involuntary movements that prominently affects the tongue. The dopaminergic mesolimbic system has its origin in cell bodies in the ventral tegmental area, which is medial and superior to the substantia nigra. These cells project to the mesial components of the limbic system: the nucleus accumbens, the ventral striatum, the nuclei of the stria terminalis, parts of the amygdala and hippocampus, the lateral septal nuclei, the entorhinal cortex, the mesial frontal cortex, and the anterior cingulate cortex. In view of the role of the mesolimbic system in emotions and memory (see Chapters 50 and 62), and the similarity in disturbances of thought and perception characteristic of schizophrenia and certain types of psychomotor (limbic system) epilepsy, Arvid Carlsson proposed that the positive symptoms of schizophrenia result from overactivity of the mesolimbic system. The idea that the mesolimbic dopaminergic system is affected in schizophrenia is supported by the finding that the earliest sign of brain disturbances in schizophrenia, detectable with positron emission tomography (PET) imaging, is a decrease in blood flow in a region of the basal ganglia (Figure 60-4). This disturbance is evident even before the prominent frontal lobe deficit becomes evident. Among the projections of the mesolimbic system, those to the nucleus accumbens are thought to be particularly important because of the extensive connections of this nucleus to the limbic system. The nucleus accumbens receives and integrates inputs from the amygdala, hippocampus, entorhinal area, anterior cingulate area, and parts of the temporal lobe. The mesolimbic P.1202 dopaminergic projection to the nucleus accumbens is thought to modulate these inputs and thereby influence the output of the nucleus accumbens to its target regions: the ventral pallidum, septum, hypothalamus, anterior cingulate area, and frontal lobes. As we have seen, some of the input sources, in particular the hippocampus, and some of the output targets, such as the cingulate cortex and the frontal lobes are thought to be disturbed in schizophrenia. Overactive modulation of the integration of the inputs to the nucleus accumbens and of the output from it could contribute to positive symptoms of schizophrenia (Figure 6012).

Figure 60-9 The clinical potency of an antipsychotic drug and the ability of the drug to block dopamine D2 receptors are strongly correlated. On the horizontal axis is the average daily dose required to achieve the same clinical effect. On the vertical axis is the concentration of drug required to bind half the receptors. The higher the concentration required, the lower the affinity for the receptor. (Adapted from Seeman et al. 1976.)

Figure 60-10 The key steps in the synthesis and degradation of dopamine and the sites of action of various psychoactive substances at the dopaminergic synapse. (Adapted from Cooper et al. 1996.) 1. Enzymatic synthesis. The dopamine precursor, dihydroxy-phenylalanine (DOPA), is synthesized from tyrosine by tyrosine hydroxylase. This action is stimulated by L-DOPA and blocked by the competitive inhibitor α-methyltyrosine. 2. Storage. Reserpine and tetrabenazine interfere with the uptake and storage of dopamine by the storage granules. Reserpine is an effective antipsychotic drug; the depletion of dopamine by reserpine is long-lasting and the storage granules appear to be irreversibly damaged. Tetrabenazine also interferes with the uptake and storage mechanism of the granules, but only transiently. 3. Release. Amphetamine and tyramide enhance dopamine release from dopaminergic neurons. 4. Receptor interaction. Typical antipsychotics, such as perphenazine and haloperidol, are particularly effective in blocking the D2 receptors and the presynaptic autoreceptors. 5. Reuptake. Dopamine activity is terminated when dopamine is taken up into the presynaptic terminal. Cocaine, amphetamine, and the anticholinergic drug benzotropine are potent inhibitors of this reuptake mechanism. Amphetamine induces a psychosis that is reversed by antipsychotic drugs. 6. Degradation. Dopamine in a free state within the presynaptic terminal can be degraded by the enzyme monoamine oxidase (MAO). Pargyline is an effective inhibitor of MAO. Dopamine can also be inactivated by the enzyme catechol-O -methyltransferase (COMT), which is believed to be localized in the postsynaptic cell.

The dopaminergic mesocortical system originates in the ventral tegmental area and projects to the neocortex, in particular the prefrontal cortex. The prefrontal cortex is involved in the temporal organization of behavior, in motivation, planning, attention, and social behavior (Chapter 20). The mesocortical system may be important in the negative symptoms of schizophrenia, symptoms that bear some resemblance to the defects seen after surgical disconnection of the frontal lobes, especially the dorsal prefrontal cortex. After loss of the dorsal prefrontal cortex, patients are poorly motivated, plan poorly, and have flattened affect. The dopaminergic mesocortical system is essential for the normal cognitive functions of the dorsolateral prefrontal cortex. As is the case with ablating the prefrontal cortex, experimental depletion of dopamine in the prefrontal cortex (using the toxin 6-hydroxydopamine) impairs the performance of monkeys in cognitive tasks. This cognitive deficit can be reversed by giving the dopamine precursor L-DOPA or the agonist P.1203 apomorphine. In fact, patients with Parkinson disease, who have lost dopaminergic neurons, not only have a motor disorder (reflecting the deficit in the dopaminergic nigrostriatal system) but also lack motivation and have flat affect and reduced spontaneity, defects that may reflect a decrease in transmission in the dopaminergic mesocortical pathways. Similarly, lesions that destroy the ventral tegmental area, which gives rise to the dopaminergic mesolimbic system, cause dementia and psychotic symptoms.

Figure 60-11 The four major dopaminergic tracts of the brain. The nigrostriatal system courses from the substantia nigra to the putamen and caudate. The tuberoinfundibular system originates in the arcuate nucleus of the hypothalamus and projects to the pituitary stalk. The mesolimbic system runs from the ventral tegmental area to many components of the limbic system. The mesocortical system projects from the ventral tegmental area to the neocortex, especially the prefrontal areas. We here only illustrate two of the four tracts. The mesolimbic system which may be involved in the positive symptoms of schizophrenia and the mesocortical system which may be involved in the negative symptoms.

These several findings led Daniel Weinberger to postulate that two dopaminergic systems are disturbed in different ways in schizophrenia. First, an increase in activity in the mesolimbic pathway (perhaps through the D2 and D3 receptors and particularly through the D4 receptors) would account for the positive symptoms. Second, decreased activity of the mesocortical connections in the prefrontal cortex would account for the negative symptoms. According to this model, the imbalance between cortical and subcortical dopaminergic transmission underlies the development of schizophrenia. Weinberger proposes that activity in the mesocortical pathway to the prefrontal cortex normally inhibits the mesolimbic pathway by feedback inhibition and that the primary defect in schizophrenia is a reduction in this activity, which leads to disinhibition and overactivity in the mesolimbic pathway (Figure 60-13). Although Weinberger's scheme is still untested, there is experimental evidence for interaction between the mesolimbic and mesocortical pathways. Christopher Pycock and his colleagues found that chemical lesioning of the mesocortical pathway in experimental animals enhances synaptic responsiveness in the mesolimbic pathway, specifically in its terminations in the nucleus accumbens. It is not known how loss of dopaminergic terminals in the prefrontal cortex leads to increased activity of the mesolimbic pathway in the nucleus accumbens. However, Pycock and his collaborators suggest that reduced activity in one pathway may result in compensatory neuronal growth in the other.

Figure 60-12 PET scans showing cerebral blood flow in schizophrenic patients during the performance of a cognitive task and after treatment with the dopamine agonist apomorphine. (From Dolan et al. 1995.) A. In patients with schizophrenia the anterior cingulate cortex fails to activate when they perform an internally generated task such as thinking of a word (as opposed to a task where the response is specified by an environmental cue, eg, saying a word displayed visually). When normal subjects are engaged in internally generated tasks, the anterior cingulate cortex is activated and the modality-specific temporal cortex around the auditory area is deactivated (PET scans not shown). In patients with schizophrenia this integrated activity in the frontotemporal system is impaired and indeed reversed: there is inadequate activation of the anterior cingulate cortex and excessive activation of the temporal lobes. B. After these same schizophrenic patients received apomorphine, a dopamine agonist, activity in their anterior cingulate is greater than in normal subjects for the same task.

P.1204

Abnormalities in Dopaminergic Transmission Do Not Account for All Aspects of Schizophrenia As these interesting but largely speculative arguments illustrate, we are far from understanding the role of dopaminergic transmission in normal mental function or in schizophrenia. The major argument for the involvement of dopaminergic pathways in schizophrenia comes from the analysis of the mechanisms of action of the antipsychotic drugs. It is difficult, in principle, to extrapolate from the mechanisms of action of a therapeutic agent to the causal mechanisms of a disease. Pharmacologic manipulation may produce changes that compensate for the disease without directly affecting the disordered mechanism itself. For example, the primary defect in Parkinson disease is a decrease in dopamine levels; but, as we have seen in Chapter 43, some symptoms can be alleviated by drugs that block cholinergic transmission. This issue can be further illustrated by the hypothetical situation of three presynaptic neurons converging on a postsynaptic neuron, with each presynaptic neuron releasing a different transmitter. Transmitter A and dopamine reduce the excitability of the postsynaptic cell, whereas transmitter B directly excites it (Figure 6014). If schizophrenia resulted from a defect in neuron P.1205 A or its transmitter, causing an excess of this modulatory transmitter to act on the postsynaptic cell, one could improve the symptoms by simply blocking the action of dopamine, the other modulatory transmitter, because this intervention would reduce net inhibitory inputs to the postsynaptic cell.

Figure 60-13 In this neuroanatomical model of schizophrenia the prefrontal cortex normally inhibits (through feedback inhibition) activity in the limbic areas and the dopaminergic mesolimbic pathway arising from the brain stem. A primary defect in schizophrenia may be depressed activity in the dopaminergic mesocortical projection from the brain stem to the frontal lobe, resulting in a loss of inhibitory feedback and consequent hyperactivity of the mesolimbic pathway. (Adapted from Weinberger 1987.)

Figure 60-14 An antischizophrenic drug that acts by blocking a dopamine receptor could ameliorate symptoms without directly acting on the neurons responsible for the disease. Here a cell receives inputs from excitatory cells (using transmitter substance B) and two types of inhibitory cells (using transmitter A or dopamine). If schizophrenia is due to an imbalance of synaptic input, specifically overactivity in the inhibitory neurons that use transmitter A, blocking the effectiveness of the dopaminergic inhibitory neurons could ameliorate the disease by reducing the net inhibition in the postsynaptic cell. However, it would be incorrect to assume that, because the block partially restored the balance and thereby improved the patient's behavior, the dopaminergic neurons were the site of pathology. (Adapted from R. Zigmond, personal communication.)

However, this model could easily prove inadequate for determining the best treatment. For instance, the dopaminergic neuron and neuron A might have very different inputs converging on them. If so, inhibiting dopaminergic transmission might cause an imbalance in the inputs and therefore inappropriate signals in the postsynaptic neuron. Even this simple example illustrates that a correlation between excess dopaminergic activity and schizophrenia, however strong, is not sufficient to allow a conclusion about the underlying cause of the disease. In addition, there are some reasons to question whether the affinity of antipsychotic agents for D2 (as well as D3 and D4) receptors is the only basis of the clinical efficacy of these drugs. Although antipsychotic drugs occupy dopamine receptors very quickly after administration, P.1206 the maximal therapeutic (antipsychotic) effects are often delayed several weeks. Thus the acute blockade of dopaminergic transmission is not likely to be sufficient for the therapeutic effect. The antipsychotic action may be secondary to other consequences in the brain that evolve over a period of several weeks. For example, activity in certain neural circuits may need to adjust to a new level of modulation. In addition, the drugs or the resulting alterations in neuronal activity might produce changes in gene expression, the consequences of which may not become manifest for one or more weeks. One late consequence of long-term dopamine blockade, which may well involve gene regulation, is an increase in the number of dopamine receptors per cell, and thus increased sensitivity to dopamine in each cell. A second late consequence, supported by electrophysiological data, is a decrease in the activity of dopaminergic neurons. Third, the delayed actions might also reflect adjustments of other neuronal systems that interact with the dopaminergic systems (see Figure 60-10). For example, most typical antipsychotic agents also act on a class of serotonin receptors, the 5-HT2 receptors at which lysergic acid diethylamide (LSD) and other psychedelic hallucinogens also act (see Chapter 61). Long-term administration of antipsychotic agents leads to a downregulation of 5-HT2 receptors that parallels in time course the therapeutic action of the antipsychotic drugs. Finally, many antipsychotic agents also bind the D1 receptor, although with low affinity, and this may enhance the action of dopamine at the receptors of the D2 group. At least 20% of patients with schizophrenia do not improve after treatment with dopaminergic blockers that act on the group of D2 receptors. But these patients often respond to atypical antipsychotic agents such as clozapine (a dibenzodiazepine), which is only a weak blocker of D2 receptors. Clozapine has the additional interesting property that it produces few, if any, parkinsonian (extrapyramidal) side effects, which characteristically occur with blockade of D2 receptors. Clozapine

and risperidone bind to D3 receptors and even more effectively to D4 receptors. As we have seen, D3 and D4 dopamine receptors are limited in their distribution to the limbic system. Moreover, clozapine is not limited in its action to the dopamine system. It also blocks the serotonin receptor 5-HT2a as well as the α1 epinephrine and H1 histamine receptors. Just as schizophrenia is a multifactorial disease and perhaps affects more than one set of dopaminergic pathways in the brain (mesolimbic and mesocortical), so it is likely that antipsychotic drugs act on more than one molecular target. Further evidence that disorders in pathways other than the dopaminergic system might contribute to schizophrenia comes from the finding that the addictive drug phencyclidine (PCP) produces a psychosis that resembles the psychosis in schizophrenia and exacerbates psychosis in patients with schizophrenia. Normal subjects given intravenous PCP experience depersonalization and feel disconnected from their environment. They also have delusions of being controlled by external agents and have auditory and visual hallucinations. PCP binds to two identified molecular targets in the brain: (1) the dopaminergic terminals in the nucleus accumbens, and (2) the N -methyl-D-aspartate (NMDA) class of glutamate receptors. NMDA receptors are present on the dopaminergic axon terminals in the prefrontal cortex and enhance dopamine release from the terminals. PCP, when it binds to the NMDA receptors, inhibits release of dopamine. In contrast, at the dopaminergic terminals in the nucleus accumbens PCP increases dopamine release and inhibits reuptake, much like amphetamine. Thus, the behavioral effects of PCP may be due in part to its ability to enhance release in the mesolimbic pathway while blocking dopamine release in the mesocortical pathway. Indeed, specific drugs developed to block NMDA receptors selectively (and used for the treatment of NMDA-induced neurotoxicity after stroke or prolonged seizure activity) have the undesirable side effect of producing psychosis, perhaps by reducing the release of dopamine in the mesocortical pathway to the frontal lobe. The existence of drugs that produce psychotic behavior by binding to the NMDA receptor indicates that psychotic behavior can probably be produced by interfering with several transmitter systems that act either in parallel or in combination with dopamine.

An Overall View In considering the biological defect in schizophrenia we have focused on current insights into the molecular mechanisms of the disease and not on the social and psychological factors that act on an individual before, during, and even after they have the disease. In this context it is useful to take note of two common misconceptions. First, it is sometimes thought that in classifying mental disorders we are classifying people; in reality, we are classifying disorders that people have. A person is not a schizophrenic—one has schizophrenia. Second, even though all the people with a particular mental illness are similar in ways that are important and all of these people will, by definition, share the defining features of the disease, the individuals who have the disease will P.1207 likely differ in quite fundamental ways that may influence both the course and the outcome of the disease. In addition to social factors, further research on schizophrenia needs to explore other contributing factors. A particularly important question is the genetic component, although genetic factors seem only to predispose people to schizophrenia. Another factor to consider is developmental abnormalities in the brain. In fact, schizophrenia is sometimes associated with what appears to be aberrant cell migration in both frontal and temporal lobes as well as with enlarged lateral ventricles, widening of cortical sulci, and reduced blood flow to the frontal lobes. Dopaminergic agonists are capable of producing psychosis, and the affinity of antischizophrenic drugs for the dopaminergic D2 and particularly the D4 receptors is directly correlated with their clinical potency in alleviating psychotic symptoms. Postmortem studies have indeed found increases in the number of dopamine receptors in these limbic areas. Indeed, almost all patients with schizophrenia show attentional and motivational deficits similar to those in patients with deficits in prefrontal cortex function. How this prefrontal defect relates to the defect in the mesolimbic dopaminergic projection is unclear. Initial clues to the answers for these questions may come from cloning one or more of the allelic variations of genes involved in schizophrenia.

Selected Readings Andreasen NC, Olsen SA, Dennert JW, Smith MR. 1982. Ventricular enlargement in schizophrenia: relationship to positive and negative symptoms. Am J Psychiatry 139:297–302.

Barondes SH. 1993. Molecules and Mental Illness. New York: Scientific American Library.

Bloom FE. 1993. Advancing a developmental origin of schizophrenia. Arch Gen Psychiatry 50:224–227.

Carpenter WT, Buchanan R. 1994. Schizophrenia. N Engl J Med 330:681–690.

Dawson E, Robin M. 1996. Schizophrenia: a gene at 6p. Curr Biol 6:268–271.

Early TS, Posner MI, Reiman EM, Raichle ME. 1989. Hyperactivity of the left striato-pallidal projection. II. Phenomenology and thought disorder. Psychiatric Dev 2:109–121.

Goodwin DW, Guze SB. 1989. Psychiatric Diagnosis, 4th ed. New York: Oxford Univ. Press.

Havens LL. 1973. Approaches to the Mind: Movement of the Psychiatric Schools From Sects Toward Science. Boston: Little, Brown.

Hyman SE, Nestler EJ. 1993. The Molecular Foundations of Psychiatry. Washington, DC: American Psychiatric Press.

LaFosse MJ, Mednick SA. 1991. A neurodevelopmental approach to schizophrenia research. In: SA Mednick (ed). Developmental Neuropathology of Schizophrenia, pp. 211-225. New York: Plenum.

Middleton FA, Strick PL. 1996. The temporal lobe is a target of output from the basal ganglia. Proc Natl Acad Sci U S A 93:8683–8687.

Plomin R, Owen MJ, McGuffin P. 1994. The genetic basis of complex human behaviors. Science 264:1733–1739.

Seeman P, Guan H-C, Van Tol HHM. 1993. Dopamine D4 receptors elevated in schizophrenia. Nature 365:441–445.

Snyder SH. 1986. Drugs and the Brain. New York: Scientific American.

Suddath RL, Christison GW, Torrey EF, Casanova MF, Weinberger DR. 1990. Anatomical abnormalities in the brains of monozygotic twins discordant for schizophrenia. N Engl J Med 322:789–794.

Weinberger DR, Berman FB, Suddath R, Fuller-Torrey E. 1992. Evidence of dysfunction of a prefrontal-limbic network in schizophrenia: a magnetic imaging and regional cerebral blood flow study of discordant monozygotic twins. Am J Psychiatry 149:890–897.

References Bassett AS. 1989. Chromosome 5 and schizophrenia: implications for genetic linkage studies. Schizophr Bull 15:393–402.

Benes FM, Davidson J, Bird ED. 1986. Quantitative cytoarchitectural studies of the cerebral cortex of schizophrenics. Arch Gen Psychiatry 43:31–35.

Bleuler E. [1911] 1950. Dementia Praecox or the Group of Schizophrenias. J Zinkin (transl). New York: International Universities Press.

Brozoski TJ, Brown RM, Rosvold HE, Goldman PS. 1979. Cognitive deficit caused by regional depletion of dopamine in prefrontal cortex of rhesus monkey. Science 205:929–932.

Carlsson A. 1974. Antipsychotic drugs and catecholamine synapses. J Psychiatr Res 11:57–64.

Cooper JR, Bloom FE, Roth RH. 1996. The Biochemical Basis of Neuropharmacology, 7th ed. New York: Oxford Univ. Press.

Dolan RJ, Fletcher P, Frith CD, Friston KJ, Frackowiak RSJ, Grasby PM. 1995. Dopaminergic modulation of impaired cognitive activation in the anterior cingulate cortex in schizophrenia. Nature 378:180.

Gottesman II. 1991. Schizophrenia Genesis: The Origins of Madness. New York: Freeman.

Havens LL. 1965. Emil Kraepelin. J Nerv Ment Dis 141:16–28.

Heston LL. 1970. The genetics of schizophrenic and schizoid disease. Science 167:249–256. P.1208

Ingvar DH. 1987. Evidence for frontal/prefrontal cortical dysfunction in chronic schizophrenia: The phenomenon of “hypofrontality” reconsidered. In: H Helmchen, FA Henn (eds). Biological Perspectives of Schizophrenia, pp. 201-211. Chichester, England: Wiley.

Jones EG. 1995. Cortical development and neuropathology in schizophrenia. In: Development of the Cerebral Cortex. Ciba Found Symp 193:277–295.

Kallmann FJ. 1938. The Genetics of Schizophrenia. New York: Augustin.

Kane J. 1987. Treatment of schizophrenia. Schizophr Bull 13:133–156.

Karayiorgou M, Morris MA, Morrow B, Shprintzen RJ, Goldberg R, Borrow J, Gos A, Nestadt G, Wolyneic PS, Lasseter VK, Eisen H, Childs B, Kazazian HH, Kucherlapati R, Antonarakis SE, Pulver AE, Housman DE. 1995. Schizophrenia susceptibility associated with interstitial deletions of chromosome 22q11. Proc Natl Acad Sci U S A 92:7612–7616.

Kety SS, Rosenthal D, Wender PH, Schulsinger F, Jacobsen B. 1975. Mental illness in the biological and adoptive families of adopted individuals who have become schizophrenic: A preliminary report based on psychiatric interviews. In: RR Fieve, D Rosenthal, H Brill (eds). Genetic Research in Psychiatry, pp. 147165. Baltimore: Johns Hopkins Univ. Press.

Kirch DG, Weinberger DR. 1986. Anatomical neuropathology in schizophrenia: Post-mortem findings. In: HA Nasrallah, DR Weinberger (eds). The Neurology of Schizophrenia, pp. 325-348. Amsterdam: Elsevier.

Klein DF, Davis JM. 1969. Diagnosis and Drug Treatment of Psychiatric Disorders. Baltimore: Williams and Wilkins.

Klein DF, Gittelman R, Quitkin F, Rifkin A. 1980. Diagnosis and Drug Treatment of Psychiatric Disorders: Adults and Children, 2nd ed. Baltimore: Williams and Wilkins.

Kraepelin E. [1909] 1919. Dementia praecox and paraphrenia. RM Barclay (transl). In: Kraepelin's Text-Book of Psychiatry, 8th ed. Edinburgh: Churchill Livingstone.

Lipska BK, Jaskiw GE, Weinberger DR. 1993. Postpubertal emergence of hyperresponsiveness to stress and to amphetamine after neonatal excitotoxic hippocampal damage: a potential animal model of schizophrenia. Neuropsychopharmacology 9:67–75.

Nauta WJH, Smith GP, Faull RLM, Domesick VB. 1978. Efferent connections and nigral afferents of the nucleus accumbens septi in the rat. Neuroscience 3:385–401.

O'Dowd BF, Seeman P, George SR. 1994. Dopamine receptors. In: SJ Peroutka (ed). Handbook of Receptors and Channels, pp. 95-123. Boca Raton, FL: CRC.

Olney JW, Labruyere J, Price MT. 1989. Pathological changes induced in cerebrocortical neurons by phencyclidine and related drugs. Science 244:1360–1362.

Posner MI, Early TS, Reiman E, Pardo JP, Dhawan M. 1988. Asymmetries in hemispheric control of attention in schizophrenia. Arch Gen Psychiatry 45:814–821.

Pycock CJ, Kerwin RW, Carter CJ. 1980. Effect of lesion of cortical dopamine terminals on subcortical dopamine receptors in rats. Nature 286:74–77.

Reveley AM, Reveley MA, Clifford CA, Murray RM. 1982. Cerebral ventricular size in twins discordant for schizophrenia. Lancet 1:540–541.

Roberts PJ, Woodruff GN, Iversen LL (eds). 1978. Advances in Biochemical Psychopharmacology. Vol. 19, Dopamine. New York: Raven.

Seeman P, Lee T, Chau-Wong M, Wong K. 1976. Antipsychotic drug doses and neuroleptic/dopamine receptors. Nature 261:717–719.

Seeman P. 1995. Dopamine receptors: Clinical correlates. In: FE Bloom, PJ Kupter (eds). Psychopharmacology: The Fourth Generation of Progress, pp. 295302. New York: Raven.

Shelton RC, Weinberger DR. 1986. X-ray computerized tomography studies in schizophrenia: A review and synthesis. In: HA Nasrallah, DR Weinberger (eds). The Neurology of Schizophrenia, pp. 207-250. Amsterdam: Elsevier.

Silbersweig DA, Stern E, Frith C, Cahill C, Holmes A, Grootoonk S, Seaward J, McKenna P, Chua SE, Schnorr L, Jones T, Frackowiak RSJ. 1995. A functional neuroanatomy of hallucinations in schizophrenia. Nature 378:176–179.

Snyder SH, Largent BL. 1989. Receptor mechanisms in antipsychotic drug action: focus on sigma receptors. J Neuropsychiatry Clin Neurosci 1:7–15.

Torack RM, Morris JC. 1988. The association of ventral tegmental area histopathology with adult dementia. Arch Neurol 45:497–501.

Van Tol HHM, Bunzow JR, Guan H-C, Sunahara RK, Seeman P, Niznik HB, Civelli O. 1991. Cloning of the gene for a human dopamine D4 receptor with high affinity for the antipsychotic clozapine. Nature 350:610–614.

Weinberger DR. 1987. Implications of normal brain development for the pathogenesis of schizophrenia. Arch Gen Psychiatry 44:660–669. 1This

enzyme colocalizes with and is thought to be identical to the enzyme nitric oxide synthase, which generates the gaseous transcellular messenger nitric oxide (Chapter 13).

Back

61 Disorders of Mood: Depression, Mania, and Anxiety Disorders Eric R. Kandel MAKING THE DISTINCTION between a disturbance of cognitive faculties (a thought disorder) and a disturbance of emotion (a mood disorder) was an important step in the early development of the modern classification of mental illness. In clinical descriptions of emotional states the term mood refers to a sustained emotional state lasting weeks or more, while the term affect (or affective response) refers to immediate or momentary emotional state of a person. Affect is more directly responsive to external stimuli, although with significant mood disorders the range of affective responses is limited. Thus, affect is to mood as the weather (rainy or sunny) is to climate (tropical, moderate, or cold). Normal affective responses serve important biological functions and range from euphoria to elation, pleasure, surprise, anger, anxiety, disappointment, sadness, grief, despair, and even depression. Three of these responses—euphoria, depression, and anxiety—can become so disordered, sustained, and dominant as to constitute a disease. We shall consider all three and discuss biological insights into these three disorders of mood. Although depression and euphoria (mania) have traditionally been referred to as disorders of affect, we use the more precise term mood. We shall then examine the anxiety states. Throughout we shall emphasize important interrelationships between the three mood disorders.

The Major Mood Disorders Can Be Either Unipolar or Bipolar The most common mood disorder, unipolar depression, was described in the fifth century BC by Hippocrates. In the Hippocratic view moods were thought to depend on P.1210 the balance of four humors—blood, phlegm, yellow bile, and black bile. An excess of black bile was believed to cause depression. In fact, the ancient Greek term for depression, melancholia, means black bile. Though this explanation of depression seems fanciful today, the underlying view that psychological disorders reflect physical processes is correct. Modern efforts to update the Hippocratic formulation were, until very recently, hindered by a lack of precision in the classification of affective disorders. In his 1917 paper Mourning and Melancholia, Sigmund Freud wrote: “Even in descriptive psychiatry the definition of melancholia is uncertain; it takes on various clinical forms (some of them suggesting somatic rather than psychogenic affections) that do not seem definitely to warrant reduction to a unity.” Only in the past two decades have relatively precise criteria for mood disorders been developed in parallel with those for cognitive disorders (see Chapter 60).

Unipolar Depression Is Most Likely Several Mood Disorders The clinical features of unipolar depression are easily summarized. In Hamlet's words, “How weary, stale, flat, and unprofitable seem to me all the uses of this world!” Untreated, an episode of depression typically lasts 4-12 months. It is characterized by an unpleasant (dysphoric) mood that is present most of the day, day in and day out, as well as intense mental anguish, the inability to experience pleasure (anhedonia), and a generalized loss of interest in the world. The diagnosis also requires at least three of the following symptoms to be present: disturbed sleep (usually insomnia with early morning awakening, but sometimes oversleeping or hypersomnia), diminished appetite and loss of weight (but sometimes overeating), loss of energy, decreased sex drive, restlessness (psychomotoragitation), slowing down of thoughts and actions (psychomotor retardation), difficulty in concentrating, indecisiveness, feelings of worthlessness, guilt, pessimistic thoughts, and thoughts about dying and suicide. Other common symptoms, not required for diagnosis, are constipation, decreased salivation, and diurnal variation in the severity of symptoms, which are usually worse in the morning. In addition to the inclusion criteria there are exclusion criteria; schizophrenia or other neurological diseases, for example, need to be excluded. There also should be no evidence of a recent death in the family or other traumatic events, since some of the symptoms of unipolar depression are also normal expressions of grief following trauma, personal loss, and mourning. When the syndrome is defined in this manner, about 5% of the world's population have major unipolar depression. In the United States 8 million people at any given time are affected. Severe depression can be profoundly debilitating. In extreme cases patients stop eating or maintaining basic personal cleanliness. Although some people have only a single episode, usually the illness is recurrent. About 70% of patients who have one major depressive episode will have at least one more episode. The average age of onset is about 28 years, but the first episode can occur at almost any age. Indeed, depression also affects young children but is often unrecognized in them. Depression also occurs in the elderly; in fact, older people who become depressed often have not had an earlier episode. Women are affected about two to three times more often than men. Unipolar depression is most likely not a single illness but a group of disorders. However, the attempt to distinguish three subtypes has been only partially successful so far. The subtypes that are commonly distinguished are melancholic depression, atypical depression, and dysthymia. Melancholic depression represents the clearest subtype among the major depressions and accounts for 40-60% of people treated for unipolar depression. Because it often has no obvious external precipitating cause—no personal loss or rejection or obvious change in life events—it was formerly referred to as endogenous depression. The disorder is characterized by six symptoms: (1) depression with diurnal variations in mood (worse in the morning), (2) insomnia with early-morning wakening, (3) anorexia with significant weight loss, (4) psychomotor agitation and mental pain, (5) loss of interest in almost all activity and lack of response to pleasurable stimuli, and (6) when severe, a complete loss of the capacity for joy (anhedonia). Patients with melancholic depression often have a history of one or more previous episodes of major depression with recovery. Many patients show characteristic abnormalities in sleep pattern, as measured by electroencephalography. These abnormalities occur primarily during the first half of the night, when the latency for the rapid eye movement (REM) phase of sleep is shortened. More than half of patients with melancholic depression have frequent awakenings. Melancholic depression sometimes leads to psychomotor retardation, to emotional or intellectual underactivity (retardation). At other times there is a rather painful state of agitation and an active and persistent preoccupation with perceived deficiencies and inadequacies of one's character. Patients with melancholic depression tend to respond preferentially to electroconvulsive therapy (ECT), tricyclic antidepressants, and selective serotonin reuptake inhibitors. Atypical depression is slightly less common than melancholic depression; accounting for about 15% of P.1211 patients hospitalized for major mood disorders. The disease is called atypical because symptoms are the opposite of melancholic depression: it first appears earlier in life and tends to be chronic rather than phasic. In addition, unlike patients with melancholic depression, patients with atypical depression cheer up temporarily when good things happen. Finally, patients with atypical depression do not have loss of appetite and weight loss but instead overeat and gain weight; they do not report insomnia but rather tend to sleep more; and their depression is worse, not better, in the evening. The patients also have prominent symptoms of anxiety. Patients with atypical depression tend to respond preferentially to monoamine oxidase inhibitors. Finally, dysthymia is a persistent but milder depression lasting for at least two years with symptoms that fall short of the criteria of a major depression. It is important to appreciate that we normally experience grief or despondency after loss of a family member, and this normal mourning can involve any of the individual symptoms of atypical or melancholic depression. Perhaps the most important distinction between bereavement and depression is that bereavement is

rarely associated with persistent functional impairment. In addition, despondent or grief-stricken people have fewer suicidal thoughts and, more important, they have lower rates of suicide than patients with atypical or melancholic depression. Most helpful in making a diagnosis of depression, however, is the finding of reactive affect. Unlike major depression, the depression normally experienced after a personal loss is not unrelenting and pervasive—it does not persist every day, all day. Two or three months after a personal loss, most people are able to experience and react to moments of pleasure and contentment that relieve the sadness, something a person with a major depression cannot do. Finally, normal mourning tends to remit after several months. It does not persist. When mourning does persist it usually reflects a transition to an episode of major depression, a transition that occurs in individuals with a genetic predisposition.

Bipolar Depressive (Manic-Depressive) Disorders Give Rise to Alternating Euphoria and Depression About 25% of patients with major depression (or two million people in the United States) will also experience a manic episode, if only a mild one. Patients who experience both depressive and manic episodes have a distinct disorder called bipolar mood disorder. The illness affects men and women equally, and the average age of onset of the first episode is a decade younger than that of unipolar depression (the onset usually occurs at age 20 rather than 30).

Figure 61-1 The incidence of bipolar and unipolar depression is higher among first-degree relatives of patients who have either disease than in the general population. (From Barondes 1993.)

Episodes of depression in bipolar disorders are clinically similar to those of the unipolar type. The manic episodes are characterized by an elevated, expansive, or irritable mood lasting at least one week, together with several of the following symptoms: over-activity, over-talkativeness (pressure of speech), social intrusiveness, increased energy and libido, flight of ideas, grandiosity, distractibility, decreased need for sleep, and reckless spending. In severe cases patients are delusional and hallucinate. Most episodes have no detectable psychosocial precipitant Bipolar disorder is typically recurrent. After an initial episode of euphoria, subsequent episodes of either depression or euphoria are likely to occur about twice as often in bipolar disorder as in unipolar disease. One of the most striking features of bipolar illness is that a subset of patients (rapid cyclers) may switch from depression to euphoria or vice versa quite rapidly, sometimes in a matter of minutes. Depression tends to become more pronounced with age and recur with greater frequency.

Mood Disorders Have a Strong Genetic Predisposition As in schizophrenia, genetic factors are important in both unipolar and bipolar mood disorders. The morbidity rate of depression is modestly higher in first-degree relatives (parents, siblings, and children) of patients P.1212 with depressive illness than in the general population (Figure 61-1). The overall concordance rate for monozygotic twin pairs with bipolar depression may reach 80%; the rate for dizygotic twins is approximately 10% (the same as for siblings).

Figure 61-2 Some patients with unipolar and bipolar disease show a functional abnormality in the prefrontal cortex ventral to the genu of the corpus collosum. During the depressive phase of the bipolar disease activity is decreased, while during the manic phase it is increased. The two images show a decrease in metabolism in patients with depression relative to controls. Both phases of the illness localize to the agranular region of the anterior cingulate gyrus ventral to the corpus collosum. Anterior, or left, is to the left. (From Drevets et al. 1997.)

Seymour Kety, Paul Wender, and David Rosenthal extended their studies of patterns of schizophrenia in the families of adoptees (Chapter 60) to include manicdepressive disorders. They found that the rate of mood disorders among the biological parents of adoptees with depressive or manic-depressive illness was higher than among the adoptive parents (and higher than the rate among biological and adoptive parents of mentally healthy adoptees). Particularly impressive was the finding that the incidence of suicide among biological relatives of adoptees with depressive illness was six times higher than among the biological relatives of normal adoptees. Furthermore, the concordance rate of affective illness in monozygotic twins reared apart is 40-60%, similar to the concordance in those reared together. These concordance rates for unipolar and bipolar depression in monozygotic twin pairs indicate that, like schizophrenia, major depression is polygenic. Several genes are likely to be involved, each making a small contribution. Nongenetic factors are also likely to be important in determining whether an affective disorder is expressed. Their importance is reflected in two important secular trends in depression over the past 50 years. Since 1940 the age of onset has become younger (28 years rather than 35), and the incidence of depression in the families of patients has increased. Perhaps people vulnerable to depression are now more likely to become depressed than they were half a century ago because of the increased stress of everyday life. In addition there may also be a genetic anticipation Genetic linkage analysis (see Chapter 3) has led to the identification of several loci that might contribute to affective illness. Although no specific gene has yet been identified, one locus on chromosome 18 (18q22-23) has the strongest supporting evidence.

Familial Unipolar and Bipolar Depressions May Reflect an Abnormality in the Functioning of the Subgenual Region of the Frontal Cortex Positron emission tomography (PET) scanning and functional magnetic resonance imaging (fMRI) studies have recently defined a potential anatomical abnormality in P.1213 the prefrontal cortex ventral to the genu in the corpus callosum that is affected in familial cases of unipolar and bipolar depression. During the depressive phase of the illness, activity in this region is decreased in patients who have either unipolar or bipolar depression. This decrease seems to be accounted for in large part by a reduction in the volume (by about 45%) of the gray matter of this part of the prefrontal cortex. In contrast, in patients with bipolar disease this region shows an increase in activity during the manic phase of the illness.

Figure 61-3 The three types of antidepressants. A. Clinically useful monoamine oxidase inhibitors are chemically diverse. These drugs are thought to act by decreasing the breakdown of biogenic amines in the brain, thereby making more neurotransmitter available for release at aminergic synapses and prolonging the action of the aminergic transmitters. The antidepressant effects of the drugs take several weeks to fully develop. B. Tricyclic antidepressant drugs (see Figure 61-6) have immediate and long-term effects. Blockage of the reuptake of biogenic amine neurotransmitters from the synapse is evident soon after administration. The therapeutic action of antidepressants usually begins 4 days to 3 weeks after starting the medication. C. Selective serotonin reuptake inhibitors are the most easily tolerated antidepressants.

This finding is of interest because other clinical studies as well as studies in experimental animals have shown that the subgenual region of the prefrontal cortex is important for mood states (Figure 61-2). This region of the prefrontal cortex has extensive connections with other regions involved in emotional behavior, such as the amygdala, the lateral hypothalamus, the nucleus accumbens, and the noradrenergic, serotonergic, and dopaminergic systems of the brain stem (Chapter 50). People who have lesions in this area have difficulty experiencing emotion and have abnormal autonomic responses to emotionally arousing stimuli. Moreover, lesions in this area severely compromise the ability to reason and make intelligent, rational decisions. Conversely, Antonio Damasio and his colleagues have observed that small irritative lesions in this region cause episodes of anger and aggressive behavior.

Unipolar Depressive and Manic-Depressive Disorders Can Be Treated Effectively There are four effective treatments for unipolar and bipolar illnesses: electroconvulsive therapy (ECT), antidepressant drugs, lithium, and anticonvulsants. Of the four, ECT has been used for the longest period of time, over 50 years. Although antidepressants are generally the first choice in the treatment of major depression, ECT is very effective. It produces full remission or marked improvement in about 85% of patients with well-defined major depression. The critical therapeutic factor in ECT is the induction of a generalized brain seizure. Since the motor component of the seizure is not necessary for therapeutic results, modern ECT is always given under anesthesia with complete muscle relaxation. On average, six to eight treatments given at two-day intervals over a period of 2-4 weeks usually suffice to produce a complete remission of symptoms. As might be predicted from our knowledge of seizure activity (Chapter 46), ECT creates P.1214 many temporary changes in brain functions. Although the therapeutic mechanism of ECT is not understood, it may be related to changes in aminergic receptor sensitivity, as we shall see later.

Figure 61-4 The major serotonergic pathways arise in the raphe nuclei. (Adapted from Heimer 1995.) A. Lateral view of the brain illustrates that the raphe nuclei form a fairly continuous collection of cell groups close to the midline throughout the brain stem. For clarity, they are illustrated here in distinct rostral and caudal groups. The rostral raphe nuclei project to a large number of forebrain structures (fibers that project laterally through the internal and external capsules to the neocortex are not shown here). B. This coronal view of the brain illustrates some of the major targets of the serotonergic raphe nuclei neurons.

The most widely used antidepressant drugs fall into three major classes:

●

Monoamine oxidase inhibitors, such as phenelzine (Figure 61-3A). These were the first effective antidepressants to be used clinically but are now used only infrequently. ●

Tricyclic compounds, or general reuptake inhibitors of biogenic amines, such as imipramine, are so named for their three-ring molecular structure (Figure 613B). These compounds inhibit the uptake of both serotonin and norepinephrine and are probably the most effective drugs for patients who are severely depressed. ●

Selective serotonin reuptake inhibitors, such as fluoxetine (Prozac) (Figure 61-3C), paroxetine (Paxil), and sertraline (Zoloft). These are the most commonly used antidepressants, and they work by selectively inhibiting the uptake of serotonin. They are most commonly used for patients who are only moderately depressed. These are, after the tricyclic compounds, the most commonly used drugs in severely ill patients.

The monoamine oxidase inhibitors and the tricyclic antidepressants produce remission or marked improvement in about 70% of patients with major depressions. When optimal doses are given, the success rate with tricyclic drugs and the specific serotonin reuptake inhibitors may reach 85%, almost as effective as ECT. Patients with bipolar depression occasionally become manic during treatment with either class of antidepressant drugs. Although a few patients with bipolar disease begin to improve immediately, there usually is a lag of 1-3 weeks before the symptoms of depression begin to improve, and 4-6 weeks are generally required for a full response Table 61-1 Serotonin Receptors Receptors Receptors linked to second-message systems linked to inhibition of adenylyl cyclase inhibition of adenylyl cyclase

Gene family

5-HT1A linked to inhibition of adenylyl cyclase

5-HT1D linked to inhibition of adenylyl cyclase

5-HT1F linked to inhibition of adenylyl cyclase

Superfamily of receptors with seven transmembrane regions coupled to G proteins

5-HT1E linked to

5-HT2A linked to

phospholipase and PI turnover

5-HT2B linked to phospholipase and PI turnover

phospholipase and PI turnover

5-HT4 linked to stimulation of adenylyl cyclase

HT6 linked to stimulation of adenylyl cyclase

5-HT1B

5-HT2C linked to 5-HT5 unknown linkage

5-

5-HT7 linked to stimulation of adenylyl cyclase

Receptors linked to an ion channel 5-HT3 5-HT = 5-hydroxytryptamine (serotonin); PI = Phosphatidylinositide.

Superfamily of ligand-gated ion channels

Figure 61-5 The noradrenergic pathways arise in the locus ceruleus. (Adapted from Heimer 1995.) A. A lateral midsagittal view demonstrates the course of the major noradrenergic pathways from the locus ceruleus and lateral brain stem tegmentum. The pigmented locus ceruleus, located immediately beneath the floor of the fourth ventricle in the rostrolateral pons, is the best understood noradrenergic nucleus in the brain. Its projections reach many areas in the forebrain, cerebellum, and spinal cord. Noradrenergic neurons in the lateral brain stem tegmentum innervate several structures in the basal forebrain, including the hypothalamus and the amygdaloid body. B. A coronal section shows the major targets of neurons from the locus ceruleus. (Adapted from Heimer 1995.)

Table 61-2 Noradrenergic Receptors Linked to Second-Messenger Systems Type

Second-mesenger system

Location

β1

Linked to stimulation of adenylyl cyclase

Cerebral cortex, cerebellum

β2

Linked to stimulation of adenylyl cyclase

Cerebral cortex, cerebellum

α1

Linked to phospholipase C, PI, PKC, DAG, Ca2+ in peripheral tissues

Brain, blood vessels, spleen

α2

Linked to inhibition of adenylyl cyclase

Presynaptic nerve terminals throughout the brain

PI = Phosphatidylinositide; PKC = Protein kinase C; DAG = Diacylglycerol.

P.1215 P.1216 Lithium salts, first reported in the psychiatric treatment of manic-depressive illness in 1949 by John Cade, are effective in terminating manic episodes and are used as mood stabilizers. Moreover, maintenance therapy with lithium is of significant prophylactic value in preventing or attenuating recurrent manic and, to a lesser extent, depressive episodes. Lithium is rarely used by itself for treatment of unipolar depression. However, it is frequently used in conjunction with monoamine oxidase inhibitors, tricyclic compounds, or selective serotonin reuptake inhibitors to augment the response of these conventional antidepressants (see Figure 61-9). Drugs effective as anticonvulsants (such as sodium valproate and carbamazepine) are also used as mood stabilizers and are quite effective in reducing psychotic symptoms in acute mania or severe depression. Antipsychotic drugs (Chapter 60) are also used frequently in combination with tricyclic drugs, and even with ECT when depression is accompanied by delusions and hallucinations.

Drugs Effective in Depression Act on Serotonergic and Noradrenergic Pathways Drugs effective in treating depression act primarily on the serotonergic and noradrenergic systems of the brain (Chapter 45). The evidence is particularly impressive for serotonin—all selective serotonin reuptake inhibitors tested have been found to be effective against depression. The action of these drugs, therefore, provides the first clues to a neurochemical basis of depressive disorders. The major serotonergic pathways have their origin in the raphe nuclei in the brain stem (Figure 614). Cells from the rostral parts of these nuclei project to the forebrain; single serotonergic neurons project to hundreds of target cells in a large, diffuse distribution. (The cells of the caudal part of the raphe nuclei project to the spinal cord.) The serotonergic receptors are traditionally classified into at least seven major types. Some types decrease adenylyl cyclase, some increase adenylyl cyclase, others are coupled to phosphatidylinositide turnover, and still others are ligand-gated ion channels (Table 61-1).

The noradrenergic pathways originate in the locus ceruleus (Figure 61-5). The axons of some locus ceruleus neurons ascend to innervate the hypothalamus and all regions of the cerebral cortex, including the hippocampus. Other neurons have descending axons that reach the dorsal and ventral horns of the spinal cord. Like serotonergic cells, noradrenergic neurons innervate broad areas and act on a number of receptor types (Table 61-2). Certain components of the noradrenergic system appear to be involved with arousal and fear (Chapter 50), while others are thought to be involved, together with the mesolimbic components of the dopaminergic system, in positive motivation and pleasure (Chapter 51). The pervasive anxiety and loss of pleasure characteristic of melancholia and atypical depression might therefore be related to dysregulation of these two components of the noradrenergic system.

An Abnormality in Biogenic Amine Transmission May Contribute to the Disorders of Mood Norepinephrine is synthesized from tyrosine, and serotonin from tryptophan (Chapter 15). The transmitters are packaged in synaptic vesicles and released into the synaptic cleft by means of exocytosis when the neuron fires an action potential. Both norepinephrine and serotonin interact with postsynaptic receptors, and this activity is limited by active reuptake of the released transmitter into the presynaptic terminals as well as into glial cells. Inside the presynaptic terminals the transmitters are packaged again into vesicles or catabolized primarily by the mitochondrial enzyme monoamine oxidase. Until recently the consensus view—expressed first in the catecholamine hypothesis and then in the more general biogenic amine hypothesis —was that depression represented P.1217 a decreased availability of either norepinephrine or serotonin or both. Mania was believed to result from the over-activity of noradrenergic systems. This hypothesis was derived from studies of the effects of various drugs on the serotonergic and noradrenergic systems of the brain. The idea originally came from the observation in 1950 that reserpine, a Rauwolfia alkaloid then used extensively in the treatment of hypertension, precipitated depressive syndromes in about 15% of treated patients. Reserpine also produced a depression-like syndrome, with motor retardation and sedation, in animals. Bernard Brodie and his colleagues found that reserpine depletes the brain of serotonin and norepinephrine (as well as dopamine) by inhibiting the uptake of the transmitter into synaptic vesicles in the presynaptic cell, thereby keeping the transmitter in the cytoplasm, where it undergoes degradation by monoamine oxidase (Figure 61-6).

Table 61-3 Effects of Long-Term Administration of Antidepressant Drugs on the Serotonergic System Function of terminal α2

Responsiveness of somatodendritic of 5-HT1A Function of terminal 5autoreceptors HT autoreceptors Antidepressant treatment Selective serotonin reuptake inhibitors Monoamine oxidase inhibitors 5-HT1A receptor agonists

Responsiveness of postsynaptic receptors

adrenergic receptors

Net serotonin transmission 5-HT receptors

Decreased

Decreased

NC

NC

Increased

Decreased Decreased

NC NC

? ND

NC or decreased NC

Increased Increased

Increased Increased

Increased Increased

Tricyclic antidepressants NC NC ND Electroconvulsive shocks NC NC NC From Blier and deMontigny 1994; NC = no change; ND = no data; 5-HT = 5-hydroxytryptamine (serotonin).

Monoamine oxidase inhibitors, such as isoniazid, were later found to be effective antidepressants. Isoniazid was initially developed in the 1950s to treat tuberculosis. In the course of clinical trials it was noted that some patients who had depression as well as tuberculosis experienced elevations in mood when treated with the drug. Isoniazid was next tried in patients with depression who did not have tuberculosis and was found to be effective. Monoamine oxidase inhibitors increase the concentration of serotonin and norepinephrine in the brain by reducing the degradation of these transmitters by monoamine oxidase. In experimental animals monoamine oxidase inhibitors prevent reserpine's sedative effects on behavior as well as its degradation of cytoplasmic monoamines. Further support for the view that monoamine oxidase inhibitors act therapeutically by increasing the availability of serotonin and biogenic amines came with the discovery of a second class of effective antidepressants: the tricyclics. These agents block the active reuptake of serotonin and norepinephrine by presynaptic neurons, thereby prolonging the action of these transmitters in the synaptic cleft (see Figure 61-6). Finally, the third group of compounds that proved to be effective in depression, the selective serotonin reuptake inhibitors, affect only serotonin and not norepinephrine. Thus, all three major classes of antidepressants maximize synaptic transmission of serotonin by inhibiting the reuptake of the transmitter or its degradation (Table 61-3). Even electroconvulsive shock increases serotonergic transmission (Table 61-3). It does so by increasing the sensitivity of the 5-HT1A receptors in the hippocampus and increasing the number of 5-HT2A receptors. The remarkable effectiveness of selective serotonin reuptake inhibitors on depression provides the most compelling evidence that enhancement of serotonergic transmission underlies the therapeutic response to some antidepressant treatments. However, the biogenic amine hypothesis fails to account for a number of important clinical phenomena. In particular, it fails to explain why the clinical response to all antidepressant drugs is so slow after administration of the drugs, whereas the tricyclic agents and the selective serotonin reuptake inhibitors rapidly block the high-affinity reuptake P.1218 P.1219 systems. This blockade is much more rapid than the clinical response. If the clinical response is a result of an increase in serotonergic synaptic transmission, what accounts for the delay in the response? In addition, the tricyclic drugs vary widely in their relative abilities to block serotonin or norepinephrine reuptake, yet their clinical efficacy in patients with depression is about the same. Finally, in some patients with depression the onset of the illness is associated not with a decrease but with an increase in the level of norepinephrine in spinal fluid and plasma, and treatment leads to reduction to a normal level.

Figure 61-6 (Opposite) Action of antidepressant and other drugs at serotonergic and noradrenergic synapses. A. Antidepressant and other drugs have five possible sites of action at serotonergic synapses. 1. Enzymatic synthesis. Both p-chlorophenylalanine and p-propyldopacetamide can effectively inhibit the enzyme tryptophan nyroxylase, which converts tryptophan to 5-OH-tryptophan, the precursor of 5-hydroxytryptophan (5-HT, serotonin). 2. Storage. Reserpine and tetrabenazine interfere with the reuptake-storage mechanism of the amine granules, causing a marked depletion of serotonin. 3. Receptor interactions. These fall into two categories. a. Autoreceptor 8-hydroxy-diprolamino-tetraline (8-OH-DPAT) is an agonist of the 5-HT autoreceptor. b. Lysergic acid diethylamide (LSD) acts as a partial agonist at postsynaptic serotonergic receptors in the central nervous system. A number of specific compounds are now candidates to act as receptor-blocking agents at various serotonergic synapses. 4. Reuptake. Tricyclic drugs with a tertiary nitrogen, such as imipramine and amitryptyline, inhibit the reuptake of serotonin into the presynaptic terminal and thus increase the efficacy of transmission. Fluoxetine and sertraline are even more selective inhibitors of serotonin uptake. 5. Degradation by monoamine oxidase (MAO). Iproniazid and clorgyline are effective inhibitors of MAO, which is localized in the outer membrane of mitochondria and can degrade serotonin present in a free state within the presynaptic terminal. 5-HIAA = 5-hydroxyindoleacetic acid. B. Antidepressants and other drugs have seven possible sites of action at noradrenergic synapses. 1. Enzymatic synthesis. a. The competitive inhibitor α-methyltyrosine blocks the reaction catalyzed by tyrosine hydroxylase. b. A dithiocarbamate derivative, FLA 63, blocks the reaction catalyzed by dopamine β-hydroxylase, which converts DOPA to dopamine. 2. Storage. Reserpine and tetrabenazine interfere with the reuptake-storage mechanism of the amine granules. The depletion of norepinephrine (NE) by reserpine is long-lasting and the storage granules are irreversibly damaged, causing permanent depletion of NE available for release transmission. Tetrabenazine also interferes with the reuptake of free cytoplasmic NE into the granules. 3. Release. Amphetamine appears to cause an increase in the net release of NE, most likely because of its ability to block the reuptake. 4. Receptor interaction. a. Clonidine is a very potent α-receptor agonist. b. Phenoxybenzamine and phentolamine are effective α-receptor blocking agents. Recent

experiments have indicated that these drugs also have a presynaptic site of action. 5. Degradation by COMT. Tropolone inhibits COMT, which inactivates NE. COMT is believed to be localized outside the postsynaptic neuron. 6. Reuptake. The tricyclic drug desipramine is a potent inhibitor of the reuptake of NE into the presynaptic terminal. As a result, NE remains in the synapse longer and has a greater postsynaptic effect. 7. Degradation by monoamine oxidase (MAO). Pargyline is an effective inhibitor of MAO, which appears to be localized in the outer membrane of mitochondria and can degrade the NE present in a free state within the presynaptic terminal. Normetanephrine (NM) is formed by the action of the enzyme catechol Omethyltransferase (COMT) on NE.

Some clues are emerging that may help to resolve these issues. For example, it is now clear that antide-pressant agents affect processes other than the reuptake and accumulation of serotonin. In addition to their rapid biochemical effects on reuptake, both monoamine oxidase inhibitors and tricyclic antidepressants produce a delayed but long-term increase in the sensitivity of serotonin receptors. Conversely, the selective serotonin reuptake inhibitors produce a delayed decrease in the sensitivity of 5HT1A and 5HT1B inhibitory autoreceptors present on many serotonergic cells, leading to increased release of serotonin. Both of these actions lead to a slow increase in the effectiveness of serotonergic synaptic transmission Given these findings, where does the biogenic amine hypothesis stand? The initial, simple form of the biogenic amine hypothesis, which states that reduction of biogenic amines leads to depression and elevation to mania, is no longer valid. There probably is no simple relationship between biogenic amines and depression. If a relationship exists at all, which seems likely, it is complicated by three factors. First, the subtypes of major depression are most likely not single disorders, but a group of disorders with several underlying pathologies. Second, disturbances in one of several transmitter systems can lead to depression. Finally, the various modulatory systems of the brain—the serotonergic, dopaminergic, and adrenergic systems—do not function independently of each other but rather interact at several levels. Specifically, the distribution of the serotonergic system overlaps with and interacts with the noradrenergic system. Moreover, receptors for the two amines coexist on the same neurons, and there is cross-talk between second messengers activated by these transmitters. Long-term administration of antidepressants fails to downregulate the β-adrenergic receptors when serotonergic systems have been eliminated experimentally. In addition, antidepressants act on the cholinergic and GABA-ergic systems. Cholinergic neurons excite the noradrenergic cells of the locus ceruleus through P.1220 muscarinic receptors, and cholinergic agonists can induce depression. Indeed, patients with a history of depression tend to be hyperresponsive to cholinergic agonists, even when their mood is normal.

Figure 61-7 The exact therapeutic action of lithium, used to treat bipolar depression, is unknown. However, lithium has been shown to affect the phosphoinositide second-messenger system. Many synaptic receptors act through a G protein to mediate the conversion of phosphoinositol diphosphate (PIP2), a membrane lipid, into diacylglycerol (DAG) and inositol triphosphate (IP3). IP3 is further broken down to inositol phosphate (IP), which is then converted to free inositol by the enzyme inositol-1-phosphatase. Lithium blocks this enzyme and therefore reduces the responsiveness of these neurons by causing IP3 to accumulate in the cytoplasm. The roles of IP3 and protein kinase C are discussed in Chapter 13.

Since most serotonergic and adrenergic receptors act on second-messenger pathways—activating or inhibiting adenylyl cyclase or stimulating phosphoinositide turnover—it is perhaps not surprising that drugs acting directly on these pathways are now being developed. For example, lithium salts, which are highly effective in bipolar disorder, block the enzyme inositol-1-phosphatase, which recycles inositol triphosphate back to inositol. This results in a buildup of inositol 1,4,5triphosphate (IP3), which is known to be active in regulating intracellular Ca2+ levels. Inhibition of this enzyme is thought to reduce the responsiveness of those neurons with transmitter receptors coupled to the IP3 pathway (Figure 61-7). This could be the way lithium acts therapeutically, perhaps by dampening excessive neural activity in mania.

Unipolar Depression May Involve Disturbances of Neuroendocrine Function As first pointed out by Edward Sachar, depression is associated with clinical signs of hypothalamic disturbance. The best-understood hypothalalmic disturbance in severe depression is neuroendocrine and is reflected in excessive secretion of adrenocorticotropic hormone (ACTH) by the pituitary, leading to excessive secretion of cortisol from the adrenal cortex. The hypersecretion of ACTH is so great that enlargement of the adrenal gland can be detected on computerized axial tomography (CAT) scans of some patients with depression. In normal people the secretion of cortisol follows a circadian rhythm; secretion peaks at 8:00 AM and is relatively lower in the evening and early morning hours. This circadian cycle is disturbed in about one-half of patients with depression, who secrete excessive amounts of cortisol throughout the day (Figure 61-8). The disturbance is not dependent on stress and is not found in other psychiatric disorders. Cortisol secretion returns to normal with recovery. Philip Gold and his colleagues found that the increased secretion of cortisol results from hypersecretion of corticotropin-releasing hormone (CTRH) from the hypothalamus, and that the level of CTRH correlates positively with depression. Release of CTRH is stimulated by norepinephrine and acetylcholine, and release of CTRH induces anxiety in experimental animals. Thus, Gold and his colleagues have suggested that CTRH and the noradrenergic system may reinforce one another. Hypersecretion of cortisol is sometimes resistant to feedback suppression by the potent synthetic corticosteroid dexamethasone, which depresses secretion of adrenocorticotropin. The dexamethasone suppression test has been used to diagnose depression because in at least 40% of rigorously diagnosed patients with depression hypersecretion of cortisol is resistant to feedback suppression by dexamethasone. However, the test is not specific; dexamethasone suppression is also abnormal in patients who have dementia, anorexia nervosa, bulimia, alcohol withdrawal, or weight loss.

There Are at Least Four Major Types of Anxiety Disorders Just as grief is a normal response to personal loss, anxiety is a normal response to threatening situations. Perceived threats that generate anxiety may be active and direct or indirect, such as the absence of people or objects P.1221 that represent security. Anxiety is adaptive; it signals potential danger and can contribute to the mastery of a difficult situation and thus to personal growth. Excessive anxiety, on the other hand, is maladaptive, either because it is too intense or because it is inappropriately provoked by events that present no real danger. Thus, anxiety is pathological when excessive and persistent, or when it no longer serves to signal danger. The key feature of anxiety disorders is increased fearfulness accompanied by subjective as well as objective manifestations. The subjective manifestations range from a heightened sense of awareness to a deep fear of impending disaster and death. The objective manifestations are a racing heart, avoidance behavior and signs of restlessness, heightened responsiveness, palpitations, tremor, sweating, increased blood pressure, dry mouth, and a desire to run or escape. Depression and anxiety often occur together. Anxiety disorders are the most common psychiatric disorders, found in 10-30% of the general population. Anxiety disorders can be subdivided into several types based on clinical characteristics and response to psychopharmacologic agents. These major categories include panic disorder, post-traumatic stress disorder, (PTSD), generalized anxiety disorder, social phobia, and obsessive-compulsive disorder (OCD).

Panic Attacks Are Brief Episodes of Terror Panic attacks are brief, recurrent, unexpected episodes of terror without a clearly identifiable cause. The attacks are usually brief, most commonly lasting 15-30 minutes; occasionally, but only rarely, they last up to an hour. An essential feature of these attacks is that they are unexpected. They do not occur in situations that normally evoke fear or in which the patient is the focus of other people's attention. The attacks are characterized by a sense of impending doom accompanied by an intense over-activity of the sympathetic nervous system (referred to as a sympathetic crisis): The heart races, there is shortness of breath; dizziness; trembling or shaking of the hands and legs; flushes or chills; chest pain; and fear of dying, or of going crazy, or of doing something uncontrolled. Shortness of breath is characteristic of panic attacks but not of the acute terror evident in battle, suggesting that panic attacks may represent a false alarm for suffocation.

Figure 61-8 Many patients with depression secrete excess ACTH and cortisol during the day. In normal subjects there is a circadian rhythm to the secretion, which peaks at 8:00 AM and then decreases progressively from the early morning hours into the evening until 3:00 AM at night (0300). By contrast, in depressed patients the plasma cortisol concentration is elevated throughout much of the 24-hour period of the day, with only a slight decline in the evening (2000 to 0200). The plot shows the mean hourly plasma cortisol concentration over a 24-hour period for seven patients with unipolar depression compared with the mean for 54 normal subjects. Each point represents the mean cortisol concentration every 60 minutes.

When panic attacks recur the resulting syndrome is called panic disorder. Attacks recur over a period ranging from months to several years and are often experienced several times a week. Panic disorders usually begin in adolescence. An interesting aspect of panic attacks is that they can be induced in some patients who have this disorder, but not in most normal subjects, by the infusion of sodium lactate into the blood or the inhalation of carbon dioxide. Thus, sodium lactate infusion provides an approach for studying the mechanism underlying this disorder because the onset of an attack can be timed precisely. Moreover, regular use of antidepressants that are effective against spontaneous panic attacks also prevent the panic induced by the infusion. Similarly, yohimbine, a drug that activates central noradrenergic neurons (by blocking the α2 adrenergic receptors that serve as inhibiting autoreceptors), precipitates panic attacks in patients but not in normal subjects, indicating that panic attacks involve an abnormality in the biogenic amine system of the brain. A significant proportion of patients with panic disorders have a genetic predisposition. Half of patients P.1222 with panic attacks also have depression, a finding that has led to the suggestion that panic attacks may be a variant of depressive illness or a precursor to it. This is consistent with the initially surprising finding that panic disorder is successfully treated with both tricyclic antidepressants and monoamine oxidase inhibitors. Now that more is known about the function of the locus ceruleus, this finding is perhaps less surprising. The noradrenergic cells in this nucleus respond most effectively to stimuli that produce intense fear. In fact, cognitive therapy for panic attacks trains patients not to act on their autonomic signals.

Post-Traumatic Stress Disorder Reflects Persistent Traces of Anxiety That Follow Traumatic Episodes An interesting variant of panic attacks is post-traumatic stress disorder. Although now appreciated as fairly common, this disorder was not clearly recognized in its present form until the 1980s. Post-traumatic stress disorder occurs in people after an extremely stressful event, such as life-threatening combat or physical abuse. It is manifested in recurrent episodes of fear, often triggered by reminders of the initial trauma. One of the most striking features of this disorder is that the memory for the traumatic experience remains powerful for decades and is readily reactivated by a variety of stimuli and stressors. This is thought to be due to the recruitment of the noradrenergic system by these reactivating stimuli. As we shall learn in Chapter 63, biogenic amines are important in modulating various memory processes. Vietnam War veterans with post-traumatic stress disorder show heightened noradrenergic functioning. They excrete high levels of norepinephrine in their urine, presumably reflecting high circulating catecholamine levels. When exposed to gunfire or other stimuli associated with combat, these veterans respond with dramatic increases in blood pressure and heart rate. When patients with post-traumatic stress disorder are given yohimbine, they experience a type of panic attack: An intense memory is accompanied by autonomic symptoms (increase in blood pressure and heart rate) and an increase in the core symptoms, such as frightening thoughts, emotional numbing, and grief.

These manifestations are all consistent with the idea that uncontrollable stress produces substantial increases in noradrenergic functioning in the brain. Propranolol and clonidine, which act to decrease noradrenergic transmission, greatly ameliorate the symptoms of post-traumatic stress disorder. Interestingly, a large percentage (about 50%) of patients with post-traumatic stress disorder also show a concurrent panic disorder.

Generalized Anxiety Disorder Is Characterized by Long-Lasting Worries The key feature of generalized anxiety disorder is unrealistic or excessive worry, lasting not minutes but continuously for six months or longer. The symptoms are motor tension (trembling, twitching, muscle aches, restlessness), autonomic hyperactivity (palpitations, increased heart rate, sweating, cold hands), and vigilance and scanning (feeling on edge, exaggerated startle response, difficulty in concentrating). The disorder sometimes follows an episode of depression. One group of drugs that is particularly effective in treating generalized anxiety disorder is the benzodiazepines, such as chlordiazepoxide (Librium) and its derivative, diazepam (Valium). Benzodiazepines produce their therapeutic effect by enhancing the activity of the GABAA receptor. GABA is the major inhibitory transmitter in the brain (Chapter 12). The GABAA receptor opens Cl- channels and the resulting influx of Cl- hyperpolarizes and thus inhibits target cells. Benzodiazepine increases the affinity of the receptor for GABA, resulting in an increase in Cl- influx through the Cl- channels and thereby prolonging the synaptic inhibition produced by GABA (Figure 61-9). The GABAA receptor has separate binding sites for GABA, barbiturates, and benzodiazepines (Chapter 11). The protein is allosteric; binding of any one of the three ligands (GABA, benzodiazepine, or barbiturate) influences the binding of the other two and facilitates GABA's action. In particular, GABA will bind more tightly when a benzodiazepine also is bound to its site on the receptor. Nevertheless, all three sites are distinct. Analysis of the primary structure of the GABA receptor indicates that there are at least three subunits (α, β, γ); benzodiazepine binds to the γ subunit. The calming effects of benzodiazepines are therefore best explained by an enhancement of certain of the inhibitory effects of GABA. Inverse agonists of benzodiazepine reduce rather than enhance GABA-ergic transmission and produce anxiety as well as predisposition to convulsions. Yet these inverse agonists bind to the benzodiazepine site on the GABA receptor and are blocked by benzodiazepine antagonists. This has raised the possibility that endogenous inverse agonists might mediate naturally occurring anxiety states. High concentrations of GABA receptors have been found in the limbic system, specifically in the amygdala, an area thought to be of central importance for emotional behavior. However, as with other mental illnesses, it is unlikely that a single transmitter system is responsible for the illness. In fact, many patients with anxiety states respond extremely well to selective serotonin reuptake inhibitors and tricyclic antidepressants.

Figure 61-9 Benzodiazepines act on the GABA channel. A. Structural model of the GABAA chloride channel. The channel protein contains at least five different subunit types, of which only three are illustrated here (α, β, γ). Benzodiazepines bind to the γ subunits, GABA to the α subunit, and barbiturates to the β subunit. All the subunits contribute to forming the Cl+ channel. When GABA binds to GABAA receptors the Cl+ channels open and the influx of Cl+ hyperpolarizes the cell. B. Diazepam, a benzodiazepine, is an effective drug in treating generalized anxiety disorders. The traces compare the responses of a mouse spinal cord neuron to GABA, the major inhibitory neurotransmitter in the brain, and to GABA in the presence of diazepam. Diazepam increases the affinity of the receptor for GABA and thus increases the Cl+ conductance and the hyperpolarizing current. C. Benzodiazepine (Benzo) modulates Cl- flux through the channel by enhancing the effect of GABA, which itself enhances the influx of Cl- into the nerve cell. As a result, basal levels of GABA become more effective in gating the channel. Benzodiazepine antagonists prevent enhancement of GABA effects but do not reduce the basal conductance of Cl-. GABA antagonists prevent gating of Cl- channels in spite of the presence of benzodiazepines.

P.1223

In Obsessive-Compulsive Disorder Obtrusive Thoughts Are a Source of Anxiety and Compulsion Obsessive-compulsive disorders are usually chronic disorders with recurrent obsessions and compulsions as the predominant features. Obsessions are persistent and intrusive ideas, thoughts, images, or impulses that commonly fall into one of two categories: doubts or fears. Obsessive doubting can penetrate daily life, leaving patients repeatedly unsure whether the apartment door was locked, whether the stove was turned off, or whether their hands are clean enough. This preoccupation can result in excessive hand washing, sometimes to the extent of soreness or removal of skin. Obsessive fears focus on unrealistic and improbable dangers, such as the prospect of killing someone driving a car or lighting the stove. Interestingly, the person experiencing these fears typically views them as alien—senseless and unwanted invasions of consciousness. When the fears first become prominent, the patient attempts to ignore or suppress them, usually unsuccessfully. Later in the course of the illness the patient may no longer actively resist these fears. To alleviate the anxiety and diminish the discomfort of the obsessive thoughts or urges, the patient often begins to carry out compulsive acts. In contrast to obsessions, which are repetitive ideas, compulsions are repetitive acts. To be defined as a compulsion a behavior must be repeated excessively and the repetition must not be realistically related to any environmental condition. The most common compulsions are handwashing, counting, checking, touching, and pulling out of hair. The severe symptoms of obsessive-compulsive disorder are thought to represent the extreme end of a behavioral continuum that includes a compulsive lifestyle that typically begins between 18 and 25 years of age. Although the symptoms may disappear or become less severe for periods of time, the disorder rarely disappears. P.1224 Indeed, people with obsessive-compulsive disorder may also have other mental illness, such as depression, other anxiety disorders (panic attacks, eating disorders), or social phobias.

Figure 61-10 Patients with obsessive-compulsive disorder tend to show hyperactivity in the head of the caudate. This hyperactivity can be reduced in one of two ways: by selective serotonin reuptake inhibitors (top), medication therapy, or cognitive therapy (bottom), psychotherapy.

Obsessive-compulsive disorder is thought to reflect a disturbance of the basal ganglia. In fact, some forms of obsessive-compulsive disorder seem to be related to Tourette syndrome, a hereditary chronic motor tic disorder that has its locus in the basal ganglia. Patients with Tourette syndrome erupt in repetitive grunts, noises, and even obscenities that are not under the patient's control. Several other neurological syndromes that involve the basal ganglia, such as postencephalitic Parkinson disease, Sydenham chorea, bilateral necrosis of the globus pallidus, and Huntington disease, often are associated with a component of obsessivecompulsive disorder. The head of the caudate nucleus and the pathway that connects the caudate with the prefrontal (orbitofrontal) cortex and cingulate gyrus seems to be hyperactive in obsessive-compulsive disorder. The caudate nucleus sends GABA-ergic inhibitory projections to the globus pallidus (one of the two major output elements of the striatum), which sends inhibitory projections to the thalamus, which then projects to the orbitofrontal cortex. The presence of serial inhibitory pathways—from the caudate nucleus to the globus pallidus, and from there to the thalamus—suggests the possibility that a disease state produces a disinhibition, which could lead to reverberating activity in this circuit. Perhaps an increase in the first inhibitory pathway causes the second pathway to become less of an inhibitor of its targets, leading to the reverberatory state. Obsessive-compulsive disorder is responsive to two types of treatments: (1) specific behavioral therapies based on conditioning (Chapter 62) and (2) specific serotonin reuptake inhibitors. The effectiveness of the serotonin reuptake inhibitors raises two questions: Is central serotonergic transmission abnormal in obsessivecompulsive disorder and, if so, can psychotherapy reverse this effect? In fact, serotonergic innervation of the striatum is extensive. This innervation is localized to the medial-ventral aspects of the head of the caudate nucleus and to the nucleus accumbens, regions that receive input from the orbitofrontal and cingulate cortex regions thought to be involved in emotional behavior. Surgical lesions of these tracts from the frontal cortex to subcortical sites has improved the symptoms of some otherwise intractable cases. After effective treatment of the disease with either serotonin reuptake inhibitors or behavioral therapy, hyperactivity of the caudate nucleus and orbitofrontal cortex decreases significantly (Figure 61-10). This suggests that psycho-therapy and pharmacologic therapy lead to a similar biological change.

An Overall View Certain major depressive illnesses may be the result of genetically determined defects in chemical synaptic transmission involving at least two major transmitter pathways of the brain: the serotonergic and noradrenergic systems. Although the mechanisms that cause the defects in transmission remain obscure, progress in studying allelic variations in the human genome provide hope that aspects of the molecular basis of affective disorders might soon be elucidated. Because there are good animal models of anxiety and we now know a great deal about the amygdala and the neural circuitry in learned fear, it is likely that anxiety may soon be better understood. Like major depression and schizophrenia, two types of anxiety—panic disorder and generalized anxiety disorder—seem to reflect alterations in synaptic functioning. Since panic disorder responds well to certain antidepressants, it too may reflect an abnormality in the biogenic amine pathways of the brain. In contrast, generalized anxiety disorder may involve the GABAA receptor system, or more likely an abnormality in the interaction of the GABAA receptor and the serotonergic system. P.1225 Perhaps the most powerful insight into obsessive-compulsive disorders is the finding that psychotherapy and selective serotonin reuptake inhibitors are equally effective in reversing the symptoms and in so doing they also reverse the anatomical abnormalities.

Selected Readings Barondes SH. 1993. Molecules and Mental Illness. New York: Scientific American Library.

Barondes SH. 1998. Mood Genes: Hunting for the Origins of Mania and Depression. New York: W.H. Freeman and Co.

Delgado PL, Charney DS, Price MD, Aghajanian GK, Landis H, Heninger GB. 1990. Serotonin function and the mechanism of antidepressant action. Arch Gen Psychiatry 47:411–419.

Gold PW, Goodwin FK, Chrousos GP. 1988. Clinical and biochemical manifestations of depression: relation to the neurobiology of stress. N Engl J Med 319:348353 and 413–420.

Goodwin DW, Guze SB. 1989. Psychiatric Diagnosis, 4th ed. New York: Oxford Univ. Press.

Goodwin FK, Jamison KR. 1990. Manic-Depressive Illness. New York: Oxford Univ. Press.

Janowsky A, Sulser F. 1987. Alpha and beta adrenoreceptor in brain. In: HY Meltzer (ed). Psychopharmacology: The Third Generation of Progress, pp. 249256. New York: Raven.

Klerman GL. 1983. The scope of depression. In: J Angst (ed). The Origins of Depression: Current Concepts and Approaches, pp. 5-25. Dahlem Konferenzen. Heidelberg: Springer.

Schwartz JM, Stoessel PW, Baxter LR, Martin KM, Phelps ME. 1996. Systematic changes in cerebral glucose metabolic rate after successful behavior modification treatment of obsessive-compulsive disorders. Arch Gen Psychiatry 53:109–113.

Triveldi MH. 1996. Functional neuroanatomy of obsessive-compulsive disorder. J Clin Psychiatry 57(Suppl 8):26–35.

References Andén N-E, Dahlström A, Fuxe K, Larsson K, Olson L, Ungerstedt U. 1966. Ascending monoamine neurons to the telencephalon and diencephalon. Acta Physiol Scand 67:313–326.

Arango V, Ernsbverger P, Marzuk PM, Chen JS, Fierney H, Stanley M, Reiss DJ, Mann J. 1990. Autoradiographic demonstration of increased serotonin 5HT2 and β-adrenergic receptor binding in the brain of suicide victims. Arch Gen Psychiatry 47:1038–1047.

Åsberg M, Träskman L, Thorén P. 1976. 5-HIAA in the cerebrospinal fluid: a biochemical suicide predictor? Arch Gen Psychiatry 33:1193–1197.

Bench CJ, Friston KJ, Brown RG, Scott LC, Frackowiak RS, Dolan RJ. 1992. The anatomy of melancholia: focal abnormalities of cerebral blood flow in major depression. Psychol Med 22(3):607–615.

Blier D, deMontigny C. 1994. Current advances in the treatment of depression. Trends Pharmacol Sci 15:220–226.

Carroll BJ, Feinberg M, Greden JF, Tarika J, Albala AA, Haskett RF, James NMcI, Kronfol Z, Lohr N, Steiner M, de Vigne JP, Young E. 1981. A specific laboratory test for the diagnosis of melancholia. Arch Gen Psychiatry 38:15–22.

Charney DS, Woods SW, Goodman WK, Heninger GR. 1987. Neurobiological mechanisms of panic anxiety: biochemical and behavioral correlates of yohimbine induced attacks. Am J Psychiatry 144:1030–1037.

Cooper JR, Bloom FE, Roth RH. 1996. The Biochemical Basis of Neuropharmacology, 7th ed. New York: Oxford Univ. Press.

Davis JM, Maas JW (eds). 1983. The Affective Disorders. Washington, DC: American Psychiatric Press.

Drevets WC, Price JL, Simpson JR Jr, Todd RD, Reich T, Vannier M, Raichle ME. 1997. Subgenual prefrontal cortex abnormalities in mood disorders. Nature 386:824–827.

Everett GM, Toman JEP. 1959. Mode of action of Rauwolfia alkaloids and motor activity. In: JH Masserman (ed). Biological Psychiatry, pp. 75-81. New York: Grune & Stratton.

Freud S. [1917] 1959. Mourning and melancholia. In: The Collected Papers, Vol. 4, pp. 152-170. New York: Basic Books.

Heimer L. 1995. The Human Brain and Spinal Cord, 2nd ed. New York, Berlin: Springer-Verlag.

Hoyer D, Clarke DE, Fozard JR, Hartig PR, Martin GR, Mylecharane EJ, Saxena PR, Humphrey PPA. 1994. International union of pharmacology classification of receptors for 5-hydroxytryptamine (serotonin). Pharmacol Rev 46:157–203.

Kety SS. 1979. Disorders of the human brain. Sci Am 241(3):202–214.

Kety SS, Rosenthal D, Wender PH, Schulsinger F, Jacobsen B. 1975. Mental illness in the biological and adoptive families of adopted individuals who have become schizophrenic: a preliminary report based on psychiatric interviews. In: RR Fieve, D Rosenthal, H Brill (eds). Genetic Research in Psychiatry, pp. 147165. Baltimore: Johns Hopkins Univ. Press.

Klein DF. 1974. Endogenomorphic depression: a conceptual and terminological revision. Arch Gen Psychiatry 31:447–454.

Klein DF. 1993. False suffocation alarm. Spontaneous panics, and related conditions: an integrative hypothesis. Arch Gen Psychiatry 50:306–317.

Kraepelin E. 1919. Dementia praecox and paraphrenia. Tr by RM Barclay from the 8th German ed. Edinburgh: Livingstone.

Nemeroff CB, Krishnan RR, Reed D, Leder R, Beam C, Dunnick R. 1992. Adrenal gland enlargement in major depression. Arch Gen Psychiatry 49:384–387. P.1226

Pletscher A, Shore PA, Brodie BB. 1956. Serotonin as a mediator of reserpine action in brain. J Pharmacol Exp Ther 116:84–89.

Sachar EJ, Asnis G, Halbreich U, Nathan RS, Halpern F. 1980. Recent studies in the neuroendocrinology of major depressive disorders. Psychiatr Clin North Am 3:313–326.

Schou M, Juel-Nielsen N, Strömgren E, Voldby H. 1954. The treatment of manic psychoses by the administration of lithium salts. J Neurol Neurosurg Psychiatry 17:250–260.

Styron W. 1990. Darkness Visible: A Memoir of Madness. New York: Random House.

Tallman JF, Gallagher DW. 1985. The GABA-ergic system: a locus of benzodiazepine action. Annu Rev Neurosci 8:21–44.

Van Praag HM. 1982. Neurotransmitters and CNS disease. Lancet 2:1259–1264.

Back

62 Learning and Memory Eric R. Kandel Irving Kupfermann Susan Iversen BEHAVIOR IS THE RESULT OF the interaction between genes and the environment. In earlier chapters we saw how genes influence behavior. We now examine how the environment influences behavior. In humans the most important mechanisms by which the environment alters behavior are learning and memory. Learning is the process by which we acquire knowledge about the world, while memory is the process by which that knowledge is encoded, stored, and later retrieved. Many important behaviors are learned. Indeed, we are who we are largely because of what we learn and what we remember. We learn the motor skills that allow us to master our environment, and we learn languages that enable us to communicate what we have learned, thereby transmitting cultures that can be maintained over generations. But not all learning is beneficial. Learning also produces dysfunctional behaviors, and these behaviors can, in the extreme, constitute psychological disorders. The study of learning therefore is central to understanding behavioral disorders as well as normal behavior, since what is learned can often be unlearned. When psychotherapy is successful in treating behavioral disorders, it often does so by creating an environment in which people can learn to change their patterns of behavior. As we have emphasized throughout this book, neural science and cognitive psychology have now found a common ground, and we are beginning to benefit from the increased explanatory power that results from the convergence of two initially disparate disciplines. The rewards of the merger between neural science and cognitive psychology are particularly evident in the study of learning and memory. In the study of learning and memory we are interested in several questions. What are the major forms of P.1228 learning? What types of information about the environment are learned most easily? Do different types of learning give rise to different memory processes? How is memory stored and retrieved? In this chapter we review the major biological principles of learning and memory that have emerged from clinical and cognitive/psychological approaches. In the next chapter we shall examine learning and memory processes at the cellular and molecular level.

Memory Can Be Classified as Implicit or Explicit on the Basis of How Information Is Stored and Recalled As early as 1861 Pierre Paul Broca had discovered that damage to the posterior portion of the left frontal lobe (Broca's area) produces a specific deficit in language (Chapter 1). Soon thereafter it became clear that other mental functions, such as perception and voluntary movement, can be related to the operation of discrete neural circuits in the brain. The successes of efforts to localize brain functions led to the question: Are there also discrete systems in the brain concerned with memory? If so, are all memory processes located in one region, or are they distributed throughout the brain? In contrast to the prevalent view about the localized operation of other cognitive functions, many students of learning doubted that memory functions could be localized. In fact, until the middle of the twentieth century many psychologists doubted that memory was a discrete function, independent of perception, language, or movement. One reason for the persistent doubt is that memory storage does indeed involve many different regions of the brain. We now appreciate, however, that these regions are not equally important. There are several fundamentally different types of memory storage, and certain regions of the brain are much more important for some types of storage than for others. The first person to obtain evidence that memory processes might be localized to specific regions of the human brain was the neurosurgeon Wilder Penfield. Penfield was a student of Charles Sherrington, the pioneering English neurophysiologist who, at the turn of the century, mapped the motor representation of anesthetized monkeys by systematically probing the cerebral cortex with electrodes and recording the activity of motor nerves. By the 1940s Penfield had begun to apply similar methods of electrical stimulation to map the motor, sensory, and language functions in the cerebral cortex of patients undergoing brain surgery for the relief of focal epilepsy. Since the brain itself does not have pain receptors, brain surgery is painless and can be carried out under local anesthesia in patients that are fully awake. Thus, patients undergoing brain surgery are able to describe what they experience in response to electrical stimuli applied to different cortical areas. On hearing about these experiments, Sherrington, who had always worked with monkeys and cats, told Penfield, “It must be great fun to put a question to the [experimental] preparation and have it answered!” Penfield explored the cortical surface in more than a thousand patients. On rare occasions he found that electrical stimulation of the temporal lobes produced what he called an experiential response —a coherent recollection of an earlier experience. These studies were provocative, but they did not convince the scientific community that the temporal lobe is critical for memory because all of the patients Penfield studied had epileptic seizure foci in the temporal lobe, and the sites most effective in eliciting experiential responses were near those foci. Thus the responses might have been the result of localized seizure activity. Furthermore, the responses occurred in only 8% of all attempts at stimulating the temporal lobes. More convincing evidence that the temporal lobes are important in memory emerged in the mid 1950s from the study of patients who had undergone bilateral removal of the hippocampus and neighboring regions in the temporal lobe as treatment for epilepsy. The first and best-studied case of the effects on memory of bilateral removal of portions of the temporal lobes was the patient called H.M., studied by Brenda Milner, a colleague of Penfield and the surgeon William Scoville. H.M., a 27-year-old man, had suffered for over 10 years from untreatable bilateral temporal lobe seizures as a consequence of brain damage sustained at age 9 when he was hit and knocked over by someone riding a bicycle. As an adult he was unable to work or lead a normal life. At surgery the hippocampal formation, the amygdala, and parts of the multimodal association area of the temporal cortex were removed bilaterally (Figure 62-1). H.M.'s seizures were much better controlled after surgery, but the removal of the medial temporal lobes left him with a devastating memory deficit. This memory deficit (or amnesia) was quite specific. H.M. still had normal short-term memory, over seconds or minutes. Moreover, he had a perfectly good longterm memory for events that had occurred before the operation. He remembered his name and the job he held, and he vividly remembered childhood events, although he showed some evidence of a retrograde amnesia for information acquired in the years just before surgery. He retained a perfectly good command of language, including his normally varied vocabulary, and his IQ remained unchanged in the range of bright-normal.

Figure 62-1 The medial temporal lobe and memory storage. A. The longitudinal extent of the temporal lobe lesion in the patient known as H.M. in a ventral view of the brain. B. Cross sections showing the estimated extent of surgical removal of areas of the brain in the patient H.M. Surgery was a bilateral, single-stage procedure. The right side is shown here intact to illustrate the structures that were removed. (Modified from Milner 1966.) C. Magnetic resonance image (MRI) scan of a parasagittal section from the left side of H.M.'s brain. The calibration bar on the right side of the panel has 1 cm increments. The resected portion of the anterior temporal lobes is indicated with an asterisk. The remaining portion of the intraventricular portion of the hippocampal formation is indicated with an open arrow. Approximately 2 cm of preserved hippocampal formation is visible bilaterally. Note also the substantial cerebellar degeneration obvious as enlarged folial spaces. (From Corkin et al. 1997.)

P.1229 What H.M. now lacked, and lacked dramatically, was the ability to transfer new short-term memory into long-term memory. He was unable to retain for more than a minute information about people, places, or objects. Asked to remember a number such as 8414317, H.M. could repeat it immediately for many minutes, because of his good short-term memory. But when distracted, even briefly, he forgot the number. Thus, H.M. could not recognize people he met after surgery, even when he met them again and again. For example, for several years he saw Milner on an almost monthly basis, yet each time she entered the room H.M. reacted as though he had never seen her before. H.M. had a similarly profound difficulty with spatial orientation. It took him about a year to learn his way around a new house. H.M. is not unique. All patients with extensive bilateral lesions of the limbic association areas of the medial temporal lobe, from either surgery or disease, show similar memory deficits.

The Distinction Between Explicit and Implicit Memory Was First Revealed With Lesions of the Limbic Association Areas of the Temporal Lobe Milner originally thought that the memory deficit after bilateral medial temporal lobe lesions affects all forms of memory equally. But this proved not to be so. Even though patients with lesions of the medial temporal lobe have profound memory deficits, they are able to learn certain types of tasks and retain this learning for as long as normal subjects. The spared component of P.1230 memory was first revealed when Milner discovered that H.M. could learn new motor skills at a normal rate. For example, he learned to draw the outlines of a star while looking at his hand and the star in a mirror (Figure 62-2). Like normal subjects learning this task, H.M. initially made many mistakes, but after several days of training his performance was error-free and indistinguishable from that of normal subjects.

Figure 62-2 The patient H.M. showed definite improvement in any task involving learning skilled movements. He was taught to trace between two outlines of a star while viewing his hand in a mirror. He improved considerably with each fresh test, although he had no recollection that he had ever done the task before. The graph plots the number of times, in each trial, that he strayed outside the outlines as he drew the star. (From Blakemore 1977.)

Later work by Larry Squire and others has made it clear that the memory capacities of H.M. and other patients with bilateral medial temporal lobe lesions are not limited to motor skills. Rather, these patients are capable of various forms of simple reflexive learning, including habituation, sensitization, classical conditioning, and operant conditioning, which we discuss later in this chapter. Furthermore, they are able to improve their performance on certain perceptual tasks. For example, they do well with a form of memory called priming, in which the recall of words or objects is improved by prior exposure to the words or object. Thus, when shown the first few letters of previously studied words, a subject with amnesia correctly selects as many previously presented words as do normal subjects, even though the subject has no conscious memory of having seen the word before (Figure 62-3) The memory capability that is spared in patients with bilateral lesions of the temporal lobe typically involves learned tasks that have two things in common. First, the tasks tend to be reflexive rather than reflective in nature and involve habits and motor or perceptual skills. Second, they do not require conscious awareness or complex cognitive processes, such as comparison and evaluation. The patient need only respond to a stimulus or cue, and need not try to remember anything. Thus, when given a highly complex mechanical puzzle to solve the patient may learn it as quickly and as well as a normal person, but will not consciously remember having worked on it previously. When asked why the performance of a task is much better after several days of practice than on the first day, the patient may respond, “What are you talking about? I've never done this task before.” Although these two fundamentally different forms of memory—for skills and for knowledge—have been demonstrated in detail in amnesia patients with lesions of the temporal lobe, they are not unique amnesiacs. Cognitive psychologists had previously distinguished these two types of memory in normal subjects. They refer to information about how to perform something as implicit memory (also referred to as nondeclarative memory), a memory that is recalled unconsciously. Implicit memory is typically involved in training reflexive motor or perceptual skills. Factual knowledge of people, places, and things, and what these facts mean, is referred to as explicit memory (or declarative memory). This is recalled by a deliberate, conscious effort (Figure 62-4). Explicit memory is highly flexible and involves the association of multiple bits and pieces of information. In contrast, implicit memory is more rigid and tightly connected to the original stimulus conditions under which the learning occurred The psychologist Endel Tulving first developed the idea that explicit memory can be further classified as episodic (a memory for events and personal experience) or semantic (a memory for facts). We use episodic memory when we recall that we saw the first flowers of spring yesterday or that we heard Beethoven's Moonlight Sonata P.1231 several months ago. We use semantic memory to store and recall objective knowledge, the kind of knowledge we learn in school and from books. Nevertheless, all explicit memories can be concisely expressed in declarative statements, such as “Last summer I visited my grandmother at her country house” (episodic knowledge) or “Lead is heavier than water” (semantic knowledge).

Figure 62-3 In a study of recall of words, amnesiacs and normal control subjects were tested under two conditions. First they were presented with common words and then asked to recall the words (free recall). Amnesiac patients were impaired in this condition. However, when subjects were given the first three letters of a word and instructed simply to form the first word that came to mind (completion), the amnesiacs performed as well as normal subjects. The baseline guessing rate in the word completion condition was 9%. (From Squire 1987.)

Figure 62-4 Various forms of memory can be classified as either explicit (declarative) or implicit (nondeclarative).

Animal Studies Help to Understand Memory The surgical lesion of H.M.'s temporal lobe encompassed a number of regions, including the temporal pole, the ventral and medial temporal cortex, the amygdala, and the hippocampal formation (which includes the hippocampus proper, the subiculum, and the dentate gyrus) as well as the surrounding entorhinal, perirhinal, and parahippocampal cortices. Since lesions restricted to any one of these several sectors of the medial temporal lobe are rare in humans, experimental lesion studies in monkeys have helped define the contribution of the different parts of the temporal lobe to memory formation. Mortimer Mishkin and Squire produced lesions in monkeys identical to those reported for H.M. and found defects in explicit memory for places and objects similar to those observed in H.M. Damage to the amygdala alone had no effect on explicit memory. Although the amygdala stores components of memory concerned with emotion (Chapter 50), it does not store factual information. In contrast, selective damage to the hippocampus or the polymodal association areas in the temporal cortex with which the hippocampus connects—the perirhinal and parahippocampal cortices—produces clear impairment of explicit memory. Thus, studies with human patients and with experimental animals suggest that knowledge stored as explicit memory is first acquired through processing in one or more of the three polymodal association cortices (the prefrontal, limbic, and parieto-occipital-temporal cortices) that synthesize visual, auditory, and somatic information. From there the information is conveyed in series to the parahippocampal and perirhinal cortices, P.1232 then the entorhinal cortex, the dentate gyrus, the hippocampus, the subiculum, and finally back to the entorhinal cortex. From the entorhinal cortex the information is sent back to the parahippocampal and perirhinal cortices and finally back to the polymodal association areas of the neocortex (Figure 62-5).

Figure 62-5 The anatomical organization of the hippocampal formation. A. The key components of the medial temporal lobe important for memory storage can be seen in the medial (left) and ventral (right) surface of the cerebral hemisphere. B. The input and output pathways of the hippocampal formation.

Thus, in processing information for explicit memory storage the entorhinal cortex has dual functions. First, it is the main input to the hippocampus. The entorhinal cortex projects to the dentate gyrus via the perforant pathway and by this means provides the critical input pathway through which the polymodal information from the association cortices reaches the hippocampus (Figure 62-5B). Second, the entorhinal cortex is also the major output of the hippocampus. The information coming to the hippocampus from the polymodal association cortices and that coming from the hippocampus to the association cortices converge in the entorhinal cortex. It is therefore understandable why the memory impairments associated with damage to the entorhinal cortex are particularly severe and why this damage affects not simply one but all sensory modalities. In fact, the earliest pathological changes in Alzheimer disease, the major degenerative disease that affects explicit memory storage, occurs in the entorhinal cortex. P.1233

Damage Restricted to Specific Subregions of the Hippocampus Is Sufficient to Impair Explicit Memory Storage Given the large size of the hippocampus proper, how extensive does a bilateral lesion have to be to interfere with explicit memory storage? Clinical evidence from several patients, as well as studies in experimental animals, suggests that a lesion restricted to any of the major components of the system can have a significant effect on memory storage. For example Squire, David Amaral, and their collegues found that the patient R.B. had only one detectable lesion after a cardiac arrest—a destruction of the pyramidal cells in the CA1 region of the hippocampus. Nevertheless, R.B. had a defect in explicit memory that was qualitatively similar to that of H.M., although quantitatively it was much milder. The different regions of the medial temporal lobe may, however, not have equivalent roles. Although the hippocampus is important for object recognition, for example, other areas in the medial temporal lobe may be even more important. Damage to the perirhinal, parahippocampal, and entorhinal cortices that spares the underlying hippocampus produces a greater deficit in memory storage, such as object recognition than do selective lesions of the hippocampus that spare the overlying cortex On the other hand, the hippocampus may be relatively more important for spatial representation. In mice and rats lesions of the hippocampus interfere with memory for space and context, and single cells in the hippocampus encode specific spatial information (Chapter 63). Moreover, functional imaging of the brain of normal human subjects shows that spatial memories involve more intense hippocampal activity in the right hemisphere than do memories for words, objects, or people, while the latter involve greater activity in the hippocampus in the dominant left hemisphere. These physiological findings are consistent with the finding that lesions of the right hippocampus give rise to problems with spatial orientation, whereas lesions of the left hippocampus give rise to defects in verbal memory (Figure 62-6).

Explicit Memory Is Stored in Association Cortices Lesions of the medial temporal lobe in patients such as H.M. and R.B. interfere only with the long-term storage of new memories. These patients retain a reasonably good memory of earlier events, although with severe lesions such as those of H.M. there appears to be some retrograde amnesia for the years just before the operation. How does this come about? The fact that patients with amnesia are able to remember their childhood, the lives they have led, and the factual knowledge they acquired before damage to the hippocampus suggests that the hippocampus is only a temporary way station for long-term memory. If so, long-term storage of episodic and semantic knowledge would occur in the unimodal or multimodal association areas of the cerebral cortex that initially process the sensory information For example, when you look at someone's face, the sensory information is processed in a series of areas of the cerebral cortex devoted to visual information, including the unimodal visual association area in the inferotemporal cortex specifically concerned with face recognition (see Box 28-1 and Chapter 28). At the same time, this visual information is also conveyed through the mesotemporal association cortex to the parahippocampal, perirhinal, and entorhinal cortices, and from there through the perforant pathway to the hippocampus. The hippocampus and the rest of the medial temporal lobe may then act, over a period of days or weeks, to facilitate storage of the information about the face initially processed by the visual association area of the inferotemporal lobe. The cells in the visual association cortex concerned with faces are interconnected with other regions that are thought to store additional knowledge about the person whose face is seen, and these connections could also be modulated by the hippocampus. Thus the hippocampus might also serve to bind together the various components of a richly processed memory of a person. Viewed in this way the hippocampal system would mediate the initial steps of long-term storage. It would then slowly transfer information into the neocortical storage system. The relatively slow addition of information to the neocortex would permit new data to be stored in a way that does not disrupt existing information. If the association areas are the ultimate repositories for explicit memory, then damage to association cortex should destroy or impair recall of explicit knowledge that is acquired before the damage. This is in fact what happens. Patients with lesions in association areas have difficulty in recognizing faces, objects, and places in their familiar world. Indeed, lesions in different association areas give rise to specific defects in either semantic or episodic memory.

Semantic (Factual) Knowledge Is Stored in a Distributed Fashion in the Neocortex As we have seen, semantic memory is that type of long-term memory that embraces knowledge of objects, facts, and concepts as well as words and their

meaning. It includes the naming of objects, the definitions of spoken words, and verbal fluency.

Figure 62-6 The role of the hippocampus in memory. We spend much of our time actively moving around our environment. This requires that we have a representation in our brain of the external environment, a representation that can be used to find our way around. The right hippocampus seems to be importantly involved in this representation, whereas the left hippocampus is concerned with verbal memory. A. The right hippocampus is activated during learning about the environment. These scans were made while subjects watched a film that depicted navigation through the streets of an Irish town. The activity during this task was compared with that in the control task where the camera was static and people and cars came by it. In the latter case there was no learning of spatial relationships and the hippocampus was not activated. Areas with significant changes in activity, indexed by local perfusion change, are indicated in yellow and orange. The scan on the left is a coronal section and the scan on the right is a transaxial section; in each panel the front of the brain is on the right and the occipital lobe on the left. (From Maguire et al. 1996.) B. The right hippocampus also is activated during the recall by licensed taxi drivers of routes around the city of London. These people spend a long time learning the intricacies of the road network in the city and are able to describe the shortest routes between landmarks as well as the names of the various streets. The right parahippocampal and hippocampal regions are significantly activated when they do this task. The scan on the left is a coronal section and the scan on the right is a transaxial section; in each panel the front of the brain is on the right and the occipital lobe on the left. Areas with significant changes in activity, indexed by local perfusion change, are depicted in yellow and orange. (From Maguire et al. 1996.) C. Three anatomical slices in the coronal (left upper), transverse (right upper), and sagittal (right lower) planes show activation (red) in the left hippocampus associated with the successful retrieval of words from long lists that have to be memorized. A = anterior, P = posterior, I = inferior.

P.1234

How is semantic knowledge built up? How is it stored in the cortex? The organization and flexibility of semantic knowledge is both remarkable and surprising. Consider a complex visual image such as a photograph of an elephant. Through experience this visual image becomes associated with other forms of knowledge about elephants, so that eventually when we close our eyes and conjure up the image of an elephant, the image is based on a rich representation of the concept of an elephant. The more associations we have made to the P.1235 image of the elephant, the better we encode that image, and the better we can recall the features of an elephant at a future time. Furthermore, these associations fall into different categories. For example, we commonly know that an elephant is a living rather than a nonliving thing, that it is an animal rather than a plant, that it lives in a particular environment, and that it has unique physical features and behavior patterns and emits a distinctive set of sounds. Moreover, we know that elephants are used by humans to perform certain tasks and that they have a specific name. The word elephant is associated with all of these pieces of information, and any one bit of information can open access to all of our knowledge about elephants.

Figure 62-7 Selective lesions in the posterior parietal cortex produce selective defects in semantic knowledge. (From Farah 1994.) A. A patient with associative agnosia is able to accurately copy drawings of a tea bag, ring, and pen but is unable to name the objects copied. B. A patient with apperceptive agnosia is unable to reproduce even simple drawings but nevertheless can name the objects in the drawings.

As this example illustrates, we build up semantic knowledge through associations over time. The ability P.1236 to recall and use knowledge—our cognitive efficiency —is thought to depend on how well these associations have organized the information we retain. As we first saw in Chapter 1, when we recall a concept it comes to mind in one smooth and continuous operation. However, studies of patients with damage to the association cortices have shown that different representations of an object—say, different aspects of elephants—are stored separately. These studies have made clear that our experience of knowledge as a seamless, orderly, and cross-referenced database is the product of integration of multiple representations in the brain at many distinct anatomical sites, each concerned with only one aspect of the concept that came to mind. Thus, there is no general semantic memory store; semantic knowledge is not stored in a single region. Rather, each time knowledge about anything is recalled, the recall is built up from distinct bits of

information, each of which is stored in specialized (dedicated) memory stores. As a result, damage to a specific cortical area can lead to loss of specific information and therefore a fragmentation of knowledge.

Figure 62-8 Neural correlates of category-specific knowledge are dependent on the intrinsic properties of the objects. (From Martin et al. 1996.) A. Regions selectively activated when subjects silently named drawings of animals include the calcarine sulcus, the left and right fusiform gyri of the temporal lobe, left putamen, left thalamus, left insula and inferior frontal region (Broca's area), and right lateral and medial cerebellum. Active regions are identified by increased blood flow. In the statistical procedure regions that are active during the naming of both animals and tools cancel each other and do not show a signal. In this panel and in part B the top pair of brain images are medial views, the lower pair are lateral views. SPM = statistical parametric maps. B. Regions selectively activated when subjects silently named tools are predominantly in areas of the left hemisphere associated with hand movements and the generation of action words.

For example, damage to the posterior parietal cortex can result in associative visual agnosia; patients cannot name objects but they can identify objects by selecting the correct drawing and can faithfully reproduce detailed drawings of the object (Figure 62-7). In contrast, damage to the occipital lobes and surrounding region can result in an apperceptive visual agnosia; patients are unable to draw objects but they can name them if appropriate perceptual cues are available (Figure 62-7). While verbal and visual knowledge about objects involve different circuitry, visual knowledge involves even further specialization. For example, visual knowledge about faces and about inanimate objects is represented in different cortical areas. As we have seen in Chapter 25, lesions in the inferotemporal cortex can result in P.1237 prosopagnosia, the inability to recognize familiar faces or learn new faces, but these lesions can leave intact all other aspects of visual recognition. Conversely, positron emission tomography (PET) imaging studies show that object recognition activates the left occipitotemporal cortex and not the areas in the right hemisphere associated with face recognition. Thus, not all of our visual knowledge is represented in the same locus in the occipitotemporal cortex. Category-specific defects in object recognition were first described by Rosaleen McCarthy and Elizabeth Warrington. They found that certain lesions interfere with the memory (knowledge) of living objects but not with memory of inanimate, manufactured objects. For example, one patient's verbal knowledge of living things was greatly impaired. When asked to define “rhinoceros” the patient responded by merely saying “animal.” But when shown a picture of a rhinoceros he responded, “enormous, weighs over a ton, lives in Africa.” The same patient's semantic knowledge of inanimate things was readily accessible through both verbal and visual cues. For example, when asked to define “wheelbarrow” he replied, “The thing we have here in the garden for carrying bits and pieces; wheelbarrows are used by people doing maintenance here on your buildings. They can put their cement and all sorts of things in it to carry it around.” To investigate further the neural correlates of categoryspecific knowledge for animate and inanimate objects, Leslie Ungerleider and her colleagues used PET scanning to map regions of the normal brain that are associated with naming animals and regions that are involved in naming of tools. They found that naming of animals and tools both involved bilateral activation of the ventral temporal lobes and Broca's area. In addition the naming animals selectively activated the left medial temporal lobe, a region involved in the earlier stages of visual processing. In contrast, the naming tools selectively activated a left premotor area, an area also activated with hand movements, as well as an area in the left middle temporal gyrus that is activated when action words are spoken. Thus, the brain regions active during object identification are dependent in part on the intrinsic properties of the objects presented (Figure 62-8).

Episodic (Autobiographical) Knowledge About Time and Place Seems to Involve the Prefrontal Cortex Whereas some lesions to multimodal association areas interfere with semantic knowledge, others interfere with the capacity to recall any episodic event experienced more than a few minutes previously, including dramatic personal events such as accidents and deaths in the family that occurred before the trauma. Remarkably, patients with loss of episodic memory still have the ability to recall vast stores of factual (semantic) knowledge. One patient could remember all personal facts about his friends and famous people, such as their names and their characteristics, but could not remember any specific events involving these individuals. The areas of the neocortex that seem to be specialized for long-term storage of episodic knowledge are the association areas of the frontal lobes. These prefrontal areas work with other areas of the neocortex to allow recollection of when and where a past event occurred (Chapter 19). A particularly striking symptom in patients with frontal lobe damage is their tendency to forget how information was acquired, a deficit called source amnesia. Since the ability to associate a piece of information with the time and place it was acquired is at the core of how accurately we remember the individual episodes of our lives, a deficit in source information interferes dramatically with the accuracy of recall of episodic knowledge.

Explicit Knowledge Involves at Least Four Distinct Processes We have learned three important things about episodic and semantic knowledge. First, there is not a single, all-purpose memory store. Second, any item of knowledge has multiple representations in the brain, each of which corresponds to a different meaning and can be accessed independently (by visual, verbal, or other sensory clues). Third, both semantic and episodic knowledge are the result of at least four related but distinct types of processing: encoding, consolidation, storage, and retrieval (Figure 62-9). Encoding refers to the processes by which newly learned information is attended to and processed when first encountered. The extent and nature of this encoding are critically important for determining how well the learned material will be remembered at later times. For a memory to persist and be well remembered, the incoming information must be encoded thoroughly and deeply. This is accomplished by attending to the information and associating it meaningfully and systematically with knowledge that is already well established in memory so as to allow one to integrate the new information with what one already knows. Memory storage is stronger when one is well motivated. Consolidation refers to those processes that alter the newly stored and still labile information so as to make it more stable for long-term storage. As we shall learn in the next chapter, consolidation involves the expression of genes and the synthesis of new proteins, giving rise to P.1238 structural changes that store memory stably over time.

Figure 62-9 Encoding and retrieving episodic memories. Areas where brain activity is significantly increased during the performance of specific memory tasks are shown in orange and red on surface projections of the human brain (left hemisphere on the right, right hemisphere on the left). A. Activity in the left prefrontal cortex is particularly associated with the encoding process. Subjects were scanned while attempting to memorize words paired with category labels: country—Denmark, metal—platinum, etc. B. Activity in the right frontal cortex is associated with retrieval. Four subjects were presented with a list of category labels and examples that were not paired with the category. The subjects were then scanned when attempting to recall the examples. In addition to right frontal activation a second posterior region in the medial parietal lobe (the precuneus) is also activated.

Storage refers to the mechanism and sites by which memory is retained over time. One of the remarkable features about long-term storage is that it seems to have an almost unlimited capacity. In contrast, short-term working memory is very limited.

Finally, retrieval refers to those processes that permit the recall and use of the stored information. Retrieval involves bringing different kinds of information together that are stored separately in different storage sites. Retrieval of memory is much like perception; it is a constructive process and therefore subject to distortion, much as perception is subject to illusions (Box 62-1). Retrieval of information is most effective when it occurs in the same context in which the information was acquired and in the presence of the same cues (retrieval cues) that were available to the subject during learning. Retrieval, particularly of explicit memories, is critically dependent on short-term working memory, a form of memory to which we now turn.

Working Memory Is a Short-Term Memory Required for Both the Encoding and Recall of Explicit Knowledge How is explicit memory recalled and brought to consciousness? How do we put it to work? Both the initial encoding and the ultimate recall of explicit knowledge (and perhaps some forms of implicit knowledge as well) are thought to require recruitment of stored information P.1239 into a special short-term memory store called working memory. As we learned in Chapter 19, working memory is thought to have three component systems.

Box 62-1 The Transformation of Explicit Memories How accurate is explicit memory? This question was explored by the psychologist Frederic Bartlett in one series of studies in which the subjects were asked to read stories and then retell them. The recalled stories were shorter and more coherent than the original stories, reflecting reconstruction and condensation of the original. The subjects were unaware that they were editing the original stories and often felt more certain about the edited parts than about the unedited parts of the retold story. The subjects were not confabulating; they were merely interpreting the original material so that it made sense on recall. Observations such as these lead us to believe that explicit memory, at least episodic (autobiographical) memory, is a constructive process like sensory perception. The information stored as explicit memory is the product of processing by our perceptual apparatus. As we saw in earlier chapters, sensory perception itself is not a faithful record of the external world but a constructive process in which incoming information is put together according to rules inherent in the brain's afferent pathways. It is also constructive in the sense that individuals interpret the external environment from the standpoint of a specific point in space as well as from the standpoint of a specific point in their own history. As discussed in Chapter 25, optical illusions nicely illustrate the difference between perception and the world as it is. Moreover, once information is stored, later recall is not an exact copy of the information originally stored. Past experiences are used in the present as clues that help the brain reconstruct a past event. During recall we use a variety of cognitive strategies, including comparison, inferences, shrewd guesses, and suppositions, to generate a consistent and coherent memory.

An attentional control system (or central executive), thought to be located in the prefrontal cortex (Chapter 19), actively focuses perception on specific events in the environment. The attentional control system has a very limited capacity (less than a dozen items). The attentional control system regulates the information flow to two rehearsal systems that are thought to maintain memory for temporary use: the articulatory loop for language and the visuospatial sketch pad for vision and action. The articulatory loop is a storage system with a rapidly decaying memory trace where memory for words and numbers can be maintained by subvocal speech. It is this system that allows one to hold in mind, through repetition, a new telephone number as one prepares to dial it. The visuospatial sketch pad represents both the visual properties and the spatial location of objects to be remembered. This system allows one to store the image of the face of a person one meets at a cocktail party. The information processed in either one of these rehearsal, working memory systems has the possibility of entering long-term memory. The two rehearsal systems are thought to be located in different parts of the posterior association cortices. Thus, lesions of the extrastriate cortex impair rehearsal of visual imagery whereas lesions in the parietal cortex impair rehearsal of spatial imagery.

Implicit Memory Is Stored in Perceptual, Motor, and Emotional Circuits Unlike explicit memory, implicit memory does not depend directly on conscious processes nor does recall require a conscious search of memory. This type of memory builds up slowly, through repetition over many trials, and is expressed primarily in performance, not in words. Examples of implicit memory include perceptual and motor skills and the learning of certain types of procedures and rules. Different forms of implicit memory are acquired through different forms of learning and involve different brain regions. For example, memory acquired through fear conditioning, which has an emotional component, is thought to involve the amygdala. Memory acquired through operant conditioning requires the striatum and cerebellum. Memory acquired through classical conditioning, sensitization, and habituation—three simple forms of learning we shall consider later—involves charges in the sensory and motor systems involved in the learning. P.1240 Implicit memory can be studied in a variety of perceptual or reflex systems in either vertebrates or invertebrates. Indeed, simple invertebrates provide useful models for studying the neural mechanisms of implicit learning.

Implicit Memory Can Be Nonassociative or Associative Psychologists often study implicit forms of memory by exposing animals to controlled sensory experiences. Two major procedures (or paradigms) have emerged from such studies, and these have identified two major subclasses of implicit memory: nonassociative and associative. In nonassociative learning the subject learns about the properties of a single stimulus. In associative learning the subject learns about the relationship between two stimuli or between a stimulus and a behavior. Nonassociative learning results when an animal or a person is exposed once or repeatedly to a single type of stimulus. Two forms of nonassociative learning are common in everyday life: habituation and sensitization. Habituation is a decrease in response to a benign stimulus when that stimulus is presented repeatedly. For example, most people are startled when they first hear the sound of a firecracker on the Fourth of July, Independence Day in the United States, but as the celebration progresses they gradually become accustomed to the noise. Sensitization (or pseudoconditioning) is an enhanced response to a wide variety of stimuli after the presentation of an intense or noxious stimulus. For example, an animal responds more vigorously to a mild tactile stimulus after it has received a painful pinch. Moreover, a sensitizing stimulus can override the effects of habituation, a process called dishabituation. For example, after the startle response to a noise has been reduced by habituation, one can restore the intensity of response to the noise by delivering a strong pinch. Sensitization and dishabituation are not dependent on the relative timing of the intense and the weak stimulus; no association between the two stimuli is needed. Not all forms of nonassociative learning are as simple as habituation or sensitization. For example, imitation learning, a key factor in the acquisition of language, has no obvious associational element.

Two forms of associative learning have also been distinguished based on the experimental procedures used to establish the learning. Classical conditioning involves learning a relationship between two stimuli, whereas operant conditioning involves learning a relationship between the organism's behavior and the consequences of that behavior.

Classical Conditioning Involves Associating Two Stimuli Since Aristotle, Western philosophers have traditionally thought that learning is achieved through the association of ideas. This concept was systematically developed by John Locke and the British empiricist school of philosophy, important forerunners of modern psychology. Classical conditioning was introduced into the study of learning at the turn of the century by the Russian physiologist Ivan Pavlov. Pavlov recognized that learning frequently consists of becoming responsive to a stimulus that originally was ineffective. By changing the appearance, timing, or number of stimuli in a tightly controlled stimulus environment and observing the changes in selected simple reflexes, Pavlov established a procedure from which reasonable inferences could be made about the relationship between changes in behavior (learning) and the environment (stimuli). According to Pavlov, what animals and humans learn when they associate ideas can be examined in its most elementary form by studying the association of stimuli. The essence of classical conditioning is the pairing of two stimuli. The conditioned stimulus (CS), such as a light, tone, or tactile stimulus, is chosen because it produces either no overt response or a weak response usually unrelated to the response that eventually will be learned. The reinforcement, or unconditioned stimulus (US), such as food or a shock to the leg, is chosen because it normally produces a strong, consistent, overt response (the unconditioned response), such as salivation or withdrawal of the leg. Unconditioned responses are innate; they are produced without learning. When a CS is followed by a US, the CS will begin to elicit a new or different response called the conditioned response. If the US is rewarding (food or water), the conditioning is termed appetitive; if the US is noxious (an electrical shock), the conditioning is termed defensive. One way of interpreting conditioning is that repeated pairing of the CS and US causes the CS to become an anticipatory signal for the US. With sufficient experience an animal will respond to the CS as if it were anticipating the US. For example, if a light is followed repeatedly by the presentation of meat, eventually the sight of the light itself will make the animal salivate. Thus, classical conditioning is a means by which an animal learns to predict events in the environment.

Figure 62-10 The capacity for a conditioned stimulus (CS) to produce a classically conditioned response is not a function of the number of times the CS is paired with an unconditioned stimulus (US) but rather the degree to which the CS and US are correlated. In this experiment on rats all animals were presented with a repeated tone (the CS) paired with an electric shock (the US) in 40% of the trials (blue vertical lines). Sometimes the shock was also presented when the tone was not present (red vertical lines). The percentage of these uncorrelated trials varied for different groups. A. An experiment in which the US occurred only with the CS. B-C. Examples in which the US was sometimes presented without the CS, either as often as the times the CS and US were paired (40%) or half as often (20%). After conditioning under the various circumstances, the degree of conditioning was evaluated by determining how effective the tone was in suppressing lever pressing to obtain food. Suppression of lever pressing is a sign of a conditioned emotional freezing response. The graph shows that in all three conditions the CS-US pairing was always 40%, but the percentage of US presentation with the absence of the CS pairing varied from 0% to 20% or 40%. When the shock occurred without the tone as often as with the tone (40%), little or no conditioning was evident. Some conditioning occurred when the shock occurred 20% of the time without the tone, and maximal conditioning occurred when the shock never occurred without the tone. (Adapted from Rescorla 1968.)

P.1241 The intensity or probability of occurrence of a conditioned response decreases if the CS is repeatedly presented without the US (Figure 62-10). This process is known as extinction. If a light that has been paired with food is then repeatedly presented in the absence of food, it will gradually cease to evoke salivation. Extinction is an important adaptive mechanism; it would be maladaptive for an animal to continue to respond to cues in the environment that are no longer significant. The available evidence indicates that extinction is not the same as forgetting, but that instead something new is learned. Moreover, what is learned is not simply that the CS no longer precedes the US, but that the CS now signals that the US will not occur. For many years psychologists thought that classical conditioning required only contiguity, that the CS precede the US by a critical minimum time interval. According to this view, each time a CS is followed by a reinforcing stimulus or US an internal connection is strengthened between the internal representation of the stimulus and the response or between one stimulus and another. The strength of the connection was thought to depend on the number of pairings of CS and US. This theory proved inadequate, however. A substantial body of empirical evidence now indicates that classical conditioning cannot be adequately explained simply by the temporal contiguity of events (Figure 62-10). Indeed, it would be maladaptive to depend solely on temporal contiguity. If animals learned to predict one type of event simply because it repeatedly occurred with another, they might often associate events in the environment that had no utility or advantage. All animals capable of associative conditioning, from snails to humans, seem to associate events in their environment by detecting actual contingencies rather than simply responding to the contiguity of events. Why P.1242

is this faculty in humans similar to that in much simpler animals? One good reason is that all animals face common problems of adaptation and survival. Learning provides a successful solution to this problem, and once a successful biological solution has evolved it continues to be selected. Classical conditioning, and perhaps all forms of associative learning, may have evolved to enable animals to distinguish events that reliably and predictably occur together from those that are only randomly associated. In other words, the brain seems to have evolved mechanisms that can detect causal relationships in the environment, as indicated by positively correlated or associated events. What environmental conditions might have shaped or maintained such a common learning mechanism in a wide variety of species? All animals must be able to recognize prey and avoid predators; they must search out food that is edible and nutritious and avoid food that is poisonous. Either the appropriate information can be genetically programmed into the animal's nervous system (as described in Chapter 3), or it can be acquired through learning. Genetic and developmental programming may provide the basis for the behaviors of simple organisms such as bacteria, but more complex organisms such as vertebrates must be capable of flexible learning to cope efficiently with varied or novel situations. Because of the complexity of the sensory information they process, higherorder animals must establish some degree of regularity in their interaction with the world. An effective means of doing this is to be able to detect causal or predictive relationships between stimuli, or between behavior and stimuli.

Operant Conditioning Involves Associating a Specific Behavior With a Reinforcing Event A second major paradigm of associational learning, discovered by Edgar Thorndike and systematically studied by B. F. Skinner and others, is operant conditioning (also called trial-and-error learning). In a typical laboratory example of operant conditioning an investigator places a hungry rat or pigeon in a test chamber in which the animal is rewarded for a specific action. For example, the chamber may have a lever protruding from one wall. Because of previous learning as well as innate response tendencies and random activity, the animal will occasionally press the lever. If the animal promptly receives a positive reinforcer (eg, food) when it presses the level, it will subsequently press the lever more often than the spontaneous rate. The animal can be described as having learned that among its many behaviors (for example, grooming, rearing, and walking) one behavior (lever-pressing) is followed by food. With this information the animal is likely to take the appropriate action whenever it is hungry. If we think of classical conditioning as the formation of a predictive relationship between two stimuli (the CS and the US), operant conditioning can be considered as the formation of a predictive relationship between a stimulus (eg, food) and a behavior (eg, lever pressing). Unlike classical conditioning, which tests the responsiveness of specific reflex responses to selected stimuli, operant conditioning involves behaviors that occur either spontaneously or without an identifiable stimulus. Operant behaviors are said to be emitted rather than elicited; when a behavior produces favorable changes in the environment (when it is rewarded or leads to the removal of noxious stimuli) the animal tends to repeat the behavior. In general, behaviors that are rewarded tend to be repeated, whereas behaviors followed by aversive, though not necessarily painful, consequences (punishment or negative reinforcement) are usually not repeated. Many experimental psychologists feel that this simple idea, called the law of effect, governs much voluntary behavior. Because operant and classical conditioning involve different kinds of association—classical conditioning involves learning an association between two stimuli whereas operant conditioning involves learning the association between a behavior and a reward—one might suppose the two forms of learning are mediated by different neural mechanisms. However, the laws of operant and classical conditioning are quite similar, suggesting that the two forms of learning may use the same neural mechanisms. For example, timing is critical in both forms of conditioning. In operant conditioning the reinforcer usually must closely follow the operant behavior. If the reinforcer is delayed too long, only weak conditioning occurs. The optimal interval between behavior and reinforcement depends on the specific task and the species. Similarly, classical conditioning is generally poor if the interval between the conditioned and unconditioned stimuli is too long or if the unconditioned stimulus precedes the conditioned stimulus. In addition, predictive relationships are equally important in both types of learning. In classical conditioning the subject learns that a certain stimulus predicts a subsequent event; in operant conditioning the animal learns to predict the consequences of a behavior.

Associative Learning Is Not Random But Is Constrained by the Biology of the Organism For many years it was thought that associative learning could be induced simply by pairing any two arbitrarily chosen stimuli or any response and reinforcer. More recent P.1243 studies have shown that associative learning is constrained by important biological factors. As we have seen, animals generally learn to associate stimuli that are relevant to their survival. This feature of associative learning illustrates nicely a principle we encountered in the earlier chapters on perception. The brain is not a tabula rasa; it is capable of perceiving some stimuli and not others. As a result, it can discriminate some relations between things in the environment and not others. Thus, not all reinforcers are equally effective with all stimuli or all responses. For example, animals learn to avoid certain foods (called bait shyness, because animals in their natural environment learn to avoid bait foods that contain poisons). If a distinctive taste stimulus (eg, vanilla) is followed by a negative reinforcement (eg, nausea produced by a poison), an animal will quickly develop a strong aversion to the taste. Unlike most other forms of conditioning, food aversion develops even when the unconditioned response (poison-induced nausea) occurs after a long delay (up to hours) after the CS (specific taste). This makes biological sense, since the ill effects of naturally occurring toxins usually follow ingestion only after some delay. For most species, including humans, food-aversion conditioning occurs only when taste stimuli are associated with subsequent illness, such as nausea and malaise. Food aversion develops poorly, or not at all, if the taste is followed by a nociceptive, or painful, stimulus that does not produce nausea. Conversely, an animal will not develop an aversion to a distinctive visual or auditory stimulus that has been paired with nausea. Evolutionary pressures have predisposed the brains of different species to associate certain stimuli, or a certain stimulus and a behavior, much more readily than others. Genetic and experiential factors can also modify the effectiveness of a reinforcer in one species. The results obtained with a particular class of reinforcer vary enormously among species and among individuals within a species, particularly in humans Food aversion may be a means by which humans ordinarily learn to regulate their diets to avoid the unpleasant consequences of inappropriate food. It may also be induced in special circumstances, as in the malaise associated with certain forms of cancer chemotherapy. Aversive conditioning to foods in the ordinary diet of patients might account in part for the depressed appetite of many patients who have cancer. The nausea that follows chemotherapy for cancer can produce aversion to foods that were tasted shortly before the treatment.

Certain Forms of Implicit Memory Involve the Cerebellum and Amygdala Lesions in several regions of the brain that are important for implicit types of learning affect simple classically conditioned responses. The best-studied case is classical conditioning of the protective eyeblink reflex in rabbits, a specific form of motor learning. A conditioned eyeblink can be established by pairing an auditory stimulus with a puff of air to the eye, which causes an eyeblink. Richard Thompson and his colleagues found that the conditioned response (eyeblink in response to a tone) can be abolished by a lesion at either of two sites. Damage to the vermis of the cerebellum, even a region as small as 2 mm2 abolishes the conditioned response, but does not affect the unconditioned response (eyeblink in response to a puff of air). Interestingly, neurons in the same area of the cerebellum show learning-dependent increases in activity that closely parallel the development of the conditioned behavior. Second, a lesion in the interpositus nucleus, a deep cerebellar nucleus, also abolishes the conditioned eyeblink. Thus, both the vermis and the deep nuclei of the cerebellum play an important role in conditioning the eyeblink, and perhaps other simple forms of classical conditioning involving skeletal muscle movement.

Maseo Ito and his colleagues have shown that the cerebellum is involved in another form of implicit memory. The vestibulo-ocular reflex keeps the visual image fixed by moving the eyes when the head moves (Chapter 41). The speed of movement of the eyes in relation to that of the head (the gain of the reflex) is not fixed but can be modified by experience. For example, when one first wears magnifying spectacles, eye movements evoked by the vestibulo-ocular reflex are not large enough to prevent the image from moving across the retina. With experience, however, the gain of the reflex gradually increases and the eye can again track the image accurately. As with eyeblink conditioning, the learned changes in the vestibulo-ocular reflex require not only the cerebellum (the flocculus) but also one of the deep cerebellar nuclei (the vestibular) in the brain stem (see Chapters 41 and 42). Finally, as we have seen in Chapter 50, lesions of the amygdala impair conditioned fear.

Some Learned Behaviors Involve Both Implicit and Explicit Forms of Memory Classical conditioning, we have seen, is effective in associating an unconscious reflexive response with a particular stimulus and thus typically involves implicit forms of memory. However, even this simple form of learning may also involve explicit memory, so that the learned response is mediated at least in part by cognitive processes. Consider the following experiment. A subject lays her hand, palm down, on an electrified grill; P.1244 a light (the CS) is turned on and at the same time she receives an electrical shock on one finger—she lifts her hand immediately (unconditioned response). After several light-shock conditioning trials she lifts her hand when the light alone is presented. The subject has been conditioned; but what exactly has been conditioned?

Figure 62-11 Recent memories are more susceptible than older memories to disruption by electroconvulsive treatment (ECT). The plot shows the responses of a group of patients who were tested on their ability to recall the names of television programs that were on the air during a single year between 1957 and 1972. Testing was done before and after the patients received ECT for treatment of depression. After ECT the patients showed a significant (but transitory) loss of memory for recent programs (1-2 years old) but not for older programs. (Adapted from Squire et al. 1975.)

It appears that the light is triggering a specific pattern of muscle activity (a reflex) that lifts the hand. However, what if the subject now places her hand on the grill, palm up, and the light is presented? If a specific reflex has been conditioned the light should produce a response that moves the hand into the grill. But if the subject has acquired information that the light means “grill shock,” her response should be consistent with that information. In fact, the subject often will make an adaptive response and move her hand away from the grill. Therefore, the subject did not simply learn to apply a fixed response to a stimulus, but rather acquired information that the brain could use in shaping an appropriate response in a novel situation. As this example makes clear, learning usually has elements of both implicit and explicit learning. For instance, learning to drive an automobile involves conscious execution of specific sequences of motor acts necessary to control the car; with experience, however, driving becomes an automatic and nonconscious motor activity. Similarly, with repeated exposure to a fact (semantic learning), recall of the fact with appropriate clues can eventually become virtually instantaneous—we no longer consciously and deliberately search our memory for it.

Both Explicit and Implicit Memory Are Stored in Stages It has long been known that a person who has been knocked unconscious selectively loses memory for events that occurred before the blow (retrograde amnesia). This phenomenon has been documented thoroughly in animal studies using such traumatic agents as electroconvulsive shock, physical trauma to the brain, and drugs that depress neuronal activity or inhibit protein synthesis in the brain. Brain trauma in humans can produce particularly profound amnesia for events that occur within a few hours or, at most, days before the trauma. In such cases older memories remain relatively undisturbed. The extent of retrograde amnesia, however, varies among patients, from several seconds to several years, depending on the nature and strength of the learning and the nature and severity of the disrupting event. Studies of memory retention and disruption of memory have supported a commonly used model of memory storage by stages. Input to the brain is processed into short-term working memory before it is transformed through one or more stages into a more permanent long-term store. A search-and-retrieval system surveys the memory store and makes information available for specific tasks. According to this model, memory can be impaired at several points. For example, there can be a loss of the contents of a memory store; as we have seen (Chapter 58), in Alzheimer's disease there actually is a loss of nerve cells in the entorhinal cortex. Alternatively, the search-and-retrieval mechanism may be disrupted by head trauma. This latter conclusion is supported by the observation that trauma sometimes only temporarily disrupts memory, since considerable memory for past events gradually returns. If stored memory were completely lost, it obviously could not be recovered. Studies of memory loss in patients undergoing electroconvulsive therapy (ECT) for depression have confirmed and extended the findings from animal experiments. Patients were examined using a memory test that could reliably quantify the degree of memory for relatively recent events (1-2 years old), old events (3-9 years old), and very old events (9-16 years old). The patients P.1245 were asked to identify, by voluntary recall, the names of television programs broadcast during a single year between 1957 and 1972. The patients were tested before ECT and then again afterward (with a different set of television programs). Both before and after ECT recall of the programs was more correct for more recent years. After ECT, however, the patients showed a significant but transitory loss of memory for more recent programs, while their recall of older programs remained essentially the same as it was before ECT (Figure 62-11). One interpretation of these findings is that until memories have been converted to a long-term form, retrieval (recall) of recent memories is easily disrupted.

Once converted to a long-term form, however, the memories are relatively stable. With time, however, both the long-term memory and the capacity to retrieve it gradually diminish, even in the absence of external trauma. Because of this susceptibility to disruption, the total set of retrievable memories changes continually with time. Several experiments studying the effects of drugs on learning support the idea that memory is time-dependent and subject to modification when it is first formed. For example, subconvulsant doses of excitant drugs, such as strychnine, can improve the retention of learning of animals even when the drug is administered after the training trials. If the drug is given to the animal soon after training, retention of learning on the following day is greater. The drug has no effect, however, when given after a long delay (several hours) after training. In contrast, inhibitors of protein synthesis selectively block the formation of longterm memory but not short-term memory when given during the training procedure.

An Overall View The neurobiological study of memory has yielded three generalizations: memory has stages, long-term memory is represented in multiple regions throughout the nervous system, and explicit and implicit memories involve different neuronal circuits. Different types of memory processes involve different regions and combinations of regions in the brain. Explicit memory underlies the learning of facts and experiences—knowledge that is flexible can be recalled by conscious effort and can be reported verbally. Implicit memory processes include forms of perceptual and motor memory—knowledge that is stimulus-bound, is expressed in the performance of tasks without conscious effort, and is not easily expressed verbally. Implicit memory flows automatically in the doing of things, while explicit memory must be retrieved deliberately. Long-term storage of explicit memory requires the temporal lobe system. Implicit memory involves the cerebellum and amygdala and the specific sensory and motor systems recruited for the task being learned. Moreover, the memory processes for many types of learning involve several brain structures. For example, learned changes of the vestibulo-ocular reflex appear to involve at least two different sites in the brain, and explicit learning involves neocortical structures as well as the hippocampal formation. Furthermore, there are reasons to believe that information is represented at multiple sites even within one brain structure. This parallel processing may explain in part why a limited lesion often does not eliminate a specific memory, even a simple implicit memory. Another important factor that may account for the failure of small lesions to adversely affect a specific memory may reside in the very nature of learning. As we shall see in the next chapter, memory involves both functional and structural changes at synapses in the circuits participating in a learning task. Although such changes are likely to occur only in particular types of neurons, the complex nature of many tasks makes it likely that these neurons are widely distributed within the pathways that mediate the response. Therefore some components of the stored information (ie, some of the synaptic changes) could remain undisturbed by a small lesion. Furthermore, the brain can take even the limited store of remaining information and construct a good representation of the original, just as the brain normally constructs conscious memory.

Selected Readings Corkin S, Amaral DG, González RG, Johnson KA, Hyman BT. 1997. H.M.'s medial temporal lobe lesion: findings from magnetic resonance imaging. J Neurosci 17:3964–3979.

Kamin LJ. 1969. Predictability, surprise, attention, and conditioning. In: BA Campbell and RM Church (eds). Punishment and Aversive Behavior, pp. 279296. New York: Appleton-Century-Crofts. P.1246

Maguire EA, Frackowiak RS, Frith CD. 1996. Learning to find your way: a role for the human hippocampal formation. Proc R Soc London B 263:1745–1750.

McClelland JL, McNaughton BL, O'Reilly RC. 1995. Why there are complementary learning systems in the hippocampus and neocortex: insights from the successes and failures of connectionist models of learning and memory. Psych Rev 3:419–457.

Milner B. 1966. Amnesia following operation on the temporal lobes. In: CWM Whitty and OL Zangwill (eds). Amnesia, pp. 109-133. London: Butterworths.

Milner B, Squire LR, Kandel ER. 1998. Cognitive neuroscience and the study of memory. Neuron 20:445–468.

Muller R. 1996. A quarter of a century of place cells. Neuron 17:813–822.

Schwartz B, Robbins SJ. 1994. Psychology of Learning and Behavior. 4th ed. New York: Norton.

Schacter D. 1996. Searching For Memory. The Brain, the Mind and the Past. New York: Harper Collins/Basic Books.

Squire LR, Kandel ER. 1999. Memory: From Mind to Molecules. New York: Freeman.

Squire LR, Zola-Morgan S. 1991. The medial temporal lobe memory system. Science 253:1380–1386.

Steinmetz JE, Lavond DG, Ivkovich D, Logan CG, Thompson RF. 1992. Disruption of classical eyelid conditioning after cerebellar lesions: damage to a memory trace system or a simple performance deficit? J Neurosci 12:4403–4426.

References Bartlett FC. 1932. Remembering: a Study in Experimental and Social Psychology. Cambridge, England: The University Press.

Blakemore C. 1977. Mechanics of the Mind. Cambridge, MA: Cambridge Univ. Press.

Domjan M, Burkhard B. 1986. The Principles of Learning and Behavior, 2nd ed. Monterey, CA: Brooks/Cole.

Drachman DA, Arbit J. 1966. Memory and the hippocampal complex II. Is memory a multiple process? Arch Neurol 15:52–61.

du Lac S, Raymond JL, Sejnowski TJ, Lisberger SG. 1995. Learning and memory in the vestibulo-ocular reflex. Annu Rev Neurosci 18:409–441.

Farah M. 1990. Visual Agnosia. Cambridge, MA: MIT Press.

Frackowiak RS. 1994. Functional mapping of verbal memory and language. Trends Neurosci 17:109–115.

Hebb DO. 1966. A Textbook of Psychology. Philadelphia: Saunders.

Martin A, Wiggs CL, Ungerleider LG, Haxby JV. 1996. Neural correlates of category-specific knowledge. Nature 379:649–652.

McCarthy, RA, Warrington EK. 1990. Cognitive Neuropsychology: A clinical Introduction. San Diego: Academic Press.

McClelland JL, McNaughton BL, O'Reilly RC. 1995. Why there are complementary learning systems in the hippocampus and neocortex: insights from the successes and failures of connectionist models of learning and memory. Psychol Rev 102:419–457.

McGaugh JL. 1990. Significance and remembrance: the role of neuromodulatory systems. Psychol Sci 1:15–25.

Pavlov IP. 1927. Conditioned Reflexes: Investigation of the Physiological Activity of the Cerebral Cortex. Anrep GV, trans. London: Oxford University Press.

Penfield W. 1958. Functional localization in temporal and deep sylvian areas. Res Publ Assoc Res Ment Dis 36:210–226.

Rescorla RA. 1968. Probability of shock in the presence and absence of CS in fear conditioning. J Comp Physiol Psychol 66:1–5.

Rescorla RA. 1988. Behavioral studies of Pavlovian conditioning. Annu Rev Neurosci 11:329–352.

Skinner BF. 1938. The Behavior of Organisms: An Experimental Analysis. New York: Appleton-Century-Crofts.

Squire LR. 1987. Memory and Brain. New York: Oxford University Press.

Squire LR, Slater PC, Chace PM. 1975. Retrograde amnesia: temporal gradient in very long term memory following electroconvulsive therapy. Science 187:77–79.

Thorndike EL. 1911. Animal Intelligence: Experimental Studies. New York: Macmillan.

Tulving E, Schacter DL. 1990. Priming and human memory systems. Science 247:301–306.

Warrington EK, Weiskrantz L. 1982. Amnesia: a disconnection syndrome? Neuropsychologia 20:233–248.

Back

63 Cellular Mechanisms of Learning and the Biological Basis of Individuality Eric R. Kandel THROUGHOUT THIS BOOK we have emphasized that all behavior is a function of the brain and that malfunctions of the brain give rise to characteristic disturbances of behavior. Behavior, in turn, is shaped by learning. How does learning act on the brain to change behavior? How is new information acquired and, once acquired, how is it retained? In the preceding chapter we saw that memory—the outcome of learning—is not a single process but has at least two forms. Implicit (declarative) memory is unconscious memory for perceptual and motor skills, whereas explicit (nondeclarative) memory is a memory for people, places, and objects that requires conscious recall. In this chapter we examine the cellular and molecular mechanisms that contribute to these two forms of memory by exploring the mechanisms that underlie simple implicit forms of memory storage in invertebrates and the more complex explicit forms in vertebrates. We shall see that the molecular mechanisms of memory storage are highly conserved throughout evolution, and that the more complex forms of learning and memory depend on many of the same molecular mechanisms used in the simplest forms. Finally, we shall consider the idea that these mechanisms contribute to individuality by changing the connectivity of neurons in our brains.

Figure 63-1 The cellular mechanisms of habituation have been investigated in the gill-withdrawal reflex of the marine snailAplysia. A. A dorsal view of Aplysia illustrates the respiratory organ (gill), which is normally covered by the mantle shelf. The mantle shelf ends in the siphon, a fleshy spout used to expel seawater and waste. A tactile stimulus to the siphon elicits the gill-withdrawal reflex. Repeated stimuli lead to habituation. B. This simplified circuit shows key elements involved in the gill-withdrawal reflex as well as sites involved in habituation. In this circuit about 24 mechanoreceptors in the abdominal ganglion innervate the siphon skin. These glutaminergic sensory cells form synapses with a cluster of six motor neurons that innervate the gill and with several groups of excitatory and inhibitory interneurons that synapse on the motor neurons. (For simplicity, only one of each type of neuron is illustrated here.) Repeated stimulation of the siphon leads to a depression of synaptic transmission between the sensory and motor neurons as well as between certain interneurons and the motor cells.

P.1248

Short-Term Storage of Implicit Memory for Simple Forms of Learning Results From Changes in the Effectiveness of Synaptic Transmission Much progress in the cellular study of memory storage has come from examining elementary forms of learning: habituation, sensitization, and classical conditioning. These cellular modifications have been analyzed in the behavior of simple invertebrates and in a variety of vertebrate reflexes, such as flexion reflexes, fear responses, and the eyeblink. Most simple forms of implicit learning change the effectiveness of the synaptic connections that make up the pathway mediating the behavior.

Habituation Involves an Activity-Dependent Presynaptic Depression of Synaptic Transmission In habituation, the simplest form of implicit learning, an animal learns about the properties of a novel stimulus that is harmless. An animal first responds to a new stimulus by attending to it with a series of orienting responses. If the stimulus is neither beneficial nor harmful, the animal learns, after repeated exposure, to ignore it. Habituation was first investigated by Ivan Pavlov and Charles Sherrington. While studying posture and locomotion, Sherrington observed a decrease in the intensity of certain reflexes, such as the withdrawal of a limb, in response to repeated stimulation. The reflex response returned only after many seconds of rest. He suggested that this decrease, which he called habituation, results from diminished synaptic effectiveness within the pathways to the motor neurons that had been repeatedly activated. This problem was later investigated at the cellular level by Alden Spencer and Richard Thompson. They found close cellular and behavioral parallels between habituation of the spinal flexion reflex in the cat and habituation of more complex behavioral responses in humans. They showed, through intracellular recordings from spinal motor neurons in cats, that habituation leads to a decrease in the strength of the synaptic connections between excitatory interneurons and motor neurons. The connections between the sensory neurons innervating the skin and the interneurons were unaffected. Since the organization of interneurons in the spinal cord of vertebrates is quite complex, further analysis of the cellular mechanisms of habituation in the flexion reflex proved difficult. Progress in this effort required a simpler system. The marine sea slug Aplysia californica, which has a simple nervous system containing only about 20,000 central nerve cells, is an excellent simple system for studying implicit forms of memory. Aplysia P.1249 has a repertory of defensive reflexes for withdrawing its gill and its siphon, a small fleshy spout above the gill used to expel seawater and waste (Figure 63-1A). These reflexes are similar to the leg withdrawal reflex studied by Spencer and Thompson. For example, a mild tactile stimulus delivered to the siphon elicits reflex withdrawal of both siphon and gill. With repeated stimulation these reflexes habituate. They can also be sensitized and classically conditioned, as we shall see later. Gill withdrawal in Aplysia has been studied in detail. In response to a novel tactile stimulus to the siphon, firing in the sensory neurons innervating the siphon generates excitatory synaptic potentials in interneurons and motor cells (Figure 63-1B). The synaptic potentials from the sensory neurons and interneurons summate both temporally and spatially to cause the motor cells to discharge repeatedly, leading to strong reflexive withdrawal of the gill. If the stimulus is repeated, the direct monosynaptic excitatory synaptic potentials produced by sensory neurons in both the interneurons and the motor cells become progressively smaller. Thus, with repeated stimulation, several of the excitatory interneurons also produce weaker synaptic potentials in the motor neurons, with the net result that the motor neuron fires much less briskly and consequently the reflex response diminishes. What reduces the effectiveness of synaptic transmission by the sensory neurons? Quantal analysis revealed that the decrease in synaptic strength results from a decrease in the number of transmitter vesicles released from presynaptic terminals of sensory neurons. These sensory neurons use glutamate as their transmitter. Glutamate interacts with two types of receptors in motor cells: one similar to the N -methyl-d-aspartate (NMDA) type of glutamate receptors of vertebrates and the other to a non-NMDA-type (Chapter 12). There is no change in the sensitivity of these receptors with habituation. How this decrease in transmitter release occurs is not yet understood; it is thought to be due in part to a reduced mobilization of transmitter vesicles to the active zone (see Chapter 14). This reduction lasts many minutes. These enduring plastic changes in the functional strength of synaptic connections thus constitute the cellular mechanisms mediating the short-term memory for habituation. Since these changes occur at several sites in the reflex circuit, memory in this instance is distributed and stored throughout the circuit, not at one specialized site. Synaptic depression of the connections made by sensory neurons, interneurons, or both is a common mechanism for habituation and explains habituation of the several well-studied escape responses of crayfish and cockroaches as well as startle reflexes of vertebrates.

Figure 63-2 Long-term habituation of the gill-withdrawal reflex in Aplysia is represented on the cellular level by a dramatic depression of synaptic effectiveness between the sensory and motor neurons. (Adapted from Castellucci et al. 1978.) A. Comparison of the synaptic potentials in a sensory and motor neuron in a control (untrained) animal and an animal that has been subjected to long-term habituation. In the habituated animal no synaptic potential is evident in the motor neuron one week after training. B. The mean percentage of physiologically detectable connections in habituated animals at three points in time after long-term habituation training.

The synaptic mechanisms underlying habituation can vary in two ways. First, the locus of the depression can be situated at any of several synaptic sites. For example, in the flexion reflex of the spinal cord there is no depression of synaptic transmission at the direct connections made by the sensory neurons on interneurons. P.1250 Rather, depression is thought to occur at downstream sites: at the synapses made by certain classes of interneurons on the motor neurons of the reflex. Second, mechanisms other than homosynaptic depression, such as enhancement of synaptic inhibition, can contribute to habituation. These studies illustrate that learning can lead to changes in synaptic strength and that the duration of the short-term memory storage is determined by the duration of the synaptic change. In turn, theses studies raise the question: How much can the effectiveness of a synapse change and how long can the change last? Whereas a single session of 10 tactile stimuli to the siphon leads to a short-term memory for habituation of the Aplysia gill-withdrawal reflex lasting minutes, four such sessions, separated by periods ranging from several hours to one day, produce a long-term memory that lasts for as long as three weeks! In naive Aplysia 90% of the sensory neurons make physiologically detectable connections onto identified gill motor neurons. In contrast, in animals trained for long-term habituation the number of such connections is reduced to 30%; this low incidence persists for a week and does not completely recover for three weeks after the training (Figure 63-2). As we shall see later, during this long-term inactivation of synaptic transmission the actual structure of the sensory neurons changes. Not all synapses are equally adaptable. The strength of some synapses in Aplysia rarely changes, even with repeated activation. However, at synapses specifically involved in learning and memory storage, such as the connections between sensory and motor neurons and some interneurons in the withdrawal-reflex circuit, a relatively small amount of training, especially if it is appropriately spaced over many minutes or hours, can produce large and enduring changes in synaptic strength. Massed training, whereby the habituating stimuli are given one after the other without rest between training sessions, produces a robust short-term memory but longterm memory is seriously compromised. This illustrates a general principle of learning psychology: Spaced training is usually much more effective than massed training in producing long-term memory.

Sensitization Involves Presynaptic Facilitation of Synaptic Transmission When an animal repeatedly encounters a harmless stimulus it learns to habituate to it. In contrast, with a harmful stimulus the animal typically learns to respond more vigorously not only to that stimulus but also to other stimuli, even harmless ones. Defensive reflexes for withdrawal and escape become heightened. This enhancement of reflex responses, called sensitization, is more complex than habituation: A stimulus applied to one pathway produces a change in the reflex strength in another pathway. Like habituation, sensitization has both a short-term and a long-term form. Thus, whereas a single shock to an animal's tail produces short-term sensitization that lasts minutes, five or more shocks to the tail produce sensitization lasting days to weeks. A noxious stimulus to the tail enhances synaptic transmission at several connections in the neural circuit of the gill-withdrawal reflex, including the connections made by sensory neurons with motor neurons and interneurons—the same synapses depressed by habituation. Thus a synapse can participate in more than one type of learning and store more than one type of memory. However, habituation and sensitization use different cellular mechanisms to produce synaptic change. Short-term habituation in Aplysia is a homosynaptic process; the decrease in synaptic strength is a direct result of activity in the sensory neurons and their central connections in the reflex pathway. In contrast, sensitization is a heterosynaptic process; the enhancement of P.1251 P.1252 synaptic strength is induced by modulatory interneurons activated by stimulation of the tail.

Figure 63-3 (Opposite) Short-term sensitization of the gill-withdrawal reflex inAplysia involves presynaptic facilitation. A. Sensitization of the gill is produced by applying a noxious stimulus to another part of the body, such as the tail. Stimuli to the tail activate sensory neurons in the tail that excite facilitating interneurons, which form synapses on the terminals of the sensory neurons innervating the siphon. At these axoaxonic synapses the facilitating interneurons enhance transmitter release from the sensory neurons (presynaptic facilitation). B. Presynaptic facilitation in the sensory neuron is thought to occur by means of three biochemical pathways. The transmitter released by the presynaptic interneuron, here serotonin (5-HT, hydroxytryptamine), binds to two receptors. One engages a G protein (Gs), which increases the activity of adenylyl cyclase. The adenylyl cyclase converts adenosine triphosphate (ATP) to cyclic adenosine monophosphate (cAMP), thereby increasing the level of cAMP in the terminal of the sensory neuron. The cAMP activates the cAMP-dependent protein kinase A (PKA) by attaching to its inhibitory regulatory subunit, thus releasing its active catalytic subunit. The catalytic subunit of PKA acts along three pathways. In pathway 1 the catalytic subunit phosphorylates K+ channels, thereby decreasing the K+ current. This prolongs the action potential and increases the influx of Ca2+, thus augmenting transmitter release. In pathway 2 vesicles containing transmitter are mobilized to the releasable transmitter pool at the active zone, and the efficiency of the exocytotic release machinery is also enhanced. In pathway 3 L-type Ca2+ channels are opened. Serotonin, acting through a second receptor, engages the G protein (Go) that activates a phospholipase C (PLC), which in turn stimulates intramembranous diacylglycerol to activate protein kinase C (PKC). Pathways 2-2a and 3-3a involve the joint action of PKA and PKC.

There are at least three groups of modulatory inter-neurons, the best studied of which release serotonin. The serotonergic and other modulatory interneurons form synapses on the sensory neurons, including axo-axonic synapses on their presynaptic terminals (Figure 63-3A). The serotonin and other modulatory transmitters released from the interneurons after a single shock to the tail bind to specific membrane-spanning receptors that activate the heterotrimeric GTP binding protein Gαs. The Gαs protein activates an adenylyl cyclase to produce the second messenger cyclic adenosine mono-phosphate (cAMP), which activates the cAMP-dependent protein kinase (PKA) (see the discussion of PKA in Chapter 13). PKA, together with protein kinase C, enhances release of transmitter from the sensory neurons' terminals for a period of minutes through the phosphorylation of several substrate proteins (Figure 63-3B). As we shall learn later, repeated sensitizing stimuli produce a strengthening of connections that lasts days.

Classical Conditioning Involves Presynaptic Facilitation of Synaptic Transmission That Is Dependent on Activity in Both the Presynaptic and the Postsynaptic Cell Classical conditioning is a more complex form of learning than sensitization. Rather than learning only about one stimulus, the organism learns to associate one type of stimulus with another. As we have learned in Chapter 62, an initially weak conditioned stimulus can become highly effective in producing a response when paired with a strong unconditioned stimulus. In reflexes that can be enhanced by both classical conditioning and sensitization, classical conditioning results in a greater and longerlasting enhancement. The siphon- and gill-withdrawal reflexes of Aplysia are examples of reflexes that can be enhanced by both classical conditioning and sensitization. The gill-withdrawal reflex can be elicited in one of two ways: by stimulating either the siphon or a nearby structure called the mantle shelf. The siphon and the mantle shelf are separately innervated by distinct populations of sensory neurons. Thus, each reflex pathway can be conditioned independently by pairing a conditioned stimulus to the appropriate area (either the siphon or the mantle shelf) with an unconditioned stimulus (a strong shock to the tail). After such paired or associative training, the response of the conditioned (or paired) pathway to stimulation is significantly enhanced compared to that of the unpaired pathway (Figure 63-4). In classical conditioning the timing of the conditioned and unconditioned stimuli is critical. The conditioned stimulus must precede the unconditioned stimulus, often within an interval of about 0.5 s. What cellular mechanisms are responsible for this requirement for temporal pairing of stimuli? In classical conditioning of the gillwithdrawal reflex of Aplysia one important feature is the timing of the convergence in individual sensory neurons of the conditioned stimulus (siphon touch) and the unconditioned stimulus (tail shock). As we have seen, an unconditioned stimulus to the tail activates facilitating interneurons that make axo-axonic connections with the presynaptic terminals of the sensory neurons that carry information from the siphon and the mantle shelf (Figure 63-4A). The resulting presynaptic facilitation ordinarily gives rise to behavioral sensitization. However, if the unconditioned stimulus (to the tail) and the conditioned stimulus (to the siphon or mantle shelf) are timed so that the conditioned stimulus just precedes the unconditioned stimulus, then the modulatory interneurons engaged by the unconditional stimulus will activate the sensory neurons immediately after the conditioned stimulus has activated the sensory neurons. This sequential activation of the sensory neurons during a critical interval by the CS and the US leads to greater presynaptic facilitation than when the two stimuli are not appropriately paired (Figure 63-4B). This novel feature unique to classical conditioning is called activity dependence.

There are presynaptic and postsynaptic components to activity-dependent facilitation. Activity in the conditioned stimulus pathway leads to Ca2+ influx into the presynaptic sensory neuron with each action potential, and this influx activates the Ca2+-binding protein calmodulin. The activated Ca2+/calmodulin binds to adenylyl cyclase, potentiating its response to serotonin and enhancing its production of cAMP. Thus, the presynaptic cellular mechanism of classical conditioning in the monosynaptic pathway of the withdrawal reflex in Aplysia is in part an elaboration of the mechanism of sensitization in this same pathway. This is because adenylyl cyclase acts as a coincidence detector. That is, it recognizes the molecular representation of both the conditioned stimulus (spike activity in the sensory neuron and the consequent Ca2+ influx) and the unconditioned stimulus (serotonin released by tail stimuli), and it responds both to the conditioned stimulus (binding to the Ca2+/ calmodulin activated by the Ca2+/influx following action potentials) and the unconditioned stimulus (binding to the Gαs activated by the binding of serotonin to a receptor). The postsynaptic component of classical conditioning is a retrograde signal to the sensory neuron. In the withdrawal reflex pathway in Aplysia the postsynaptic motor cell has two types of receptors to glutamate: nonNMDA and NMDA-type receptors. As we have learned in Chapter 11, the extracellular mouth of the NMDA-type P.1253 receptor-channel is plugged by Mg2+ at the resting membrane potential. Thus, under normal circumstances and during habituation and sensitization only the nonNMDA receptor is activated because the NMDA receptor is blocked by Mg2+. However, when the conditioned stimulus and unconditioned stimulus are paired appropriately during classical conditioning, the motor neuron fires a whole train of action potentials. The depolarization of the postsynaptic cell expels Mg2+ from the NMDA-type receptor-channel and Ca2+ flows into the cell. The Ca2+ influx is thought to activate signaling pathways in the motor cell that give rise to a retrograde messenger that is taken up in the presynaptic terminals of the sensory cell, where it acts to enhance transmitter release even further.

Figure 63-4 Classical conditioning of the gill-withdrawal reflex in Aplysia. A conditioned stimulus (CS) applied to the mantle shelf is paired with an unconditioned stimulus (US) applied to the tail. As a control, a CS applied to the siphon is not paired with the US. (Adapted from Hawkins et al. 1983.) A. A shock to the tail (US) excites facilitating interneurons that form synapses on the presynaptic terminals of sensory neurons innervating the mantle shelf and siphon. This is the mechanism of sensitization (A1). B. When the mantle pathway is activated by a CS just before the US, the action potentials in the mantle sensory neurons prime them so that they are more responsive to subsequent stimulation from the (serotonergic) facilitating interneurons in the US pathway. This is the mechanism of classical conditioning; it both amplifies the response of the CS pathway and restricts the amplification to that pathway (B1). Recordings of the excitatory postsynaptic potentials produced in an identified motor neuron by the mantle and siphon sensory neurons were made before training (Pre) and 1 hour after training (Post). After training the excitatory postsynaptic potential due to input from the mantle (paired) sensory neuron (B2) is considerably greater than the one due to the siphon (unpaired) neuron (A2). C. The experimental protocol for classical conditioning compares the responses of paired and unpaired stimuli mediated by siphon and mantle sensory neurons. In the mantle sensory neurons the action potentials produced by the CS are paired with those produced by the US (tail stimulus). In a siphon sensory neuron the action potentials produced by the CS are not paired with the same US.

Thus, three signals in a siphon sensory neuron must converge to produce the large increase in transmitter release that occurs with classical conditioning: (1) activation

of adenylyl cyclase by Ca2+ influx, representing the conditioned stimulus; (2) activation of serotonergic P.1254 receptors coupled to adenylyl cyclase, representing the unconditioned stimulus; and (3) a retrograde signal indicating that the postsynaptic cell has been adequately activated by the uncondtioned stimulus.

Long-Term Storage of Implicit Memory for Sensitization and Classical Conditioning Involves the cAMP-PKA-MAPK-CREB Pathway Molecular Biological Analysis of Long-Term Sensitization Reveals a Role for cAMP Signaling in LongTerm Memory As with habituation and most other forms of learning, practice makes perfect. Repeated experience consolidates memory by converting the short-term form into a longterm form. These physiological consequences of repeated training have been best studied for sensitization. In Aplysia a single training session (or a single application of serotonin to the sensory neurons) gives rise to short-term sensitization, lasting only minutes, that does not require new protein synthesis. However, five training sessions produce long-term sensitization, lasting several days, that requires new protein synthesis. Further spaced training produces sensitization that persists for weeks. These behavioral studies of Aplysia (and similar ones in vertebrates) suggest that short-term and long-term memory are two independent but overlapping processes that blend into one another. Several findings point to this interpretation. First, both short- and long-term memory for sensitization of the gill-withdrawal reflexes involve changes in the strength of connections at several synaptic sites, including the synaptic connections between sensory and motor neurons (Figure 63-5A). Second, in both the long-term and short-term processes the increase in the synaptic strength of the connections between the sensory and motor neurons is due to the enhanced release of transmitter. Third, the same transmitter (serotonin) released by stimulation of the tail produces short-term facilitation after a single exposure and long-term facilitation after five or more repeated exposures. Finally, cAMP and PKA, intracellular second-messenger pathways that are critically involved in short-term memory, are also recruited for long-term memory (Figure 63-5B). Despite these similarities, short- and long-term memory are distinct processes that can be distinguished by several criteria. In humans, epileptic seizure or head trauma affects long-term memory but not short-term memory. A similar dissociation between short- and long-term memory can be demonstrated in experimental animals using inhibitors of protein or mRNA synthesis to block long-term memory selectively. As we saw in the preceding chapter, the process by which transient short-term memory is converted into a stable long-term memory is called consolidation. Consolidation of long-term implicit memory for simple forms P.1255 P.1256 of learning involves three processes: gene expression, new protein synthesis, and the growth (or pruning) of synaptic connections.

Figure 63-5 (Facing page) Persistent synaptic enhancement with long-term sensitization. A. Long-term sensitization of the gill-withdrawal reflex of Aplysia involves facilitation of transmitter release at the connections between sensory and motor neurons. 1. The recordings show representative synaptic potentials in a siphon sensory neuron and a gill motor neuron in a control animal and in an animal that received longterm sensitization training by repeated stimulation of its tail. The record was obtained one day after the end of training. 2. The median amplitude of the post-synaptic potentials (PSP) in an identified gill motor neuron is greater in sensitized animals one day after training than in control animals. 3. The effect of sensitization on the neural circuit of the gill- and siphon-withdrawal reflex is measured here by the median duration of withdrawal of the siphon (see Figure 63-1). (Pre = score before training; post = score after training.) The experimental group was tested one day after the end of training. (Adapted from Frost et al. 1985.) B. Long-term sensitization of the gill-withdrawal reflex of Aplysia leads to two major changes in the sensory neurons of the reflex: persistent activity of protein kinase A and structural changes in the form of the growth of new synaptic connections. Both the short-term and long-term facilitation are initiated by a serotonergic interneuron. Short-term facilitation (lasting minutes to hours), resulting from a single tail shock or a single pulse of serotonin, leads to covalent modification of preexisting proteins (short-term pathway). As shown in Figure 63-3, serotonin acts on a postsynaptic receptor to activate the enzyme adenylyl cyclase, which converts ATP to the second messenger cAMP. In turn, cAMP activates the cAMP-dependent protein kinase A, which phosphorylates and covalently modifies a number of target proteins, leading to enhanced transmitter availability and release. The duration of these modifications is a measure of the short-term memory. Long-term facilitation (lasting one or more days) involves the synthesis of new proteins. The switch for this inductive mechanism is initiated by protein kinase A (PKA), which recruits the mitogen-activated kinase (MAPK) and together they translocate to the nucleus (long-term pathway), where PKA phosphorylates the cAMPresponse element binding (CREB) protein. The transcriptional activators bind to cAMP response elements (CRE) located in the upstream region of two types of cAMPinducible genes. To activate CREB-1, PKA needs also to remove the repressive action of CREB-2, which is capable of inhibiting the activation capability of CREB-1. PKA is thought to mediate the derepression of CREB-2 by means of another protein, MAPK. One gene activated by CREB encodes a ubiquitin hydrolase, a component of a specific ubiquitin protease that leads to the regulated proteolysis of the regulatory subunit of PKA. This cleavage of the (inhibitory) regulatory subunit results in persistent activity of PKA, leading to persistent phosphorylation of the substrate proteins of PKA, including both CREB-1 and the protein involved in the short-term process. The second gene activated by CREB encodes another transcription factor C/EBP. This binds to the DNA response element CAAT, which activates genes that encode proteins important for the growth of new synaptic connections.

Figure 63-6 Long-term habituation and sensitization in Aplysia involve structural changes in the presynaptic terminals of sensory neurons. (Adapted from Bailey and Chen 1983.) A. When measured 1 day or 1 week after training, the number of presynaptic terminals is highest in sensitized animals (about 2800) compared with control (1300) and habituated animals (800). B. Long-term habituation leads to a loss of synapses and long-term sensitization leads to an increase in synapses.

How do genes and proteins operate in the consolidation of long-term functional changes? Studies of long-term sensitization of the gill-withdrawal reflex indicate that with repeated application of serotonin the catalytic subunit of PKA recruits another second messenger kinase, the mitogen-activated protein (MAP) kinase, a kinase commonly associated with cellular growth. Together the two kinases translocate to the nucleus of the sensory neurons, where they activate a genetic switch (see the discussion of transcriptional regulation in Chapter 13). Specifically, the catalytic subunit phosphorylates and thereby activates a transcription factor called CREB-1 (c AMP r esponse e lement b inding protein). This transcriptional activator, when phosphorylated, binds to a promoter element called CRE (the c AMP r esponse e lement). By means of the MAP kinase the catalytic subunit of PKA also acts indirectly to relieve the inhibitory actions of CREB-2, a repressor of transcription. The presence of both a repressor (CREB-2) and an activator (CREB-1) of transcription at the very first step in long-term facilitation suggests that the threshold for putting information into long-term memory is highly regulated. Indeed, we can see in everyday life that the ease with which short-term memory is transferred into long-term memory varies greatly depending on attention, mood, and social context. In fact, when the repressive action of CREB-2 is relieved (by injecting, for example, a specific antibody to CREB-2), a single pulse of serotonin, which normally produces only short-term facilitation lasting minutes, is able to produce long-term facilitation, the cellular homolog of long-term memory. Under normal circumstances the physiological relief of the repressive action of CREB-2 and the activation of CREB-1 induce expression of downstream target genes, two of which are particularly important: (1) the enzyme ubiquitin carboxyterminal hydrolase, which activates proteasomes to make PKA persistently active, and (2) the transcription factor C/EBP, one of the components of a gene cascade necessary for the growth of new synaptic connections. The induction of the hydrolase is a key step in the recruitment of a regulated proteolytic P.1257 complex: the ubiquitin-dependent proteosome. As in other cellular contexts, ubiquitin-mediated proteolysis also produces a cellular change of state, here by removing inhibitory constraints on memory. One of the substrates of this proteolytic process is the regulatory subunit of PKA.

Figure 63-7 The three major afferent pathways in the hippocampus. (Arrows denote the direction of impulse flow.) The perforant fiber pathway from the entorhinal cortex forms excitatory connections with the granule cells of the dentate gyrus. The granule cells give rise to axons that form the mossy fiber pathway, which connects with the pyramidal cells in area CA3 of the hippocampus. The pyramidal cells of the CA3 region project to the pyramidal cells in CA1 by means of the Schaffer collateral pathway. Long-term potentiation (LTP) is nonassociative in the mossy fiber pathway and associative in the other two pathways.

PKA is made up of four subunits: two regulatory submits inhibit two catalytic subunits (Chapter 13). Long-term training and the induction of the hydrolase degrades about 25% of the regulatory (inhibitory) subunits in the sensory neurons. As a result, the catalytic subunits continue phosphorylating proteins important for enhancing transmitter release and strengthening the synaptic connections, including CREB-1, long after the second messenger, cAMP, has returned to its basal level (Figure 635B). This is the simplest mechanism for long-term memory: a second-messenger kinase critical for the short-term process is made persistently active for up to 24 hours by repeated training, without requiring a continuous signal of any sort. The kinase becomes autonomous and does not require either serotonin, cAMP, or PKA. The second and more enduring consequence of the activation of CREB-1 is a cascade of gene activation that leads to the growth of new synaptic connections. It is this growth process that provides the stable, self- maintained state of long-term memory. In Aplysia the number of presynaptic terminals in the sensory neurons of the gillwithdrawal pathway increases and becomes twice as great in the long term in sensitized animals as in untrained animals (Figure 63-6). This structural change is not limited to the sensory neurons. In animals that have been sensitized for the long term, the dendrites of the motor neurons grow to accommodate the additional synaptic input. Such morphological changes do not occur with short-term sensitization. Long-term habituation, in contrast, leads to pruning of synaptic connections. The long-term inactivation of the functional connections between sensory and motor neurons reduces the number of terminals for each neuron by one-third (Figure 636), and the proportion of terminals with active zones from 40% to 10%.

Genetic Analyses of Implicit Memory Storage for Classical Conditioning Also Implicate the cAMPPKA-CREB Pathway How general is the role of the cAMP-PKA-CREB pathway in long-term memory storage? Does it apply to other species and other types of learning? The fruit fly Drosophila is particularly amenable to genetic manipulation. As first shown by Seymour Benzer and his students, Drosophila can be classically conditioned, and four interesting mutations in single genes that lead to a learning deficit have been isolated: dunce, rutabaga, amnesiac, and PKA-R1. Studies of these mutants have given

rise to two general conclusions. First, all of the mutants that fail to show classical conditioning also fail to show sensitization. Second, all four mutants have a defect in the cAMP cascade. Dunce lacks phosphodiesterase, an enzyme that degrades cAMP. As a result, this mutant has abnormally high levels of cAMP that are thought to be beyond the range of normal modulation. Rutabaga is defective in the Ca2+/calmodulin-dependent adenylyl cyclase and therefore has a low basal level of cAMP. Amnesiac lacks a peptide transmitter that acts on adenylyl cyclase, and PKA-R1 is defective in PKA. More recently a reverse genetic approach has been used to explore memory storage in Drosophila. Various transgenes (see Chapter 3) are placed under the control P.1258 of an inducible promoter that is heat-sensitive, so that by heating and cooling the fly a particular gene can be turned on or off. This inducible control over gene expression, which we shall return to again later in the chapter, is useful for studying synaptic or behavioral plasticity in adult animals. It minimizes any potential effect that a transgene might produce on the development of the brain and therefore allows one to read out the selective effect of the gene on adult behavior.

Figure 63-8 Long-term potentiation (LTP) of the mossy fiber pathway to the CA3 region of the hippocampus. A. Experimental arrangement for studying LTP in the CA3 region of the hippocampus. Stimulating electrodes are placed so as to activate two independent pathways to the CA3 pyramidal cells: The commissural pathway from the CA3 region of the contralateral hippocampus and the ipsilateral mossy fiber pathway. B. Whole-cell voltage-clamp recording allows injection of both fluoride and the Ca2+ chelator BAPTA into the cell body of the CA3 neuron. Together these two drugs are thought to block all second-messenger pathways in the postsynaptic cell. Despite this drastic biochemical blockade of the postsynaptic cell, LTP in the mossy fiber pathway is unaffected and is therefore thought to be presynaptically induced. In contrast, these injections do block LTP in the commissural pathway. This pathway requires activation of the N -methyl-D- aspartate (NMDA) receptor, and here induction of LTP is postsynaptic. (Adapted from Zalutsky and Nicoll 1990).

The first such experiment involved inducing the expression of transgenes that blocked the catalytic subunit of PKA. William Quinn and his colleagues found that blocking the action of PKA, even transiently, interferes with the fly's ability to learn and to form short-term memory. A similar disruption of learning and memory was observed in a mutant of a Drosophila homolog of the PKA catalytic subunit. These experiments indicate the importance of the cAMP signal transduction pathway is critical for associative learning and short-term memory in Drosophila. Long-term memory after repeated training in Droso-phila also requires new protein synthesis. Drosophila expresses P.1259 both a CREB activator and a CREB-2 repressor. Jerry Yin, Tim Tully, and their colleagues found that overexpression of the repressor (CREB-2), which presumably prevents the expression of cAMP-activated genes, selectively blocks long-term memory without interfering with learning or short-term memory. Conversely, overexpression of the CREB activator results in immediate long-term memory, even with a training procedure that produces only short-term memory in wild-type flies.

Figure 63-9 Long-term potentiation (LTP) in the Schaffer collateral pathway to the CA1 region of the hippocampus. A. Experimental setup for studying LTP in the CA1 region of the hippocampus. The Schaffer collateral pathway is stimulated electrically and the response of the population of pyramidal neurons is recorded. B. Comparison of early and late LTP in a cell in the CA1 region of the hippocampus. The graph is a plot of the slope (rate of rise) of the excitatory postsynaptic potentials (EPSP) in the cell as a function of time. The slope is a measure of synaptic efficacy. Excitatory postsynaptic potentials were recorded from outside the cell. A test stimulus was given every 60 s to the Schaffer collaterals. To elicit early LTP a single train of stimuli is given for 1 s at 100 Hz. To elicit the late phase of LTP four trains are given separated by 10 min. The resulting early LTP lasts 2-3 hours, whereas the late LTP lasts 24 or more hours.

Explicit Memory in Mammals Involves Long-Term Potentiation in the Hippocampus What mechanisms are used to store explicit memory—information about people, places, and objects? One important component of the medial temporal system of higher vertebrates involved in the storage of explicit memory is the hippocampus (Chapter 62). As first shown by Per Andersen, the hippocampus has three major pathways: (1) the perforant pathway, which projects from the entorhinal cortex to the granule cells of the dentate gyrus; (2) the mossy fiber pathway, which contains the axons of the granule cells and runs to the pyramidal cells in the CA3 region of the hippocampus; and (3) the Schaffer collateral pathway, which consists of the excitatory collaterals of the pyramidal cells in the CA3 region and ends on the pyramidal cells in the CA1 region (Figure 63-7). In 1973 Timothy Bliss and Terje Lom•' discovered that each of these pathways is remarkably sensitive to the history of previous activity. A brief high-frequency train of stimuli (a tetanus) to any of the three major synaptic pathways increases the amplitude of the excitatory postsynaptic potentials in the target hippocampal neurons. This facilitation is called long-term potentiation (LTP). The mechanisms underlying LTP are not the same in all three pathways. LTP can be studied in the intact animal, where it can last for days and even weeks. It can also be examined in slices of hippocampus and in cell culture for several hours. We shall first consider the mossy fiber pathway. P.1260

Long-Term Potentiation in the Mossy Fiber Pathway Is Nonassociative The mossy fiber pathway consists of the axons of the granule cells of the dentate gyrus. The mossy fiber terminals release glutamate as a transmitter, which binds to both NMDA and non-NMDA receptors on the target pyramidal cells. However, in this pathway the NMDA receptors have only a minor role in synaptic plasticity under most conditions; blocking the NMDA receptors has no effect on LTP. Similarly, blocking Ca2+ influx into the postsynaptic pyramidal cells in the CA3 region does not affect LTP (Figure 63-8). Instead, LTP in the mossy fiber pathway region has been found to depend on Ca2+ influx into the presynaptic cell after the tetanus. The Ca2+ influx appears to activate Ca2+/calmodulin-dependent adenylyl cyclase thereby increasing the level of cAMP and activating PKA in the presynaptic neuron, just as in the sensory neurons of Aplysia during associative learning. Moreover, mossy fiber LTP can be regulated by a modulatory input. This input is noradrenergic and engages β-adrenergic receptors, which activate adenylyl cyclase, as does the serotonergic input in Aplysia.

Long-Term Potentiation in the Schaffer Collateral and Perforant Pathways Is Associative The Schaffer collateral pathway connects the pyramidal cells of the CA3 region of the hippocampus with those of the CA1 region (Chapter 5 and Figures 63-7 and 639A). Like the mossy fiber terminals, the terminals of the Schaffer collaterals also use glutamate as transmitter, but LTP in the Schaffer collateral pathway requires activation of the NMDA-type of glutamate receptor (Figures 63-9B and 63-10). Therefore, LTP in CA1 cells has two characteristic features that distinguish it from LTP in the mossy fiber pathway, both of which derive from the known properties of the NMDA receptor. First, LTP in the Schaffer collateral pathway typically requires activation of several afferent axons together, a feature called cooperativity. This feature derives from the fact that the NMDA receptor-channel becomes functional and conducts Ca2+ only when two conditions are met: Glutamate must bind to the postsynaptic NMDA receptor and the membrane potential of the postsynaptic cell must be sufficiently depolarized by the cooperative firing of several afferent axons to expel Mg2+ from the

mouth of the channel (Figure 63-10). Only when Mg2+ is expelled can Ca2+ influx into the postsynaptic cell occur. Calcium influx initiates the persistent enhancement of synaptic transmission by activating two calcium-dependent serine-threonine protein kinases—the Ca2+/calmodulin-dependent protein kinase and protein kinase C—as well as PKA and the tyrosine protein kinase fyn. Second, LTP in the Schaffer collateral pathway requires concomitant activity in both the presynaptic and postsynaptic cells to adequately depolarize the post-synaptic cell, a feature called associativity. As we have seen, to initiate the Ca2+ influx into the postsynaptic cell, a strong presynaptic input sufficient to fire the postsynaptic cell is required. The finding that LTP in the Schaffer collateral pathway requires simultaneous firing in both the postsynaptic and presynaptic neurons provides direct evidence for Hebb's rule, proposed in 1949 by the psychologist Donald Hebb: “When an axon of cell A… excites cell B and repeatedly or persistently takes part in firing it, some growth process or metabolic change takes place in one or both cells so that A's efficiency as one of the cells firing B is increased.” As discussed in Chapter 56, a similar principle is involved in fine-tuning synaptic connections during the late stages of development. The induction of LTP in the CA1 region of the hippocampus depends on four postsynaptic factors: postsynaptic depolarization, activation of NMDA receptors, influx of Ca2+, and activation by Ca2+ of several second-messenger systems in the postsynaptic cell. The mechanisms for the expression of this LTP, on the other hand, is still uncertain. It is thought to involve not only P.1261 P.1262 an increase in the sensitivity and number of the postsynaptic non-NMDA (AMPA) receptors to glutamate as a result of being phosphorylated by the Ca2+/calmodulindependent protein kinase, but also an increase in transmitter release from the presynaptic terminals of the CA3 neuron (Figure 63-11). Evidence for enhanced presynaptic function is based on two observations. First, biochemical studies suggest that the release of glutamate is enhanced during LTP. Second, as we shall see later, quantal analysis indicates that the probability of transmitter release increases greatly during LTP.

Figure 63-10 (Opposite) A model for the induction of the early phase of long-term potentiation. According to this model NMDA and non-NMDA receptorchannels are located near each other in dendritic spines. A. During normal, low-frequency synaptic transmission glutamate (Glu) is released from the presynaptic terminal and acts on both the NMDA and non-NMDA receptors. The non-NMDA receptors here are the AMPA type. Na+ and K+ flow through the non-NMDA channels but not through the NMDA channels, owing to Mg2+ blockage of this channel at the resting level of membrane potential. B. When the postsynaptic membrane is depolarized by the actions of the non-NMDA receptor-channels, as occurs during a high-frequency tetanus that induces LTP, the depolarization relieves the Mg2+ blockage of the NMDA channel. This allows Ca2+ to flow through the NMDA channel. The resulting rise in Ca2+ in the dendritic spine triggers calcium-dependent kinases (Ca2+/calmodulin kinase and protein kinase C) and the tyrosine kinase Fyn that together induce LTP. The Ca2+/calmodulin kinase phosphorylates non-NMDA receptor-channels and increases their sensitivity to glumate thereby also activating some otherwise silent receptor channels. These changes give rise to a postsynaptic contribution for the maintenance of LTP. In addition, once LTP is induced, the postsynaptic cell is thought to release (in ways that are still not understood) a set of retrograde messengers, one of which is thought to be nitric oxide, that act on protein kinases in the presynaptic terminal to initiate an enhancement of transmitter release that contributes to LTP.

Figure 63-11 Maintenance of the early phase of LTP in the CA1 region of the hippocampus depends on an increase in presynaptic transmitter release. Quantal analysis of LTP in area CA1 is based on a coefficient of variation of evoked responses. This analysis assumes that the number of quanta of transmitter released follows a binomial distribution, where the coefficient of variation (mean squared/variance) provides an index of transmitter release from the presynaptic terminal that is independent of quantal size. (From Malinow and Tsien 1990.) A. With LTP the ratio of mean squared to variance increases, indicating an increase in transmitter release. This increase occurs only in the pathway that is paired with depolarization of the postsynaptic cell. It does not occur in a control pathway that is not paired. B. At normal rates of stimulation the number of failures in transmission is significant (60%). After LTP the percentage of failures decreases to 20%, another indication that LTP is presynaptic.

Since induction of LTP requires events only in the postsynaptic cell (Ca2+ influx through NMDA channels), whereas expression of LTP is due in part to a subsequent event in the presynaptic cells (increase in transmitter release), the presynaptic cells must somehow receive information that LTP has been induced. There is now evidence that calcium-activated second messengers, or perhaps Ca2+ itself, causes the postsynaptic cell to release one or more retrograde messengers from its active dendritic spines. Recent pharmacological and genetic experiments have identified nitric oxide (NO), a gas that diffuses readily from cell to cell, as one of the possible candidate retrograde messengers involved in LTP. These studies of the Schaffer collateral pathway indicate that LTP in CA1 uses two associative mechanisms in series: a Hebbian mechanism (simultaneous firing in both the pre- and postsynaptic cells) and activity-dependent presynaptic facilitation. A similar set of mechanisms is responsible for LTP in the perforant pathway. As we saw earlier, two associative mechanisms in series also contribute to classical conditioning in Aplysia.

Long-Term Potentiation Has a Transient Early and a Consolidated Late Phase As with memory storage (Chapter 62), LTP has phases. One stimulus train produces an early, short-term phase of LTP (called early LTP) lasting 1-3 hours; this component does not require new protein synthesis. Four or more trains induce a more persistent phase of LTP (called late LTP) that lasts for at least 24 hours and requires new protein and RNA synthesis. As we have seen, the mechanisms for the early, short-term phase are quite different in the Schaffer collateral and mossy fiber

pathways. However, the mechanisms for the late, long-term phase in the two pathways appear similar. In both pathways late-phase LTP requires the synthesis of new mRNA and protein and recruits the cAMP-PKA-MAPK-CREB signaling pathway. What are the properties of this late phase of LTP? Does long-term explicit memory storage, like implicit P.1263 P.1264 memory storage, also require the growth of new synaptic connections? In fact, cellular-physiological studies are beginning to suggest that the late phase of LTP involves the activation, perhaps the growth, of additional presynaptic machinery for transmitter release and the insertion of new clusters of postsynaptic receptors.

Figure 63-12 The early and late phases of LTP are evident in the synaptic transmission between a single CA3 cell and a single CA1 cell. (From Bolshakov et al. 1997.) A. A single CA3 cell can be stimulated selectively to produce a single elementary synaptic potential in a CA1 cell. When the CA3 cell is stimulated repeatedly at low frequency, it gives rise to either an elementary response of the size of a miniature synaptic potential or a failure. B. In control cells there are many failures; the synapse has a low probability of releasing vesicles. The distribution of the amplitudes of many responses can be approximated by two Gaussian curves, one centered on zero (the failures) and the other centered on 4 pA (the successful responses). These histograms are consistent with the type of synapse illustrated here, in which a single CA3 cell makes a single connection on a CA1 cell. This connection has a single active zone from which it releases a single vesicle in an all-or-none manner (failures or successes). C. With the early phase of LTP the probability of release rises significantly, but the two Gaussian curves in the distribution of responses is consistent with the view that a single release site still releases only a vesicle but now with a high probability of release. D. When the late phase of LTP is induced by a cAMP analog (Sp-cAMPS), the distribution of responses no longer fits two Gaussian curves but instead requires three or four Gaussian curves, suggesting the possibility that new presynaptic active zones and postsynaptic receptors have grown. These effects are blocked by anisomycin, an inhibitor of protein synthesis.

Charles Stevens and his colleagues and Steven Siegelbaum and Vadim Bolshakov have now examined LTP by stimulating a single presynaptic CA3 neuron and recording from a single CA1 postsynaptic cell. When the CA3 neuron is stimulated repeatedly at a low rate, most of the time the CA1 cell fails to respond with a synaptic potential. Only on occasion does activity in the presynaptic neuron lead to a small response, about 4 pA in amplitude, in the postsynaptic cell (Figure 63-12A). This response is approximately the size of a single spontaneous miniature synaptic potential (Chapter 14). When many failures and unitary responses are collected and measured, the failures of release and the unitary responses can be described by two random (Gaussian) distributions, one centered at zero, corresponding to the failures of release, and the other centered around 4 pA, corresponding both to successful responses and to the size of spontaneously released miniature synaptic potentials (Figure 63-12B). These distributions lend themselves to a surprisingly clear anatomical explanation. They suggest that a single CA3 neuron makes only a single functional synaptic contact on a CA1 neuron. This single synaptic contact appears to have only one active zone from which the transmitter content of only a single vesicle is released, in an all-or-none way, by a presynaptic action potential. In the basal state (where there are many more failures than responses) the probability of release of the vesicle is low. Thus, this situation is not very different from other central synaptic connections where a single release site typically releases only a single vesicle in an all-or-none fashion (Chapter 15). What happens during the early phase of LTP? In the early phase the number of failures decreases and the number of successes increases, but the amplitude histograms of the responses and failures are still fit by two Gaussian distributions (corresponding to failures of release and successful responses). This indicates that the early phase of LTP produces no change in the number of synapses, the number of active zones, or the maximal number of vesicles released with each action potential (Figure 63-12C). Thus the early phase of LTP represents a functional change—an increase in the probability of transmitter release—without structural changes. An action potential still releases only one vesicle of transmitter from a single release site, but now it does so more reliably. An equivalent of the late-phase LTP can be induced chemically, by exposing the neurons to permeant cAMP. After the late phase of LTP begins the distribution of successful responses changes dramatically and can no longer be approximated by two Gaussian functions. The responses now are not simply zero and 4 pA but are 8, 12, and even 20 pA in amplitude, so that several Gaussian curves are required to describe the distribution of responses (Figure 63-12D). This change suggests that during the late phase of LTP a single action potential in a single CA3 cell releases several vesicles of transmitter onto the CA1 neuron. Since each release site is thought to release only one vesicle in an all-or-none fashion, such an increase in the number of vesicles released would seem to entail growth of new pre- synaptic release sites as well as new clusters of post-synaptic receptors. Consistent with this idea, and with the properties of the late phase of LTP, the generation of these new distributions requires new protein synthesis (Figure 63-13).

Genetic Interference With Long-Term Potentiation Is Reflected in the Properties of Place Cells in the Hippocampus LTP is an artificially induced change in synaptic strength produced by electrical stimulation of synaptic pathways. Does this form of synaptic plasticity exist naturally? If so, how does it affect the normal processing of information for memory storage in the hippocampus? In 1971 John O'Keefe and John Dostrovsky made the remarkable discovery that the hippocampus contains a cognitive map of the spatial environment in which an animal moves. The location of an animal in a particular space is encoded in the firing pattern of individual pyramidal cells, the very cells that undergo LTP when their afferent pathways are stimulated electrically. A mouse's hippocampus has about a million pyramidal cells. Each of these cells is potentially a place cell, encoding a position in space. When an animal moves around, different place cells in the hippocampus fire. For example, one cell will fire only when the animal's head enters a particular area in the north end of the space, while other cells will fire when the animal takes other positions at the south end of that space (Figure 63-14A,63-14B). Thus, the mouse's whereabouts are signaled by the discharge of a unique population of hippocampal place cells. By this means the animal is thought to form a “place field,” an internal representation of the space that it occupies. When the animal enters a new environment, new place fields are formed within minutes and are stable P.1265 P.1266 for weeks to months. The same pyramidal cells may signal different information in different environments and can therefore be used in more than one spatial map.

Figure 63-13 A model for the early and late phase of LTP. A single train of action potentials leads to early LTP by activating NMDA receptors, Ca2+ influx into the postsynaptic cell, and a set of second messengers. With repeated trains the Ca2+ influx also recruits an adenylyl cyclase, which activates the cAMP-dependent protein kinase (cAMP kinase) leading to its translocation to the nucleus, where it phosphorylates the CREB protein. CREB in turn activates targets that are thought to lead to structural changes. Mutations in mice that block PKA or CREB reduce or eliminate the late phase of LTP. The adenylyl cyclase can also be modulated by dopaminergic and perhaps other modulatory inputs. BDNF = brain-derived neurotrophic factor; C/EBPβ = transcription factor; P = phosphate; R(AB) dominant negative PKA; tPA tissue plasminogen activator.

Figure 63-14A The firing patterns of pyramidal cells in the hippocampus create an internal representation of the animal's location within its surrounding. A mouse is attached to a recording cable and placed inside a cylinder (49 cm in diameter by 34 cm high). The other end of the cable goes to a 25channel commutator attached to a computer-based spike-discrimination system. The cable is also used to supply power to a light-emitting diode mounted on the headstage the mouse carries. The entire apparatus is viewed with an overhead TV camera whose output goes to a tracking device that detects the position of the mouse. The output of the tracker is sent to the same computer used to detect spikes, so that parallel time series of positions and spikes are recorded. The occurrence of spikes as a function of position is extracted from the basic data and is used to form two-dimensional firing-rate patterns that can be numerically analyzed or visualized as color-coded firing-rate maps. (Based on Muller et al. 1987.)

The rapid formation of place fields and their persistence for weeks offer an excellent opportunity to ask, How are place fields formed and maintained? Is LTP important for the formation or maintenance of place fields? To address these questions two types of mutations have been examined in mice, each of which interferes with LTP in a different way. One mutation was produced by Joe Tsien, Susumu Tonegawa, and their colleagues by selectively knocking out NMDA R1, one of the subunits of the NMDA receptor, in the pyramidal cells of the CA1 region. This restricted knockout, limited to just the CA1 region, disrupts LTP in the Schaffer collateral pathway completely (Box 63-1). In the other mutation, produced by Mark Mayford and his colleagues, a persistently active form of the Ca2+/calmodulin-dependent kinase is expressed throughout the hippocampus. This mutated gene product does not affect LTP produced at 100 Hz stimulation, the frequency commonly used in the laboratory, but it does interfere with LTP produced at low frequencies of stimulation, in the range of 1-10 Hz (Box 63-1). These lower frequencies are interesting because they are in the physiological range of a prominent spontaneous rhythm in the hippocampus, called the theta rhythm, that occurs in an animal as it moves in the environment. In both types of mutants the interference with LTP does not prevent the formation of place fields. Although the place fields formed in the absence of LTP are larger and fuzzier in outline than normal, LTP is not required for the basic transformation of sensory information into P.1267 place fields. LTP is required for fine-tuning the properties of place cells and ensuring their stability over time.

Figure 63-14B The firing-rate patterns from four successive recording sessions in a single cell from a wild-type mouse and a mouse carrying a gene for a persistently active Ca2+/calmodulin-dependent kinase. Before each recording session the animal was taken out of the cylinder and reintroduced into it. In each of the four sessions the positional firing pattern for the wild-type cell is stable. By contrast, the pattern of the mutant cell is unstable in sessions 2 and 3.

For example, pyramidal cells that encode for overlapping positions in space fire synchronously when the animal enters the space represented by those cells. Thomas McHugh and his colleagues found that this correlated firing is lost in mice lacking a functional NMDA receptor in the CA1 region. Alex Rotenberg found that the defect is more severe in mice that overexpress an activated form of the Ca2+/calmodulin-dependent protein kinase. As noted earlier, in wild-type mice a place field forms within minutes after an animal enters a new en-vironment and, once formed, remains stable in that environment for months. In contrast, when mutant mice are removed from a space and then put back into the same space, cells that were previously active in that space form different place fields. This instability of place cells is reminiscent of the memory defect in H.M. and other patients with lesions of the medial temporal lobe. Each time these patients enter the same space, they act as if they have never seen it before.

Associative Long-Term Potentiation Is Important for Spatial Memory If LTP is a synaptic mechanism for maintaining a coherent spatial map over time, then defects in LTP should interfere with spatial memory. One spatial memory test is a water maze in which a mouse must find a platform hidden under opaque water in a pool. When released at random locations around the pool, the mouse must use contextual (spatial) cues—markings on the walls of the room in which the pool is located—to find the platform. This task requires the hippocampus. In a simple noncontextual P.1268 P.1269 P.1270 P.1271 P.1272 (nonspatial) version of this test the platform is raised above the surface of the water or marked with a flag so that it is visible, permitting the mouse to navigate to the platform directly. This task does not require the hippocampus.

Box 63-1 Restricting Gene Knockout and Regulating Transgene Expression Biological analysis of learning requires the establishment of a causal relation between specific molecules and learning. This relationship, which has been difficult to demonstrate in mammals, can now be studied in mice either by the use of transgenes or the selective knockout of genes. With transgenes a new gene is introduced into the brain under the control of a promoter that expresses that gene in a specific region of the brain. With gene knockout specific gene deletions are induced in embryonic stem cells through homologous recombination (see Figure 3-8). Experiments using transgenes and gene knockout have made it possible to examine the roles of NMDA receptors and different second-messenger kinases in a variety of learning mechanisms in the hippocampus, including long-term potentiation, spatial learning, and the development and maintenance of a cognitive map of space. With conventional gene knockout techniques animals inherit the genetic deletions in all of their cell types. Global genetic deletion may cause developmental defects that interfere with the later functioning of neural circuits important for memory storage. As a result, interpretation of the results from conventional knockout mice runs into two types of difficulties. First, it is often difficult to exclude the possibility that the abnormal phenotype observed in mature animals results directly or indirectly from a developmental defect. Second, global gene knockout makes it difficult to attribute abnormal phenotypes to a particular type of cell within the brain. To improve the utility of gene knockout and transgene technology, methods have been developed to restrict gene expression locally or temporally. One method for restricting gene knockout locally exploits the Cre/loxP system, a site-specific recombination system, derived from the P1 phage, in which the Cre recombinase catalyzes recombination between 34 bp loxP recognition sequences (Figure 63-15). The loxP sequences can be inserted into the genome of embryonic stem cells by homologous recombination such that they flank one or more exons of the gene one is interested in. Thus the gene encoding the R1 subunit of the NMDA receptor can be floxed and then ablated selectively in the CA1 region of the hippocampus. Loss of the R1 subunit leads to loss of LTP. Moreover, mice that lack this gene only in the CA1 region of the hippocampus show a deficiency in spatial memory (Figure 63-17). In contrast, these mice show no deficit in tasks that do not involve the hippocampus, such as learning simple visual discrimination. In addition to regional restriction of gene expression, effective use of genetically modified mice requires control over the timing of gene expression. The ability to turn a transgene on and off gives the investigator an additional degree of flexibility and can exclude the possibility that any abnormality observed in the phenotype of the mature animal is the result of a developmental defect produced by the transgene. This can be done in mice by constructing a gene that can be turned on or off by giving a drug. One starts by creating two lines of mice (Figure 63-16). One line carries a particular transgene, for example CaMKII-Asp 286, a mutated form of the gene CaMK-II coding for a constitutively active kinase (line 1). Instead of being attached to its normal promoter, the transgene is attached to the promoter tet-O that is ordinarily found only in bacteria. This promoter cannot, by itself, turn on the gene; it needs to be activated by a specific transcriptional regulator. Thus, a second transgene expressed in the second line of mice encodes a hybrid transcriptional regulator called tetracycline transactivator (tTA) that recognizes and binds to the tet-O promoter (line 2). Expression of tTA is placed under the control of a region-specific promoter, such as the promoter for CaMKII. When the two lines of mice are mated some of the offspring will carry both transgenes. In these mice the tTA binds to the tet-O promoter and activates the mutated CaMKII gene. This mutant causes abnormalities in long-term potentiation. But when the animal is given doxycycline, the drug binds to the transcription factor tTA causing it to undergo a change in shape that makes it come off the promoter (Figure 63-16). The cell stops expressing CaMKII and long-term potentiation returns to normal, demonstrating that the transgene acts on the adult synapse and does not interfere with the development of the synapse. One can also generate mice that express a mutant form of tTA called reverse tTA (rtTA). This transactivator will not bind to tet-O unless the animal is fed doxycycline. In this case the transgene is always turned off unless the drug is given.

Figure 63-15 (Opposite) Using the Cre/loxP system to restrict the region of gene knockout. A. A mouse homozygous for the floxed R1 subunit of the NMDA receptor (line 1) is generated from embryonic stem cells by conventional techniques and is crossed to a second mouse that contains a Cre transgene under the control of a transcriptional promoter from the CamKII gene (line 2). In progeny that are homozygous for the floxed gene and that carry the Cre transgene, the floxed gene will be deleted by Cre/loxP recombination but only in those cell types in which the Cre geneassociated promoter is active. By this means efficient gene knockout is accomplished in postmitotic neurons in a highly restricted manner, limited to the CA1 pyramidal cells of the hippocampus. B. LacZ staining reveals the region where recombination was successful and led to the removal of a floxed stopper sequence that allows LacZ to be expressed. When the Cre recombinase is combined with the promoter for the Ca2+/calmodulin-dependent kinase, the transgene is restricted to the CA1 region. This is evident in the section of the brain illustrated here. (From Tsien et al. 1996a.)

Figure 63-16 Using the tetracycline system to control the timing of gene expression. Two independent lines of transgenic mice are mated so that two transgenes are introduced into a single mouse. In the tetracycline system a bacterial transcription factor, the tetracycline transactivator (tTA), recognizes a bacterial promoter (the tetO promoter). When the transactivator binds to the promoter it activates its downstream gene, in this case a constitutively active form of CaMKII, CaMKII-Asp286. When the animal is given doxycycline the drug binds to the transcription factor, tTA, producing a conformational change in tTA that causes it to come off the promoter. (From Mayford et al. 1996)

Figure 63-17 (Opposite) Mice that lack the NMDA receptor in the CA1 region of the hippocampus have a defect in LTP and in spatial memory. A. Field excitatory postsynaptic potentials (fEPSP) were recorded in the stratum radiatum in the CA1 region of both mutant and wild-type mice. After a 30-min period of baseline recording a tetanus (100 Hz for 1 s) was applied (arrow). Activity in the pathway remained unchanged in the mutant but became potentiated in the wild-type, indicating that knockout of the NMDA receptor abolishes LTP. B. Mice that lack the NMDA receptor in CA1 have impaired spatial memory. 1. In the Morris maze a platform is submerged in one quadrant of an opaque fluid in a circular tank. To avoid remaining in the water the mice have to learn to find the platform and climb onto it. 2. Mutant mice are slower in learning to find the submerged platform. The graph represents the escape latencies of mice trained to find the hidden platform using spatial (contextual) cues. The mutant mice display a longer latency in every block of trials (four trials per day) than do the wild-type mice. Also, mutant mice do not reach the optimal performance attained by the control mice, even though the mutants show some improvement. 3. After the mice have been trained in the Morris maze, the platform is taken away and the mice are given a transfer test for memory. A wild-type mouse focuses its search in the quadrant that formerly contained the platform because it remembers the platform as being there. The mutant mouse, which does not remember where the platform was, spends an equal amount of time (25%) in all quadrants. a. Illustrative examples. b. Actual data. (From Tsien et al 1996b.)

Richard Morris demonstrated that when NMDA receptors are blocked by the injection of a pharmacological antagonist into the hippocampus, the animal can navigate to the visible platform in the noncontextual version of the water maze test but cannot find its way to the submerged platform in the contextual version. These experiments suggested that some mechanism involving NMDA receptors in the hippocampus, perhaps LTP, is involved in spatial learning. More direct evidence for this correlation has come from genetic experiments with the two types of mutant mice described in Box 63-1. In the first type of mutant the R1 subunit of the NMDA receptor of the pyramidal cells of the CA1 region is selectively knocked out. As a result, basal transmission is normal but LTP is completely disrupted (Figure 63-17A). Although this disruption is restricted to the Schaffer collateral pathway, these mice nevertheless have a serious deficit in spatial memory when tested in the water maze (Figure 63-17B and C). These findings provide the most compelling evidence so far that the NMDA channels and NMDA-mediated synaptic plasticity in the Schaffer collateral pathway are important for spatial memory. In the second type of mutant, expression of the persistently active form of the Ca2+/calmodulin-dependent protein kinase can be turned on and off at will. Expression of the kinase selectively interferes with LTP when the frequency of electrical stimulation is between 1 and 10 Hz, and this results in an instability in the hippocampal place cells (Figure 63-18). These mutant mice also do not remember spatial tasks. But when the transgene is turned off, the LTP becomes normal and the animal's capability for spatial memory is restored! These two sets of experiments based on the restricted knockout of the NMDA receptor and the regulated expression of the Ca2+/calmodulin-dependent kinase make it clear that LTP in the Schaffer collateral pathway is important for spatial memory. How are defects in the various phases of LTP reflected in defects in the phase of memory storage? Indeed, the memory deficits are surprisingly selective. Selective expression in the hippocampus of the transgene that blocks cAMP-dependent protein kinase selectively disrupts the late phase of LTP in the Schaffer collateral pathway. Animals with this deficit have normal learning abilities and normal short-term memory when tested at one hour, but they cannot convert short-term memory into stable long-term memory. They have defective long-term memory when tested at 24 hours after training. Essentially similar results are obtained in mice that have a knockout of several isoforms of CREB-1, as well as in normal wild-type mice that are exposed to pharmacological inhibitors of protein synthesis or camp-dependent protein kinase. These animals learn well and have normal short-term memory but poor long-term memory. Thus, interference with the early and late component of LTP in the Schaffer collateral pathway interferes with both short- and long-term memory, whereas selective interference with the late component of LTP interferes only with the consolidation of long-term memory. Together, these experiments provide insight into the genetic chain of causation that connects molecules to LTP, LTP to place cells, and place cells to the outward behavior of the animal as reflected in both short- and long-term spatial memory.

Is There a Molecular Alphabet for Learning? The changes in synaptic efficacy that we have encountered in studies of both implicit and explicit forms of storage raise three key issues in a neurobiological approach to learning. First, the finding that the molecular mechanisms of some associative forms of synaptic plasticity are based on those of nonassociative forms in the same cell suggests that there may be a molecular alphabet for synaptic plasticity—simpler forms of plasticity might represent elements of more complex forms. Of course, all of these synaptic mechanisms are embedded in distributed neural circuits with considerable additional computational power, which can thus add substantial complexity to the actions of individual cells. Second, the molecular mechanisms of elementary forms of associative memory storage used in both implicit and explicit learning are similar. In the two processes we have considered—activity-dependent presynaptic facilitation for storing implicit memory and associative LTP for storing explicit memory—the plasticity of neuronal function seems to derive from the associative properties of specific proteins: from the ability of proteins, such as adenylyl cyclase and the NMDA receptor, to respond conjointly to two independent signals. Finally, despite clear differences in behavioral logic in the neural systems recruited for the task, implicit and explicit memory storage seem to use elements of a P.1273 P.1274

common genetic switch, involving cAMP-dependent protein kinase, MAP kinase, and CREB, to convert labile short-term memory into long-term memory.

Figure 63-18 Reversal of the deficit in LTP and in spatial memory in the CA1 region of the hippocampus. A. Field excitatory postsynaptic potentials (fEPSP) slopes before and after tetanic stimulation were recorded and expressed as the percentage of pretetanus baseline. Stimulation at 10 Hz (arrow) for 1.5 min induced a transient depression in activity followed by potentiation in wild-type mice but only a slight depression and no potentiation in transgenic mice. Doxycycline treatment (Dox) reversed the defect in the transgenic mice so that they show potentiation compared with wild type. B. The Barnes maze measures the same spatial memory system explored in the Morris water maze. This maze consists of a platform with 40 holes, only one of which (marked in black) leads to an escape tunnel that allows the mouse to exit the platform. The mouse is placed in the center of the platform. Because mice do not like open, well-lit spaces, they try to escape from the platform. The only way they can do that is to find the one hole that leads to the escape tunnel. The most efficient way of doing that (and the only way of meeting the criteria set for the task by the experimenter) is to use the distinctive markings on the four walls. C. Percentage of transgenic and wild-type mice that met the learning criterion on the Barnes circular maze. Three groups of mice were tested: transgenics with and without doxycycline and wild-types. Transgenics that received doxycycline performed as well as wild-types, whereas those without the doxycycline did not learn the task.

Figure 63-19 Training expands the existing representation of the fingers in the cortex. A. A monkey was trained for 1 hour per day to perform a task that required repeated use of the tips of fingers 2, 3, and occasionally 4. After a period of repeated stimulation the portion of area 3b representing the tips of the stimulated fingers was substantially greater (3) than in untrained monkeys (2) measured 3 months before training). (Adapted from Jenkins et al. 1990.) B. A human subject trained to do a rapid sequence of finger movements will improve in accuracy and speed after three weeks of daily (10-20 min) training. In these MRI scans of local blood oxygenation level-dependent signals in the primary motor cortex, the region activated in trained subjects (after three weeks of training) is larger than the region activated in control subjects who performed unlearned finger movements in the same hand. The change in cortical representation with the learned motor sequence persisted for several months.

Changes in the Somatotopic Map Produced by Learning May Contribute to the Biological Expression of Individuality Learning, we have seen, can lead to structural alterations in the brain. How common are these changes in determining the functional architecture of the mature brain? This question has been examined in the somatosensory cortex. The four maps of the body surface in the primary somatic sensory cortex vary among individuals in a manner that reflects different usage of sensory pathways. The connections of afferent pathways in the cortex can expand or retract depending on activity (see Chapter 20). Reorganization of afferent inputs is also evident at lower levels in the brain, specifically at the level of the dorsal column nuclei, which contain the first synapses of the somatic sensory system. Therefore, organizational changes probably occur throughout the somatic afferent pathway as well. As we grow up each of us is exposed to different combinations of stimuli and develops motor skills in different ways. Thus all brains—even the brains of identical twins who share the P.1275 same genes—are uniquely modified by experience. This distinctive modification of brain architecture, along with a unique genetic makeup, constitutes a biological basis for individuality. The process by which experience alters the somatosensory maps in the cortex is illustrated in an experiment in which adult monkeys were trained to use only their middle three fingers to obtain food. After several thousand trials of this behavior the area of cortex devoted to the middle finger expanded greatly (Figure 63-19). Practice alone therefore may strengthen the effectiveness of existing patterns of connections. Experiments such as this one suggest that early development of the input connections to cortical neurons in the somatic sensory system may depend on correlated activity in different afferent axons. As we have seen, cooperative activity in different afferent fibers stabilizes the development of ocular dominance columns in the visual system (Chapter 56). In turn, the use of correlated firing to fine-tune cortical connections may depend on mechanisms that require correlated firing similar to those of LTP. For example, when the skin of two adjacent fingers of a monkey were surgically connected to ensure that the connected fingers were always used together, the correlation of inputs from the joined fingers abolished the normally sharp discontinuity between areas in the somatosensory cortex that receive inputs from these digits (see Figure 19-8).

Neuronal Changes Associated With Learning Provide Insights Into Psychiatric Disorders The demonstration that learning produces changes in the effectiveness of neural connections has revised our view of the relationship between social and biological processes in the shaping of behavior. Until recently the majority view in medicine and psychiatry was that biological and social determinants of behavior act on separate levels of the mind. For example, psychiatric illnesses were traditionally classified as either organic or functional. Organic mental illnesses included the dementias, such as Alzheimer disease, and the toxic psychoses, such as those that follow the chronic use of alcohol or cocaine. Functional mental illnesses included the various depressive syndromes, the schizophrenias, and the neuroses. This distinction dates to the nineteenth century, when neuropathologists examined the brains of patients coming to autopsy and found gross and readily demonstrable distortions in the architecture of the brain in some psychiatric diseases but not in others. Diseases that produce anatomical evidence of brain lesions were called organic; those lacking these features were called functional. The experiments reviewed in this chapter show that this distinction is no longer tenable. Everyday events—sensory stimulation, deprivation, and learning—can effectively weaken synaptic connections in some circumstances and strengthen them in others. We no longer think that only certain diseases (“organic diseases”) affect mentation through biological changes in the brain. The basis of contemporary neural science is that all mental processes are biological and therefore any alteration in those processes is necessarily organic. In the attempt to understand the biological basis of a particular mental illness we must ask, to what degree is this biological process determined by genetic and developmental factors? To what degree is it determined by a toxic or infectious agent, or by a developmental abnormality? To what degree is it socially determined? Even those mental disturbances that are considered most heavily determined by social factors must have a biological aspect, since it is the activity of the brain that is being modified. Insofar as social intervention works, whether through psychotherapy, counseling, or the support of family or friends, it must work by acting on the brain, quite likely on the strength of connections between nerve cells. Just because structural changes may not initially be detected following cognitive therapy does not rule out the possibility that important biological changes are nevertheless occurring. They may simply be below the level of detection with the limited techniques available to us. Demonstrating the biological nature of mental functioning requires more sophisticated anatomical methodologies than the light-microscopic histology of nineteenth century pathologists. We must develop a neuropathology of mental illness based on functional as well as structural analysis. The new imaging techniques—positron emission tomography and functional magnetic resonance imaging, among others—have opened the door to the noninvasive exploration of the human brain on a cellbiological level, the level of resolution that is required to understand the physical mechanisms of mentation and therefore of mental disorders. This approach is now being pursued in the study of schizophrenia and depression It is intriguing to think that insofar as psychotherapy is successful in changing behavior, it may do so by producing alterations in gene expression. If so, successful psychotherapeutic treatment of neurosis or character disorders should also produce structural changes in the nervous system. Thus, we face the attractive possibility that as brain imaging techniques improve, these techniques might ultimately be useful not only for diagnosing various neurotic illnesses but also for monitoring the progress of psychotherapy.

Figure 63-20 Genetic and acquired illnesses both have a genetic component. Genetic illnesses result from the expression of altered genes or allelic variants, whereas acquired illnesses (neuroses) involve the modulation of gene expression by environmental stimuli as a result of learning, leading to the transcription of a previously inactive gene. The gene is illustrated as having two segments. A coding region is transcribed into a messenger RNA (mRNA) by an RNA polymerase. The mRNA in turn is translated into a specific protein. A regulatory segment consists of an enhancer region and a promoter region (see Chapter 13, Box 13-1). In this example the RNA polymerase can transcribe the gene when the regulatory protein binds to the enhancer region. For the regulatory protein must first be phosphorylated before it can act on the enhancer. Only when it is phosphorylated can CREB bind the adapter protein, the CREB binding protein (CBP), which allows the phosphorylated form of CREB to interact with the transcriptional machinery. A. Inherited disease such as schizophrenia. 1. Under normal conditions the phosphorylated regulatory protein binds to the enhancer segment, thereby activating the transcription of the structural gene, leading to the production of the normal protein. 2. A mutant form of the coding region of the structural gene, in which a thymidine (T) has been substituted for a cytosine (C), leads to transcription of an altered messenger RNA. This in turn produces an abnormal protein, giving rise to the disease state. This alteration in gene structure becomes established in the germ line, is heritable, and contributes to the disease. B. Acquired disease such as post-traumatic stress syndrome. 1. If the regulatory protein for a normal structural gene is not phosphorylated, it cannot bind to the promoter site and thus gene translation cannot be initiated. 2. In this case a specific experience leads to the activation of serotonin (5-HT) and cAMP, which activate the cAMP-dependent protein kinase. The catalytic unit translocates to the nucleus and phosphorylates the regulatory protein CREB, which then can bind to the enhancer segment and thus initiate gene transcription. By this means an abnormal learning experience could lead to the expression of a protein that gives rise to symptoms of a neurotic disorder.

P.1276 P.1277 In studying the specific molecular changes that underlie memory storage, we should look for altered gene expression in abnormal as well as normal mental states. There is now substantial evidence that the susceptibility to major psychotic illnesses—schizophrenia and manic-depressive disorders—is heritable and is due to allelic variations. The cell-biological data on learning and long-term memory reviewed here suggest that neurotic illnesses, acquired by learning, also are likely to involve alterations of gene expression but alterations due to disordered regulation (Figure 63-20). Development, hormones, stress, drug addiction, alcoholism, and learning are all factors that alter gene expression by modifying the binding of transcriptional regulatory proteins to each other and to the regulatory regions of genes. It is likely that at least some neurotic illnesses (or components of them), as well as various forms of drug addiction, result from reversible defects in gene regulation.

An Overall View Studies on synaptic plasticity suggest there are two overlapping stages in the development and maintenance of synaptic strength. The first stage, the initial steps of synapse formation, occurs primarily early in development and is under the control of genetic and developmental processes. The second stage, the fine-tuning of developed synapses by experience, begins during late stages of development and continues to some degree throughout life. An attractive possibility is that the activitydependent cellular mechanisms involved in the associative learning of the mature organism may be similar to the activity-dependent mechanisms at work during critical periods of development. The ongoing modification of synapses throughout life means that all behavior of an individual is produced by genetic and developmental mechanisms acting on the brain—that everything the brain produces, from the most private thoughts to the most public acts, should be understood as a biological process. Environmental factors and learning bring out specific capabilities by altering either the effectiveness or the anatomical connections of existing pathways. The synthesis of neurobiology, cognitive psychology, neurology, and psychiatry that we have emphasized throughout this book is filled with promise. Modern cognitive psychology has shown that the brain stores an internal representation of the world, while neurobiology has shown that this representation can be understood in terms

of individual nerve cells and their interconnections. This synthesis has given us a better perspective on perception, action, learning, and memory. It also provides us with a profound new biological insight into the nature of mental illnesses. Although early behaviorist psychology led the way in exploring observable aspects of behavior, advances in modern cognitive psychology indicate that investigations that fail to consider brain mechanisms cannot adequately explain behavior. As recently as 10 years ago it would have been difficult to establish the existence of an internal representation directly, since internal mental processes were essentially inaccessible to experimental analysis. However, as we have seen throughout this book, cell biology, molecular biology, and brain imaging have now made biological experiments on elementary aspects of internal mental processes feasible. Contrary to the expectations of some, biological analysis is unlikely to diminish our fascination with thinking or to make thinking trivial by reduction when we frame the issues in terms of molecular biology. Rather cell biology and molecular biology have expanded our vision, allowing us to perceive previously unanticipated interrelationships between biological and psychological phenomena. The boundary between cognitive psychology and neural science is arbitrary and always changing. It has been imposed not by the natural contours of the disciplines, but by lack of knowledge. As our knowledge expands, the biological and behavioral disciplines will merge at certain points; it is at these points that our understanding of mentation will rest on more secure ground. As we have tried to illustrate in this book, the merger of biology and cognitive psychology is more than a sharing of methods and concepts. The joining of these two disciples represents the emerging conviction that scientific descriptions of mentation at several different levels will all eventually contribute to a unified biological understanding of behavior.

Selected Readings Abel T, Nguyen PV, Barad M, Deuel TAS, Kandel ER, Bourtchouladze R. 1997. Genetic demonstration of a role for PKA in the late phase of LTP and in hippocampal-based long-term memory. Cell 88:615–626.

Dudai Y. 1989. The Neurobiology of Memory: Concepts, Findings, Trends. Oxford: Oxford Univ. Press. P.1278

Hawkins RD, Kandel ER, Siegelbaum SA. 1993. Learning to modulate transmitter release: themes and variations in synaptic plasticity. Annu Rev Neurosci 16:625–665.

Lisman J. 1994. The CaM kinase II hypothesis for the storage of synaptic memory. Trends Neurosci 17:406–412.

Merzenich MM, Recanzone EG, Jenkins WM, Allard TT, Nudo RJ. 1988. Cortical representational plasticity. In: PR Rakic, WR Singer (eds). Neurobiology of Neocortex, pp. 41-67. New York: Wiley.

Squire LR, Kandel ER. 1999. Memory: mind to molecules. New York: Sci Am Lib 1.

Tully T, Bolwig G, Christensen J, Connolly M, Del Vecchio J, DeZazzo J, Dubnau J, James C, Pinto S, Regulski M, Svedberg B, Velinzon K. 1997. A return of genetic dissection of memory in Drosophila. Function and Dysfunction in the Nervous System. Cold Spring Harb Symp Quant Biol 61:207–218.

References Bailey CH, Chen MC. 1983. Morphological basis of long-term habituation and sensitization in Aplysia. Science 220:91–93.

Bliss TVP, Lom•' T. 1973. Long-lasting potentiation of synaptic transmission in the dentate gyrus of the anesthetized rabbit following stimulation of the perforant path. J Physiol (Lond) 232:331–356.

Bonhoeffer T, Staiger V, Aertsen A. 1989. Synaptic plasticity in rat hippocampal slice cultures: local “Hebbian” conjunction of pre- and postsynaptic stimulation leads to distributed synaptic enhancement. Proc Natl Acad Sci U S A 86:8113–8117.

Bolshakov VY, Golan H, Kandel ER, Siegelbaum SA. 1997. Recruitment of new sites of synaptic transmission during the cAMP-dependent late phase of LTP at CA3CA1 synapses in the hippocampus. Neuron 19:635–651.

Bourtchouladze R, Frenguelli B, Blendy J, Cioffi D, Schutz G, Silva A. 1994. Deficient long-term memory in mice with a targeted mutation of the cAMP responsive element-binding protein. Cell 79:59–68.

Castellucci VF, Carew TJ, Kandel ER. 1978. Cellular analysis of long-term habituation of the gill-withdrawal reflex in Aplysia californica. Science 202:1306–1308.

Chain DG, Casadio A, Schacher S, Hedge AN, Valbrun M, Yamamoto N, Goldberg AL, Bartsch D, Kandel ER, Schwartz JH. 1999. Mechanisms for generating the autonomous cAMP-dependent protein kinase for long-term facilitation in Aplysia. Neuron 22:147–156.

Frost WN, Castellucci VF, Hawkins RD, Kandel ER. 1985. Monosynaptic connections made by the sensory neurons of the gill and siphon withdrawal reflex in Aplysia participate in the storage of long-term memory for sensitization. Proc Natl Acad Sci U S A 82:8266–8269.

Grant SGN, O'Dell TJ, Karl KA, Stein PL, Soriano P, Kandel ER. 1992. Impaired long-term potentiation, spatial learning, and hippocampal development in fyn mutant mice. Science 258:1903–1910.

Gustafsson B, Wigström H, Abraham WC, Huang Y-Y. 1987. Long-term potentiation in the hippocampus using depolarizing current as the conditioning stimulus to single volley synaptic potential. J Neurosci 7:774–780.

Hawkins RD, Abrams TW, Carew TJ, Kandel ER. 1983. A cellular mechanism of classical conditioning in Aplysia: activity-dependent amplification of presynaptic facilitation. Science 219:400–405.

Hebb DO. 1949. The Organization of Behavior: A Neuropsychological Theory. New York: Wiley.

Hegde AN, Inokuchi K, Pei W, Casadio A, Ghirardi M, Chain DG, Martin KC, Kandel ER, Schwartz JH. 1997. Ubiquitin C-terminal hydrolase is an immediate-early gene essential for long-term facilitation in Aplysia. Cell 89:115–126.

Huang Y-Y, Kandel ER. 1994. Recruitment of long-lasting and protein kinase A-dependent long-term potentiation in the CA1 region of hippocampus requires repeated tetanization. Learning & Memory 1:74–82.

Huang Y-Y, Kandel ER, Varshavsky L, Brandon EP, Qi M, Idzerda RL, McKnight GS, Bourtchouladze R. 1995. A genetic test of the effects of mutations in PKA on mossy fiber LTP and its relation to spatial and contextual learning. Cell 83:1211–1222.

Huang Y-Y, Li X-C, Kandel ER. 1994. cAMP contributes to mossy fiber LTP by initiating both a covalently-mediated early phase and a macromolecular synthesisdependent late phase. Cell 79:69–79.

Jenkins WM, Merzenich MM, Ochs MT, Allard T, Guic-Robles E. 1990. Functional reorganization of primary somatosensory cortex in adult owl monkeys after behaviorally controlled tactile stimulation. J Neurophsiol 63:82–104.

Kandel ER. 1989. Genes, nerve cells, and the remembrance of things past. J Neuropsychiatry 1:103–125.

Lin XY, Glanzman DL. 1994. Long-term potentiation of Aplysia sensorimotor synapses in cell culture: regulation by postsynaptic voltage. London: Proc R Soc 255:113–118.

Malinow R, Tsien RW. 1990. Presynaptic enhancement shown by whole cell recordings of LTP in hippocampal slices. Nature 357:134–139.

Mayford M, Bach ME, Huang Y-Y, Wang L, Hawkins RD, Kandel ER. 1996. Control of memory formation through regulated expression of a CaMKII transgene. Science 274:1678–1683.

McHugh TJ, Blum KI, Tsien JZ, Tonegawa S, Wilson MA. 1996. Impaired hippocampal representation of space in CA1-specific NMDAR1 knockout mice. Cell 87:1339–1349.

Muller RU, Kubie JL, Ranck JB Jr. 1987. Spatial firing patterns of hippocampal complex-spike cells in a fixed environment. J Neurosci 7:1935–1950. P.1279

O'Keefe J, Dostrovsky J. 1971. The hippocampus as a spatial map: preliminary evidence from unit activity in the freely-moving rat. Brain Res 34:171–175.

Pavlov IP. 1927. Conditioned Reflexes: An Investigation of the Physiological Activity of the Cerebral Cortex. GV Anrep (transl). London: Oxford Univ. Press.

Rotenberg A, Mayford M, Hawkins RD, Kandel ER, Muller RU. 1996. Mice expressing activated CaMKII lack low frequency LTP and do not form stable place cells in the CA1 region of the hippocampus. Cell 87:1351–1361.

Schuman EM, Madison DV. 1994. Locally distributed synaptic potentiation in hippocampus. Science 263:532–536.

Schuman EM, Madison DV. 1991. A requirement for the intercellular messenger nitric oxide in long-term potentiation. Science 254:1503–1506.

Sherrington CS. 1906. The Integrative Action of the Nervous System. New Haven, CT: Yale Univ. Press.

Silva AJ, Paylor R, Wehner JM, Tonegawa S. 1992. Impaired spatial learning in α-calcium-calmodulin kinase II mutant mice. Science 257:206–211.

Silva AJ, Stevens CF, Tonegawa S, Wang Y. 1992. Deficient hippocampal long-term potentiation in α-calcium-calmodulin kinase II mutant mice. Science 257:201–206.

Spencer AW, Thompson RF, Nielson DR Jr. 1966. Response decrement of the flexion reflex in the acute spinal cat and transient restoration by strong stimuli. J Neurophysiol 29:240–252.

Stevens C, Wang Y. 1994. Changes in reliability of synaptic function as a mechanism for plasticity. Nature 371:704–707.

Thompson RF, Spencer WA. 1966. Habituation: a model of phenomenon for the study of neural substrates of behavior. Psychol Rev 173:16–43.

Tsien JZ, Chen DF, Gerber D, Tom C, Mercer EH, Anderson DJ, Mayford M, Kandel ER, Tonegawa S. 1996a. Subregion- and cell type-restricted gene knockout in mouse brain. Cell 87:1317–1326.

Tsien JZ, Huerta PT, Tonegawa S. 1996b. The essential role of hippocampal CA1 NMDA receptor-dependent synaptic plasticity in spatial memory. Cell 87:1327–1338.

Tsien RW, Malinow R. 1990. Long-term potentiation: Presynaptic enhancement following postsynaptic activation of Ca2+-dependent protein kinases. Cold Spring Harb Symp Quant Biol 55:147–159.

Weisskopf MG, Castillo PE, Zalutsky RA, Nicoll RA. 1994. Mediation of hippocampal long-term potentiation by cyclic AMP. Science 265:1878–1882.

Yin JCP, Wallach JS, Del Vecchio M, Wilder EL, Zhuo H, Quinn WG, Tully T. 1994. Induction of a dominant negative CREB transgene specifically blocks long-term memory in Drosophila. Cell 79:49–58.

Zalutsky RA, Nicoll RA. 1990. Comparison of two forms of long-term potentiation in single hippocampal neurons. Science 248:1619–1624.

Back

IX Language, Thought, Mood, Learning, and Memory

The Hippocampus Is Involved in Processing Spatial Memory in Humans. Much human behavior takes place in familiar environments in which knowledge of spatial layouts has become part of so-called semantic memory. In this study, positron emission tomography (PET) is used to examine the neural substrates of topographical memory retrieval by licensed London taxi drivers with many years' experience while they recalled complex routes around the city. Route recall, shown here from Hyde Park to Primrose Hill, results in activation of a network of specific brain regions, including the right hippocampus. Recall of famous landmarks for which the drivers had no knowledge of the topographical location activated similar parts of the brain, except for the right hippocampus. This suggests that the right hippocampus is used specifically for navigation in large-scale spatial environments. In contrast, nontopographical semantic memory retrieval involves the left inferior frontal gyrus. (Based on images from Maguire, EA, Frakowiak RS, Frith CD 1996. Learning to find your way: a role for the human hippocampal formation. Proc R Soc London B 263:1745-1750.)

MOTOR AND SENSORY CENTERS take up less than one-half of the cerebral cortex in humans. The rest of the cortex is occupied by the association areas, which coordinate events arising in the motor and sensory centers. Three association areas—the prefrontal, parietal temporal occipital, and limbic—are involved in cognitive behavior planning, thinking, feeling, perception, speech, learning, memory, emotion, and skilled movements. Most of the early evidence relating cognitive functions to the association areas came from clinical studies of brain-damaged patients. For example, the study of language in patients with aphasia has yielded important information about how human mental processes are distributed in the two hemispheres of the brain. More recently, studies using experimental animals, including genetically modified mice, have provided important insight into the neural mechanisms that underlie mental functions other than language. Genetic manipulation in experimental animals also helps evaluate the relative contribution of genes and learning to specific types of behavior. Even the highest cognitive abilities have a genetic component. Composing music is an excellent example. Music conforms to complex, unusually abstract rules that must be learned, yet clearly it has genetic components intertwined with its learned aspects. The great composer Johann Sebastian Bach had many children, five of whom were distinguished musicians and composers. His only grandson also was a composer and harpsichordist to the Court of Prussia. In 1730 Bach proudly wrote that he was able to “put on a vocal and instrumental concert with my own family.” Today's neural science is cognitive neural science, a merger of neurophysiology, anatomy, developmental biology, cell and molecular biology, and cognitive psychology. This discipline is grounded in the idea, first stated by Hippocrates more than two thousand years ago, that the proper study of the mind begins with the brain. Until two decades ago the study of higher mental function was approached in two complementary ways: through psychological observation and through invasive experimental physiology. In the first part of the P.1166 twentieth century, to avoid untestable concepts and hypotheses, psychology became rigidly concerned with behaviors defined strictly in terms of observable stimuli and responses. Orthodox behaviorists thought it unproductive to deal with consciousness, feeling, attention, or even motivation. By concentrating only on observable motor actions behaviorists asked, What can an organism do and how does it do it? Indeed, careful quantitative analysis of stimuli and responses has contributed greatly to our understanding of the acquisition and use of “implicit” knowledge. However, humans and other higher animals also have “explicit” knowledge. Thus we also need to ask, What does the animal know about the world and how does it come to know it? How is that knowledge represented in the brain? And how does explicit knowledge differ from implicit knowledge? The modern effort to understand the neural mechanisms of higher mental functions began at the end of the eighteenth century when Franz Joseph Gall, a German neuroanatomist, proposed that particular mental functions are discretely localized in the brain. By the mid nineteenth century clinical neurologists, who regarded their patients as “natural experiments” in brain function, studied brain lesions at autopsy to discover where particular brain functions are located. In 1861 Pierre Paul Broca, using evidence from the damaged brains of aphasic patients, convinced the scientific establishment that speech is controlled by a specific area of the left frontal lobe. Soon afterward the control of voluntary movement was localized and the various primary sensory cortices for vision, audition, somatic sensation, and taste were delineated. Neural science is only beginning to analyze the nature of the internal representations that cognitive psychologists have insisted intervenes between stimulus and response, and the very real dynamic P.1167 mental processes studied by psychoanalysts. Neural science has not yet been able to address directly the subjective sense of individuality, will, and purpose that is common to us all. In the past, ascribing a particular behavioral feature to mental process that could not be directly observed meant that the process must be excluded from study because no reliable techniques were available to examine brain function in the context of behavior. In this part of the book we show that, because the nervous system has become more accessible to behavioral experiments, internal representations of experience can be explored in a controlled manner. A key concern of cognitive psychology and psychoanalysis is the relative importance of genetic and learned factors in forming a mental representation of the world. These disciplines can be strengthened by the insights into behavior that neurobiology now offers. The task for the years ahead is to produce a psychology that—though still concerned with problems of mental representation, cognitive dynamics, and subjective states of mind—is grounded firmly in empirical neural science.

Back

Resources Appendices

Appendix A Current Flow in Neurons John Koester THIS SECTION REVIEWS THE basic principles of electrical circuit theory. Familiarity with this material is important for understanding the equivalent circuit model of the neuron developed in Chapters 5,6,7,8,9. The section is divided into three parts:

●

The definition of basic electrical parameters. ●

A set of rules for elementary circuit analysis. ●

Adescription of current flow in circuits with capacitance.

Definition of Electrical Parameters Potential Difference (V or E) Electrical charges exert an electrostatic force on other charges: Like charges repel, opposite charges attract. As the distance between two charges increases, the force that is exerted decreases. Work is done when two charges that initially are separated are brought together: Negative work is done if their polarities are opposite, and positive work if they are the same. The greater the values of the charges and the greater their initial separation, the greater the work that is done (work ∫

0f(r)

r

dr, where f is electrostatic force and r is the initial distance between the two charges). Potential difference is a measure of this work. The potential difference between two points is

the work that must be done to move a unit of positive charge (1 coulomb) from one point to the other, ie, it is the potential energy of the charge. One volt (V) is the energy required to move 1 coulomb a distance of 1 meter against a force of 1 newton.

Current (I) A potential difference exists within a system whenever positive and negative charges are separated. Charge separation may be generated by a chemical reaction (as in a battery) or by diffusion between two electrolyte solutions with different ion concentrations across a permeability-selective barrier, such as a cell membrane. If a region of charge separation exists within a conducting medium, then charges move between the areas of potential difference: positive charges are attracted to the P.1281 region with a more negative potential, and negative charges go to the regions of positive potential. The resulting movement of charges is current flow, which is defined as the net movement of positive charge per unit time. In metallic conductors current is carried by electrons, which move in the opposite direction of current flow. In nerve and muscle cells current is carried by positive and negative ions in solution. One ampere (A) of current represents the movement of 1 coulomb (of charge) per second.

Conductance (g) Any object through which electrical charges can flow is called a conductor. The unit of electrical conductance is the siemen (S). According to Ohm's law, the current that flows through a conductor is directly proportional to the potential difference imposed across it.1

As charge carriers move through a conductor, some of their potential energy is lost; it is converted into thermal energy due to the frictional interactions of the charge carriers with the conducting medium. Each type of material has an intrinsic property called conductivity (σ), which is determined by its molecular structure. Metallic conductors have very high conductivities; they conduct electricity extremely well. Aqueous solutions with high ionized salt concentrations have somewhat lower values of σ, and lipids have very low conductivities—they are poor conductors of electricity and are therefore good insulators. The conductance of an object is proportional to σ times its crosssectional area, divided by its length:

The length dimension is defined as the direction along. which one measures conductance. For example, the conductance measured along the cytoplasmic core of an axon is reduced if its length is increased or its diameter decreased (Figure A-1).

Figure A-1 Geometric factors, together with intrinsic conductivity, determine the conductance of an object. A. Conductance is inversely proportional to the length of a conductor. B. Conductance is directly proportional to the cross-sectional area of a conductor.

Electrical resistance (R) is the reciprocal of conductance, and is a measure of the resistance provided by an object to current flow. Resistance is measured in ohms (Ω):

Capacitance (C) A capacitor consists of two conducting plates separated by an insulating layer. The fundamental property of a capacitor is its ability to store charges of opposite sign: positive charge on one plate, negative on the other. A capacitor made up of two parallel plates with its two conducting surfaces separated by an insulator (anair gap) is shown in Figure A-2A. There is a net excess of positive charges on plate x, and an equal number of excess negative charges on plate y, resulting in a potential difference between the two plates. One can measure thispotential difference by determining how much work is required to move a positive test charge from the surface of y to that of x. Initially, when the test charge is at y, it is attracted by the negative charges on y, and repelled less strongly by the more distant positive charges on x. The result of these electrostatic interactions is a force f that opposes the movement of the test charge from y to x. As the test charge is moved to the left across the gap, the attraction by the negative charges on y diminishes, but the repulsion by the positive charges on x increases, with the result that the net electrostatic force exerted on the test charge is constant everywhere between x and y (Figure A-2A). Work (W) is force (f) times the distance (D) over which the force is exerted:

Therefore, it is simple to calculate the work done in moving the test charge from one side of the capacitor to the P.1282 other. It is the shaded area under the curve in Figure A-2A. This work is equal to the difference in electrical potential energy, or potential difference, between x and y.

Figure A-2 The factors that affect the potential difference between two plates of a capacitor. A. As a test charge is moved between two charged plates it must overcome a force. The work done against this force is the potential difference between the two plates. B. Increasing the charge density increases the potential difference. C. Increasing the area of the plates increases the number of charges required to produce a given potential difference. D. Increasing the distance between the two plates increases the potential difference between them.

Capacitance is measured in farads (F). The greater the density of charges on the capacitor plates, the greater the force acting on the test charge, and the greater the resulting potential difference across the capacitor (Figure A-2B). Thus, for a given capacitor, there is a linear relationship between the amount of charge (Q) stored on its plates and the potential difference across it:

where the capacitance, C, is a constant. The capacitance of a parallel-plate capacitor is determined by two features of its geometry: the area (A) of the two plates, and the distance (D) between them. Increasing the area of the plates increases capacitance, because a greater amount of charge must be deposited on each side to produce the same charge density, which is what determines the force f acting on the test charge (Figure A-2A and C). Increasing the distance D between the plates does not change the force acting on the test charge, but it does increase the work that must be done to move it from one side of the capacitor to the other (Figure A-2A and D). Therefore, for a given charge separation between the two plates, the potential difference between them is proportional to the distance. Put another way, the greater the distance the smaller the amount of charge that must be deposited on the plates to produce a given potential difference, and therefore the smaller the capacitance (Equation A-1). These geometrical determinants of capacitance can be summarized by the equation:

As shown in Equation A-1, the separation of positive and negative charges on the two plates of a capacitor results in a potential difference between them. The converse of this statement is also true: The potential difference across a capacitor is determined by the excess of positive and negative charges on its plates. In order for the potential across a capacitor to change, the amount of electrical charges stored on the two conducting plates must change first.

Rules for Circuit Analysis A few basic relationships that are used for circuit analysis are listed below. Familiarity with these rules will help in understanding the electric circuit examples that follow.

Conductance The symbol for a conductor is:

Figure. No Caption Available.

P.1283 A variable conductor is represented this way:

Figure. No Caption Available.

A pathway with infinite conductance (zero resistance) is called a short circuit, and is represented by a line:

Figure. No Caption Available.

Conductances in parallel add:

Figure. No Caption Available.

Conductances in series add reciprocally:

Figure. No Caption Available.

Resistances in series add, while resistances in parallel add reciprocally.

Current An arrow denotes the direction of current flow (net movement of positive charge). Ohm's law is

When current flows through a conductor, the end that the current enters is positive with respect to the end that it leaves:

Figure. No Caption Available.

The algebraic sum of all currents entering or leaving a junction is zero (we arbitrarily define current approaching a junction as positive, and current leaving a junction as negative). In the following

Figure. No Caption Available.

the currents for junction x are:

In the following circuit

Figure. No Caption Available.

the currents for junction y are:

P.1284 Current follows the path of greatest conductance (least resistance). For conductance pathways in parallel, the current through each path is proportional to its conductance value divided by the total conductance of the parallel combination:

Figure. No Caption Available.

Capacitance The symbol for a capacitor is:

Figure. No Caption Available.

The potential difference across a capacitor is proportional to the charge stored on its plates:

Potential Difference The symbol for a battery, or electromotive force is:

Figure. No Caption Available.

It is often abbreviated by the symbol E. The positive pole is always represented by the longer bar. Batteries in series add algebraically, but attention must be paid to their polarities. If their polarities are the same, their absolute values add:

Figure. No Caption Available.

If their polarities are opposite, they subtract:

Figure. No Caption Available.

The convention used here for potential difference is that VAB = (VA- VB). A battery drives a current around the circuit from its positive to its negative terminal:

Figure. No Caption Available.

For purposes of calculating the total resistance of a circuit the internal resistance of a battery is set at zero. The potential differences across parallel branches of a circuit are equal:

Figure. No Caption Available.

Figure A-3 Time course of charging a capacitor. A. Circuit before the switch (S) is closed. B. Immediately after the switch is closed. C. After the capacitor has become fully charged. D. Time course of changes in Ic and Vc in response to closing of the switch.

Figure. No Caption Available.

As one goes around a closed loop in a circuit, the algebraic sum of all the potential differences is zero:

P.1285

Current Flow in Circuits With Capacitance Circuits that have capacitive elements are much more complex than those that have only batteries and conductors. This complexity arises because current flow varies with time in capacitive circuits. The time dependence of the changes in current and voltage in capacitive circuits is illustrated qualitatively in the following three examples.

Circuit With Capacitor Current does not actually flow across the insulating gap in a capacitor; rather it results in a build-up of positive and negative charges on the capacitor plates. However, we can measure a current flowing into and out of the terminal of a capacitor. Consider the circuit shown in Figure A-3A. When switch S is closed (Figure A-3B), a net positive charge is moved by the battery E onto plate a, and an equal amount of net positive charge is withdrawn from plate b. The result is current flowing counterclockwise in the circuit. Since the charges that carry this current flow into or out of the terminals of a capacitor, building up an excess of plus and minus charges on its plates, it is called a capacitive current (Ic). Because there is no resistance in this circuit, the battery E can generate a very large amplitude of current, which will charge the capacitance to a value Q × E × C in an infinitesimally short period of time (Figure A-3D).

Circuit With Resistor and Capacitor in Series Now consider what happens if a resistor is added in series with the capacitor in the circuit shown in Figure A-4A. The maximum current that can be generated when switch S is closed (Figure A-4B) is now limited by Ohm's law (I = V/R). Therefore, the capacitor charges more slowly. When the potential across the capacitor has finally reached the value Vc = Q/C = E (Figure A-4C), there is no longer a difference in potential around the loop, ie, the battery voltage (E) is equal and opposite to the voltage across the capacitor, Vc. The two thus cancel out, and there is no source of potential difference left to drive a current around the loop. Immediately after the switch is closed the potential difference is greatest, so current flow is at a maximum. As the capacitor begins to charge, however, the net potential difference (Vc = E) available to drive a current becomes smaller, so that current flow is reduced. The result is that an exponential change in voltage and in current flow occurs across the resistor and the capacitor. Note that in this circuit resistive current must equal capacitative current at all times (see Rules for Circuit Analysis, above).

Circuit With Resistor and Capacitor in Parallel Consider now what happens if we place a parallel resistor and capacitor combination in series with a constant P.1286 P.1287 current generator that generates a current IT (Figure A-5A). When switch S is closed current starts to flow around the loop. Initially, in the first instant of time after the current flow begins, all of the current flows into the capacitor, ie, IT=Ic. However, as charge builds up on the plates of the capacitor, a potential difference Vc is generated across it. Since the resistor and capacitor are in parallel, the potential across them must be equal; thus, part of the total current begins to flow through the resistors, such that IRR = VR = Vc (Figure A-5B). As less and less current flows into the capacitor, its rate of charging will become slower; this accounts for the exponential shape of the curve of voltage versus time. Eventually, a plateau is reached at which the voltage no longer changes. When this occurs, all of the current flows through the resistor, and Vc=VR=ITR (Figure A-5C).

Figure A-4 Time course of charging a capacitor in series with a resistor from a constant voltage source (E). A. Circuit before the switch (S) is closed. B. Shortly after the switch is closed. C. After the capacitor has settled at its new potential. D. Time course of current flow, of the increase in charge deposited on the capacitor, and of the increased potential differences across the resistor and the capacitor.

Figure A-5 Time course of charging a capacitor in parallel with a resistor from a constant current source. A. Circuit before the switch (S) is closed. B. Shortly after the switch is closed. C. After the charge deposited on the capacitor has reached its final value. D. Time course of changes in Ic, Vc, IR, and VR in response to closing of the switch.

Footnote 1Note

the analogy of this formula for current flow to the other formulas for describing flow; eg, bulk flow of a liquid due to a hydrostatic pressure; flow of a solute in response to a concentration

gradient; flow of heat in response to a temperature gradient, etc. In each case flow is proportional to the product of a driving force times a conductance factor. P.1288

Appendix B Ventricular Organization of Cerebrospinal Fluid: Blood-Brain Barrier, Brain Edema, and Hydrocephalus John Laterra Gary W. Goldstein A BARRIER TO THE ENTRY of blood-borne substances to the brain has been recognized for at least a century. Evidence for the blood-brain barrier was first obtained in the nineteenth century, when it was observed that acidic vital dyes stain the brain if the dye is injected into the cerebrospinal fluid (CSF) but not if injected into the blood stream. This barrier maintains a stable environment for neurons to function effectively. It excludes many toxic substances and protects neurons from circulating neurotransmitters such as norepinephrine and glutamate, the blood levels of which can increase greatly in response to stress or even after a meal. Exclusion results primarily from specialized anatomic properties of brain endothelial cells that limit the passive diffusion of water-soluble substances across vessel walls. As a result, many metabolites required for brain growth and function must be transported selectively across the endothelial surface. Specific endothelial transporters deliver energy substrates, essential amino acids, and peptides from blood to brain and remove metabolites from the brain.

Differentiated Properties of Brain Capillary Endothelial Cells Account for the Blood-Brain Barrier

Anatomy of the Blood-Brain Barrier Brain microvessels are composed of endothelial cells, pericytes with smooth muscle-like properties that reside adjacent to capillaries, and astroglial processes that ensheath more than 95% of the abluminal microvessel surface (Figure B-1). It was originally thought that the glial foot processes formed the blood-brain barrier, but electron-microscopic studies identified the endothelial cell as the principal anatomic site of the blood-brain barrier (Figure B-2). The blood-brain barrier results from specialized properties of the endothelial cells, their intercellular junctions, and a relative lack of vesicular transport. In capillaries of peripheral organs and in the relatively few brain capillaries that do not form a barrier (eg, the circumventricular organs) blood-borne polar molecules P.1289 diffuse passively across vessels through spaces between endothelial cells, through specialized cytoplasmic fenestrations, or by fluid-phase or receptor-mediated endocytosis. Fluid-phase endocytosis is a relatively nonspecific process by which endothelial cells (and most other cells) engulf and then internalize molecules encountered in the extracellular space by vesicular endocytosis. Receptormediated endocytosis is a specific process in which a ligand first binds to a membrane receptor on the external surface of the cell, is internalized by means of clathrin-coated vesicles, and is transported across the cell membrane. Once within the cell, the vesicle may fuse with an endosome and release its ligand.

Figure B-1 The ultrastructural features of the capillary endothelial cells of the brain differ from those of general (systemic) capillaries. The endothelial cells of barrier capillaries are relatively lacking in pinocytotic vesicles, contain an increased number of mitochondria believed to support energy-dependent transport properties, and are interconnected by very complex interendothelial tight junctions. These anatomic features in conjunction with specific transport systems (see Figure B-5) result in highly selective transport of water-soluble compounds across the barrier endothelium. Astrocyte foot processes almost completely surround the blood-brain barrier capillaries and are thereby believed to influence barrier-specific endothelial differentiation. In contrast, systemic capillaries have interendothelial clefts, fenestrae, and prominent pinocytotic vesicles. These features of systemic capillaries allow relatively nonselective diffusion across the capillary wall. (From Goldstein and Betz 1986.)

Endothelial cells of blood-brain barrier vessels are relatively deficient in vesicular transport. They also are not fenestrated. Instead they are interconnected by complex arrays of tight junctions (Figure B-2C). These junctions between the endothelial cells block diffusion across the vessel wall. All endothelial cells are interconnected by tight junctional complexes but normally have low resistance (5–10 ω/cm2). In the vessels of the bloodbrain barrier, however, the resistance is very high (2000 ω/cm2), and molecules as small as K+ ions are excluded (Figure B-3).

Selectivity of the Blood-Brain Barrier Normal development and brain function require a large number of compounds that must be able to cross brain microvessels. Entry into the CSF is achieved primarily in three ways: (1) by diffusion of lipid-soluble substances, (2) by facilitative and energy-dependent receptor-mediated transport of specific water-soluble substances, and (3) by ion channels.

Lipid-Soluble Substances The brain is separated from blood only by a very large surface of endothelial cell membranes (approximately 180 cm2/g in gray matter). This permits the efficient exchange of lipid-soluble gases such as O2 and CO2, an exchange limited only by the surface area of the blood vessel and by cerebral blood flow. Barrier vessels are impermeable to poorly lipid-soluble molecules such a mannitol, as compared to very lipid-soluble compounds such as butanol. The permeability coefficient of the blood-brain barrier for many substances is directly proportional to the lipid solubility of the substance as measured by the oil-water partition coefficient (Figure B-4). An example of this effect is in the correlation between the relative abuse potential of psychoactive drugs such as nicotine and heroin and the high oil-water partition coefficients of these drugs. Increasing the lipid solubility of pharmacologic agents within strict limits will enhance their delivery to the brain. Drugs with very high oil-water partition coefficients are poorly soluble in blood and bind to serum protein albumin, properties that reduce delivery to the brain. However, the permeability P.1290 of some substances, such as glucose and vinca alkaloids, is not predicted accurately by the lipid solubility of the substance. This observation is explained by the presence of selective endothelial transport or enzyme systems that increase or inhibit substrate permeability.

Figure B-2 Interendothelial tight junctions are the basis of the anatomic blood-brain barrier. A. When injected into arteries that supply the brain, the electron-dense tracer horseradish peroxidase is easily visualized within the brain vessel lumens (dark staining) at top but is excluded from entering the brain by interendothelial tight junctions (TJ). (From Reese and Karnovsky 1967.) B. When injected into the subarachnoid space, horseradish peroxidase readily diffuses between the perivascular astroglial foot processes and across the abluminal basement membrane (BM) but fails to penetrate interendothelial tight junctions (TJ). The luminal space appears at the top of the electron micrographs in both A and B. (From Brightman and Reese 1969.) C. Freeze-fracture photomicrograph of isolated brain microvessels, showing complex arrays of interendothelial tight junctions. (From Shivers et al. 1984.)

Blood-Brain Barrier Transport Properties Most substances that must cross the blood-brain barrier are not lipid soluble and therefore cross by specific carrier-mediated transport systems (Figure B-5). Because the brain uses glucose exclusively as its source of energy, the hexose transporter (glucose transporter isotype-1, Glut1) of the blood-brain barrier endothelial cells has been particularly well characterized. Glut1 consists of 492 amino acids and has 12 putative transmembrane domains, similar to other transporters. It is a facilitative, saturable, and stereospecific transporter that functions at both the luminal and the abluminal endothelial cell membranes. Because it is not energy dependent, it cannot move glucose against a concentration gradient. The net flux of glucose is driven by the relatively higher concentration of glucose in plasma. Transport is half-saturated at glucose concentrations of 5 to 10 mM. More than 99% of the glucose molecules that enter blood-brain barrier endothelial cells are shuttled across for use by neurons and glia. The gene that codes for Glut1 resides on human chromosome 1. Whereas the complete absence of Glut1 is likely to be incompatible with life, deficient Glut1 expression P.1291 is thought to be responsible for a rare clinical syndrome consisting of mental retardation, epilepsy, and persistent low CSF glucose concentration (ie, hypoglycorrhachia).

Figure B-3 Time course of K+ concentration in the extracellular fluid of cerebral cortex (A), neck muscle (B), and sagittal sinus (A and B) following the bolus injection of KCl in the aortic arch. Note that the extracellular fluid K+ concentration of cerebral cortex remains essentially unchanged because of the blood-brain barrier to ions. In contrast, K+ diffuses rapidly across nonbarrier vessels into the extracellular space of muscle. (From Hansen et al. 1977.)

Figure B-4 The oil-water partition coefficient indicates the relationship between lipid solubility and brain uptake of selected compounds. The distribution into olive oil relative to water for each test substance serves as a measure of its lipid solubility. The brain uptake is determined by comparing the extraction of each test substance relative to a highly permeable tracer during a single passage through the cerebral circulation. In general, compounds with higher oil-water partition coefficients show increased entry into brain. Uptake of the anticonvulsants phenobarbital and phenytoin is lower than predicted from their lipid solubility partly because of their binding to plasma proteins. This explains the slower onset of anticonvulsant activity of these agents compared to diazepam. Uptake of glucose and L-DOPA is greater than predicted by their lipid solubility because specific carriers facilitate their transport into the brain capillary. (From Goldstein and Betz 1986.)

Amino acids are transported across barrier endothelial cells primarily by three distinct carrier systems: the L system, the A system, and the ASC system. These carriers are characterized by their different patterns and mechanisms of transport, and by their preference for different amino acid analogs. Large neutral amino acids with branched or ringed side chains, such as leucine and valine, are transported primarily by the L system. The L system is a Na+-independent, facilitative transporter and is located at luminal and abluminal endothelial membranes. It can be inhibited experimentally by 2-aminobicycloheptane-2-carboxylic acid (BCH). Like glucose, large neutral amino acids are transported from blood down a concentration gradient. This carrier system transports systemically administered L-DOPA, the dopamine precursor that is the mainstay for treating Parkinson disease. Competitive inhibition of the transport of large neutral amino acids by elevated levels of phenylalanine may explain some of the neurotoxicity associated with untreated phenylketonuria, because phenylalanine is transported by the L system. Glycine and neutral amino acids with short linear or polar side chains, such as alanine or serine, are preferentially transported by the A system. Unlike the L system, this carrier is energy dependent, Na + dependent, and experimentally inhibited by α-methylaminoisobutyric acid (MeAIB). The ASC system is also an energy-dependent and Na+-dependent transporter that preferentially recognizes alanine, serine, and cysteine. ASC-mediated transport is insensitive to both BCH and MeAIB. In contrast to the L carrier, the Aand ASC transport systems are located exclusively at the abluminal endothelial cell surface. The physiological consequence of this localization is that the small neutral amino acids are transported primarily out of the brain up a concentration gradient through these

carriers. The Asystem may limit the accumulation of the inhibitory neurotransmitter glycine within the spinal cord and the excitatory neurotransmitter glutamate within the brain. The energy and Na+ exchange required for these systems is supplied by Na+P.1292 K+-ATPase, which also is localized to the abluminal endothelial membrane.

Figure B-5 A complex system of polarized transporter proteins and ionic channels determine the specific movement of water-soluble compounds and ions across barrier endothelial cells. Some transporters (eg, Glut1 and L system) facilitate the movement of substrates down concentration gradients, and others (eg, A system and Na+-K+-ATPase) actively transport substrates via energy-dependent mechanisms. Enzyme systems such as amino acid decarboxylase (AADC) and monoamine oxidase (MAO) function as a metabolic barrier by converting within the barrier endothelial cells substances such as L-DOPA to 3,4-dihydroxyphenylacetic acid.

Another transport system found to be most abundant in the blood-brain barrier microvessels belongs to a family of transmembranous proteins initially described for their ability to impart multiple drug resistance (MDR) to tumor cells. These transmembranous transporters remove a broad range of natural and synthetic hydrophobic toxins from cells that express the transporters. The MDR transporter (ie, p-glycoprotein) in the blood-brain barrier influences the delivery to the brain of many compounds used for cancer chemotherapy (eg, vinca alkaloids, actinomycin-D) and for other therapeutic purposes (eg, cyclosporin). Because p-glycoproteins pump certain steroid hormones, they may also have a physiological role. MDR transporters are expressed by blood-brain barrier microvessels but not by vessels of most other tissues. Mice genetically engineered to lack MDR1a gene expression no longer express blood-brain barrier p-glycoprotein and are much more sensitive than wild-type controls to centrally acting toxic compounds, indicating that MDR gene expression at the blood-brain barrier protects the brain from circulating neurotoxins.

Ion Channels and Exchangers Specific ion channels and ion transporters mediate electrolyte movement across the blood-brain barrier. Evidence from transport studies across brain microvessels P.1293 in vivo and from patch-clamp studies of cultured brain microvessel endothelial cells support the existence of a nonselective luminal ion channel that is inhibited by both amiloride and atrial natriuretic peptide. The existence of luminal Na+/H+ and Cl-/HCO3- exchangers has been suggested but is less well substantiated. The external membrane of brain endothelial cells has a relatively high

concentration of Na+-K+-ATPase that exchanges extracellular K+ with intracellular Na+ in an energy-dependent manner. In conjunction with K+ channels in astrocytes, this abluminal endothelial pump may play an important role in removing extracellular K+ released during intense neuronal activity (see Chapter 2). In addition, the nonselective luminal ion channel, a distinct abluminal K+ channel, and abluminal Na+-K+-ATPase may work together to regulate tightly the entry of Na+ and the release or recycling of K+.

The Metabolic Blood-Brain Barrier Transport systems and carriers are not the only components that regulate the composition of the interstitial fluid. A similarly important role is also played by certain enzyme systems specific to the blood-brain barrier. The first recognized and still the best characterized example is the barrier to L-DOPA. Plasma L-DOPA enters brain endothelial cells by means of the L-system amino acid transporter. The relatively high amounts of DOPA decarboxylase and monoamine oxidase in endothelial cells of the barrier rapidly metabolize L-DOPA to 3,4-dihydroxyphenylacetic acid, thereby inhibiting the entry of L-DOPA to the brain (Figure B-5). This explains why effective Parkinson disease therapy requires that L-DOPA be given together with an inhibitor of DOPA decarboxylase. Other bloodborne amines, including catecholamines, are also inactivated by monoamine oxidases of the barrier endothelium. In addition to its proposed role in cystine transport, the abundant endothelial enzyme of the blood-brain barrier, γ-glutamyl transpeptidase, detoxifies glutathione-bound compounds and vasoactive leukotrienes.

Some Areas of the Brain Do Not Have a Blood-Brain Barrier Not all cerebral blood vessels are entirely impermeable. Leaky areas include the posterior pituitary and circumventricular organs such as the area postrema, subfornical organ, the laminar terminalis, subcommissural organ, median eminence, and neurohypophysis. In the posterior pituitary most of the capillaries are fenestrated. Capillaries that are not fenestrated contain many cytoplasmic vesicles that are thought to transport substances across the endothelial cell. These structural features account for the enhanced transport across these cells. The absence of a blood-brain barrier in these regions is consistent with their physiological functions. In the pituitary, neurosecretory products have to pass across endothelial cells into the circulation. The subfornical organ is a chemoreceptive area that monitors blood angiotensin II levels to regulate water balance and other homeostatic functions. These leaky regions are isolated from the rest of the brain by specialized ependymal cells called tanycytes located along the ventricular surface close to the midline. The tanycytes are coupled by tight junctions and prevent free exchange between the circumventricular organs and the CSF.

Brain-Derived Signals Induce Endothelial Cells to Express Blood-Brain Barrier Properties The cellular and molecular signals that induce endothelial expression of the blood-brain barrier phenotype have been elusive. The neural anlagen of the brain is vascularized very early in development through the invasion of proliferating vessels derived from an extraneural vascular plexus. These perineural vessels are composed of fenestrated endothelial cells that have no blood-brain barrier. Soon after penetrating neural tissue (within 2–4 days in the rat), fenestrations are lost. The subsequent expression of different blood-brain barrier properties on the endothelium occurs gradually, suggesting a maturational cascade. The blood-brain barrier properties expressed by brain endothelial cells are believed to be induced by cells within the surrounding brain. Thus, barrier properties will develop in peripheral endothelial cells that invade brain tissue transplants but not in brain endothelial cells that invade peripheral tissue transplants. The cellular origin and biochemical nature of the brain parenchymal signals that induce endothelial barrier formation are not known but may originate from perivascular astroglia. Consistent with an important role for such parenchymal signals is the observation that brain endothelial cells rapidly lose their blood-brain barrier properties when isolated in culture and reexpress barrier properties when reimplanted in the central nervous system. Of the principal cell types that comprise the brain—neurons, oligodendroglia, and astroglia— astroglia are thought to be particularly important for P.1294 this function because of their close association with the abluminal endothelial surface in mature brain. Astroglial cells, particularly in conjunction with cyclic adenosine monophosphate agonists, specifically increase the complexity of interendothelial tight junctions.

Figure B-6 Distribution of CSF. (Adapted from Carpenter 1978 and Fishman 1992.) A. Sites of formation, circulation, and absorption of CSF. All spaces containing CSF communicate with each other. Choroidal and extrachoroidal sources of the fluid exist within the ventricular system. CSF circulates to the subarachnoid space and is absorbed into the venous system via the arachnoid villi. The presence of arachnoid villi adjacent to the spinal roots supplements the absorption into the intracranial venous sinuses. (Adapted from Fishman 1992.) B. The subarachnoid space is bounded externally by the arachnoid membrane and internally by the pia mater, which extends along blood vessels that penetrate the surface of the brain. (Adapted from Carpenter 1978.)

Disorders of the Blood-Brain Barrier A variety of pathological situations are associated with altered blood-brain barrier function. Many brain tumors contain vessels with a poorly developed blood-brain barrier. The least aggressive lowgrade astrocytomas may contain vessels with close-to-normal barrier characteristics. In contrast, malignant primary tumors (ie, anaplastic astrocytoma, glioblastoma) and brain metastases of systemic cancers contain vessels that are excessively leaky and lack the differentiated transport properties of normal blood-brain barrier vessels. The abnormal vessel permeability accounts for the excessive accumulation of interstitial fluid (called vasogenic edema) commonly associated with brain tumors. The abnormal properties of tumor endothelial cells are presumably explained either by the absence of normal interactions between astrocytes and capillaries or by the secretion of factors by tumor cells. Vascular endothelial growth factor/vascular permeability factor is one such factor that may account for the excessive proliferation and permeability of the glioblastoma vessel. Another condition in which the blood-brain barrier is altered is bacterial meningitis. The blood-brain barrier is normally impermeable to antibiotics such as penicillin. Bacterial meningitis, abscesses, and their associated inflammatory responses cause a partial breakdown of the barrier. This barrier response appears to be P.1295 mediated in part by the accumulation of vasoactive eicosanoids and inflammatory cytokines such as tumor necrosis factor. Although this barrier dysfunction accounts for some of the adverse

neurological effects of these infections, it also results in an enhanced ability to deliver antibiotics to the site of infection within the brain. Because the development and function of the normal brain is linked closely to specific anatomical, biochemical, and transport properties of the blood-brain barrier, specific defects in genes that code for barrier endothelial proteins might account for inherited brain disorders. The first developmental disorder of blood-brain barrier transport has been described. Patients with this syndrome are normal at birth but soon develop poorly controlled seizures, diminished brain growth, and mental retardation in association with a substantially diminished concentration of glucose in the CSF. Glucose enters the CSF through Glut1. This transporter is also found in red blood cells. In these patients red blood cell Glut1 is reduced by approximately 50%, suggesting that this syndrome is due to reduced Glut1 gene expression and a subsequent decrease in blood-to-brain glucose transport. The genetic basis for this disorder has yet to be fully defined.

Cerebrospinal Fluids Has Several Functions CSF communicates with brain interstitial fluid and is therefore important in maintaining a constant external environment for neurons and glia. The primarily oneway flow of CSF from the ventricular system, around the spinal cord, into the subarachnoid space around the brain, and into the venous sinuses is a major route for removing potentially harmful brain metabolites. CSF also provides a mechanical cushion to protect the brain from impact with the bony calvarium when the head moves. By its buoyant action, CSF allows the brain to float, thereby reducing its effective weight in situ to less than 50 g. CSF may also serve as a lymphatic system for the brain and as a conduit for polypeptide hormones that are secreted by hypothalamic neurons and that act at remote sites in the brain. The pH of CSF affects both pulmonary ventilation and cerebral blood flow—another example of the homeostatic role of CSF.

Figure B-7 Transport of CSF within the arachnoid villi is thought to be achieved by giant vacuoles. This mechanism could account for the one-way bulk flow of CSF from the subarachnoid space to the venous system. The arachnoid cells have tight intercellular junctions. Some vesicles are large enough to encompass red blood cells. (Adapted from Fishman 1992.)

Cerebrospinal Fluid Is Secreted by the Choroid Plexus CSF is secreted in the lateral ventricles mainly by the choroid plexus (Figure B-6A), which consists of capillary networks surrounded by cuboidal or columnar epithelium. CSF flows from the lateral ventricles through the interventricular foramina of Monro into the third ventricle. From there it flows into the fourth ventricle through the cerebral aqueduct of Sylvius and then through the foramina of Magendie and Luschka into the subarachnoid space. The subarachnoid space lies between the arachnoid and the pia mater, which, together P.1296 with the dura mater, form the three meningeal layers that cover the brain (Figure B-6B). Within the subarachnoid space, fluid flows down the spinal canal and also upward over the convexity of the brain (Figure B-6A). CSF flowing over the brain extends into the sulci and the depths of the cerebral cortex in extensions of the subarachnoid space along blood vessels called Virchow-Robin spaces. Small solutes diffuse freely between the interstitial fluid and the CSF in these perivascular spaces and across the ependymal lining of the ventricular system, facilitating the movement of metabolites from deep within the hemispheres to cortical subarachnoid spaces and the ventricular system. The total CSF volume has not been measured accurately but is estimated to be approximately 140 ml. The lateral and third ventricles contain approximately 12 ml, and the spinal subarachnoid space about 30 ml as measured by computerized tomography. The subarachnoid space and major cisterns (eg, cisterna magna and mesencephalic cistern) of the brain contain most of the CSF. CSF is absorbed through the arachnoid granulations and villi. Arachnoid granulations consist of collections of villi. They are typically found in clusters that are visible herniations of the arachnoid membrane through the dura and into the lumen of the superior sagittal sinus and other venous structures (see Figure B-6A). The villi themselves are visible microscopically and separate CSF from venous blood. Cells of the villus membrane may actively form vacuoles that transport fluid from one side of the cell to the other (Figure B-7).

Figure B-8 Relationships between intracranial fluid compartments and the blood-brain and blood-CSF barriers. The tissue elements indicated in parentheses form the barriers. Arrows indicate the direction of fluid flow under normal conditions. (Adapted from Carpenter 1978.)

Table B-1 Comparision of Serum and Cerebrospinal Fluid Component

CSF1

Serum1

Water content (%)

99

93

Protein (mg/dl) Glucose (mg/dl)

35 60

7000 90

Na+ (meq/liter)

295 138

295 138

K +(meq/liter)

2.8

4.5

Ca2+(meq/liter)

2.1

Mg2+(meq/liter)

0.3

1.7

Cl-(meq/liter)

119

102

pH

7.33

7.41

Osmolarity (mOsm/liter)

1

4.8

Average or representative values.(From Fishman 1980.)

The granulations appear to function as valves that allow one-way flow of CSF from the subarachnoid spaces into venous blood. This one-way flow of CSF is sometimes called bulk flow because all constituents of CSF leave with the fluid, including small molecules, proteins, microorganisms, and red blood cells. The rate of formation of CSF in adults is 0.35 ml/minute or about 500 ml/day, so that the entire volume of CSF is turned over three to four times per day (Figure B-8). The choroid plexus is structurally similar to the distal and collecting tubules of the kidney, using capillary filtration and epithelial secretory mechanisms to maintain the chemical stability of the CSF. The capillaries that traverse the choroid plexus are freely permeable to plasma solutes. A barrier exists, however, at the level of the epithelial cells that make up the choroid plexus. This barrier is responsible for carrier-mediated active transport (Figure B-9). The secretory capacities of the choroid plexus are bidirectional, accounting for both continuous production of CSF and active transport of metabolites out of the central nervous system into the blood. CSF and extracellular fluids of the brain are in a steady state under normal physiological circumstances. The concentrations of K+, Ca2+, bicarbonate, and glucose in CSF are lower than in blood plasma, and CSF is P.1297 also more acidic (Table B-1). These differences are due to regulation of the constituents of CSF by active transport. Under normal conditions, blood plasma and CSF are in osmotic equilibrium, because water follows the osmotic gradient created by active transport of solutes.

Figure B-9 Flow of molecules across the blood-CSF barrier is regulated by several mechanisms in choroid epithelial cells. Some micronutrients such as vitamin C are transported into epithelial cells by an energy-dependent active transporter located at the basolateral membrane and released into CSF at the apical surface by facilitated diffusion, which requires no energy. Essential ions are also exchanged between CSF and blood plasma. Transport of an ion in one direction is linked to the transport of a different ion in the opposite direction, as in the exchange of Na+ ions for K+ ions. (From Spector and Johanson 1989.)

The Composition of Cerebrospinal Fluid May Be Altered in Disease The gross appearance of the CSF has clinical significance. Normally it is clear and colorless. It may appear cloudy when it contains many leukocytes or has a high protein content. It may also appear grossly bloody or yellow (xanthochromia) when blood pigments are left behind after a hemorrhage or when its protein content is greater than 150 mg/dl, indicating that bilirubin (bound to albumin) has been brought from the plasma to the CSF. Normal CSF does not contain red blood cells. White blood cell counts greater than 4/mm3 are pathological. In acute bacterial meningitis the count may be a thousandfold greater. Cells may be increased moderately in viral infections or in response to cerebral infarction, brain tumors, or other damage to cerebral tissue. Tumor cells in CSF can be collected and identified by their characteristic morphology and cell type-specific proteins. Protein content may be increased by many pathological processes of the brain or spinal cord, because of changes in vascular permeability or changes in CSF dynamics due to altered function of choroid plexus or arachnoid granulations. In multiple sclerosis and a few other inflammatory diseases the γ-globulin content of CSF is disproportionately increased to more than 13% of total protein. When this increment in γ-globulin content of CSF is present without a corresponding increase in P.1298 blood γ-globulin, it cannot be attributed to vascular leak and instead results from the production of immunoglobulins within the central nervous system. Similarly, detection by immunoelectrophoresis of two or more oligoclonal immunological species in CSF that are not present in serum indicates immune-mediated brain disease. Oligoclonal immunoglobulins are present in CSF in about 90% of patients with multiple sclerosis. Protein content greater than 500 mg/dl is usually a manifestation of a block in the spinal subarachnoid space by a solid tumor, meningeal cancer, or other compressing lesion.

Figure B-10 Techniques for continuous measurement of intracranial pressure. (From Jennett and Teasdale 1981.)

The concentration of glucose in the CSF is decreased in acute bacterial infections but only rarely in viral infections. In chronic diseases a CSF glucose content less than 40 mg/dl is a symptom of a tumor in the meninges; of fungal, yeast, or tuberculosis infection; or of sarcoidosis. The basis for the reduced CSF glucose content is not yet understood. It may be due to impaired transport into CSF; excessive glycolysis by organisms, blood cells, tumor cells, or the brain itself; or combinations of these mechanisms.

Increased Intracranial Pressure May Harm the Brain In considering the factors that regulate intracranial pressure, the cranium and spinal canal can be regarded as a closed system. According to the Monro-Kellie doctrine, an increase in the volume of any one of the contents of the calvarium—brain tissue, blood, CSF, or other brain fluids—will produce increased intracranial pressure because the bony calvarium rigidly fixes the total cranial volume. Mass lesions and their frequently associated interstitial edema commonly increase intracranial pressure. Changes in arterial and intracranial venous pressures may also influence intracranial pressure by their actions on intracranial blood volume and CSF dynamics. Acute changes in arterial or venous pressures can change intracranial pressure dramatically. Chronic changes may be compensated for by several mechanisms, including venous collateralization and increased absorption or decreased formation of CSF. CSF pressure is ordinarily measured by lumbar puncture, a procedure in which a needle is inserted through the skin, between the fourth and fifth lumbar vertebrae, and into the lumbar subarachnoid space, with the patient lying sideways (lateral decubitus position). Because the spinal cord extends only to the first lumbar vertebra, there is no risk of injuring the cord. When the CSF flows freely through the needle, the hub of the needle is attached to a manometer and the fluid is allowed to rise. The normal pressure is 65–195 mm CSF (or water) or 5–15 mm Hg. In measuring the lumbar CSF pressure as a guide to intracranial pressure, it is assumed that pressures are equal throughout the neuraxis. Normally this is a reasonable assumption; however, in many disease states (eg, brain tumor or obstruction of CSF pathways) this may not be true. For this reason, and also because the lumbar needle cannot be left in place for prolonged periods, catheters are sometimes inserted into the lateral ventricles to measure the pressure there (Figure B-10). P.1299 Equally effective are pressure-sensitive transducers that can be inserted under the skull in the epidural or subarachnoid space for continuous monitoring of intracranial pressure. Continuous monitoring has the advantage of identifying transient elevations in intracranial pressure that can occur in certain disorders such as normal pressure hydrocephalus.

Brain Edema Is A State Of Increased Brain Volume Due To Increased Water Content Brain edema may be local (eg, from a surrounding contusion, infarct, or tumor) or generalized. The brain is divided into distinct compartments by relatively noncompliant membranes. Local brain edema may cause herniation of brain tissue across these membranes from one compartment into another. Specific examples include herniation of cingulate gyrus across the falx cerebri, temporal lobe uncus across the cerebellar tentorium, or the cerebral cortex through calvarial defects after surgery. Vasogenic edema is the most common form of brain edema. It is attributed to increased permeability of brain capillary endothelial cells, which increases the volume of the extracellular fluid. White matter is generally affected more than gray because of the tendency of edema fluid to accumulate along tracts of white matter. Vasogenic edema is most easily visualized using T2-weighted magnetic resonance imaging. Pathological increases in blood-brain barrier permeability also can be visualized by computerized tomography and magnetic resonance imaging after intravenous administration of contrast agents that selectively enter the brain through the affected vessels. Pathologically increased blood brain barrier permeability, particularly that associated with brain tumors, can be corrected by systemically administered glucocorticoids. The mechanism by which glucocorticoids enhance blood-brain barrier function is poorly understood. Cytotoxic edema refers to the intracellular swelling of injured neurons, glia, and endothelial cells. It occurs in hypoxia from asphyxia or global cerebral ischemia after cardiac arrest because failure of the ATP-dependent Na+-K+ pump allows Na+, and therefore water, to accumulate within cells. Another cause of cytotoxic edema is water intoxication, a consequence of the acute systemic hypoosmolarity caused by excessive ingestion of water or administration of hypotonic intravenous fluids. Acute hyponatremia, induced for example by inappropriate secretion of antidiuretic hormone or renal saltwasting from secretion of atrial natriuretic hormone, can cause cellular swelling and brain edema. Under these circumstances water moves from extracellular to intracellular sites. Cytotoxic edema may also accompany vasogenic edema in encephalitis, trauma, and stroke.

Hydrocephalus Is An Increase In The Volume Of The Cerebral Ventricles Hydrocephalus has three possible causes: oversecretion of CSF, impaired absorption of CSF, or obstruction of CSF pathways. Oversecretion of CSF is rare but is thought to occur in some functioning tumors of the choroid plexus (papillomas) because removal of the tumor may relieve the hydrocephalus. These tumors are associated with subarachnoid hemorrhage and high CSF protein content, which could also impair the absorption of CSF. Impaired absorption of CSF may result from any condition that raises intracranial pressure, such as thrombosis of cerebral veins or sinuses. Impaired CSF absorption at the arachnoid villi is a common cause of communicating hydrocephalus (enlargement of the entire ventricular system without obstruction of CSF flow) following subarachnoid hemorrhage, trauma, or bacterial meningitis.

Impaired CSF absorption is also believed to be the cause of normal-pressure hydrocephalus, which is characterized by dementia, urinary incontinence, and a disorder of gait called apraxia. Brain imaging reveals communicating hydrocephalus, and routine lumbar puncture typically shows normal intracranial pressure. Continuous intracranial pressure monitoring reveals episodic elevations in intracranial pressure, however, suggesting that intermittent intracranial hypertension causes the condition. Cisternography reveals alterations in the flow of CSF in these patients. In normal patients technetiumlabeled albumin injected into the lumbar subarachnoid space can be traced by a gamma camera up to the cortical convexities where the arachnoid granulations are located; however, the label does not enter the ventricles. In patients with normal-pressure hydrocephalus the isotopic label reaches the cortical convexities after a prolonged delay and may reflux into the ventricles. If identified early, normal-pressure hydrocephalus can be treated surgically by shunting CSF using a ventriculoperitoneal catheter. Obstruction of CSF pathways may result from tumors, congenital malformations, or scarring. A particularly vulnerable site for all three mechanisms is the narrow aqueduct of Sylvius. Aqueductal stenosis may result from congenital malformations or gliosis due to P.1300 intrauterine infection or hemorrhage. Later in life the aqueduct may be occluded by tumor. The outlets of the fourth ventricle may be obstructed by congenital atresia of the foramina of Luschka and Magendie, which may lead to enlargement of all four ventricles (Dandy-Walker syndrome). In early life the cranial vault enlarges with the ventricles; after the sutures fuse, cranial volume is fixed and hydrocephalus develops at the expense of brain volume.

Selected Readings Bradbury MWB (ed). 1992. Physiology and Pharmacology of the Blood-Brain Barrier. New York: Springer.

Del-Bigio MR. 1993. Neuropathological changes caused by hydrocephalus. Acta Neuropathol (Berlin) 85:573–585.

Doczi T. 1993. Volume regulation of the brain tissue—a survey. Acta Neurochir (Wien) 121:1–9.

Doyle DJ, Mark PW. 1992. Analysis of intracranial pressure. J Clin Monit 8:81–90.

Fishman RA. 1975. Brain edema. N Engl J Med 293:706–711.

Fishman RA. 1992. Cerebrospinal Fluid in Diseases of the Nervous System. Philadelphia, PA: Saunders.

Goldstein GW, Betz AL. 1986. The blood-brain barrier. Sci Am 255(3):74–83.

Greer M. 1988. Carrier drugs: presidential address, American Academy of Neurology, 1987. Neurology 38:628–632.

Kalaria RN, Gravina SA, Schmidley JW, Perry G, Harik SI. 1988. The glucose transporter of the human brain and blood-brain barrier. Ann Neurol 24:757–764.

Katzman R, Pappius HM. 1973. Brain Electrolytes and Fluid Metabolism. Baltimore, MD: Williams & Wilkins.

Keep RF, Xiang J, Betz AL. 1993. Potassium transport at the blood-brain and blood-CSF barriers. Adv Exp Med Biol 331:43–54.

Laterra J, Stewart PA, Goldstein GW. 1991. Development of the blood-brain barrier. In: RA Polin, WW Fox (eds). Neonatal and Fetal Medicine—Physiology and Pathophysiology, pp. 1525–1531. Philadelphia, PA: Saunders.

Lyons MK, Meyer FB. 1990. Cerebrospinal fluid physiology and the management of increased intracranial pressure. Mayo Clin Proc 65:684–707.

Mooradian AD, Morin AM, Cipp LJ, Haspel HC. 1991. Glucose transport is reduced in the blood-brain barrier of aged rats. Brain Res 551:145–149.

Nilsson C, Lindvall-Axelsson M, Owman C. 1992. Neuroendocrine regulatory mechanisms in the choroid plexus— cerebrospinal fluid system. Brain Res Rev 17:109–138.

Pardridge W (ed). 1993. The Blood-Brain Barrier: Cellular & Molecular Biology. New York: Raven.

Rapoport SI. 1976. Blood-Brain Barrier in Physiology and Medicine. New York: Raven.

Ropper AH, Kennedy SF (eds). 1988. Neurological and Neurosurgical Intensive Care. Rockville, MD: Aspen.

Segal MB. 1993. Extracellular and cerebrospinal fluids. J Inherit Metab Dis 16:617–638.

References Betz AL, Goldstein GW. 1986. Specialized properties and solute transport in brain capillaries. Annu Rev Physiol 48:241–250.

Borgesen SE, Gjetrris F. 1982. The predictive value of conductance to outflow of CSF in normal pressure hydrocephalus. Brain 105:65–86.

Borgesen SE, Gjetrris F. 1987. Relationships between intracranial pressure, ventricular size, and resistance to CSF outflow. J Neurosurg 67:535–539.

Brightman MW, Reese TS. 1969. Junctions between intimately apposed cell membranes in the vertebrate brain. J Cell Biol 40:648–677.

Carpenter MB. 1978. Human Neuroanatomy, 7th ed. Baltimore, MD: William & Wilkins.

DeVivo DC, Trifiletti R, Jacobson RI, Harik SI. 1990. Glucose transporter deficiency causing persistent hypoglycorrhachia: a unique cause of infantile seizures and acquired microcephaly. Ann Neurol 29:414–415.

Ehrlich P. 1885. Das Sauerstoff-Bedörfnis des Organismus. Eine Farbenanalytische Studie. Berlin: Hirschwold, cited by Friedemann 1942.

Friedemann U. 1942. Blood-brain barrier. Physiol Rev 22:125–145.

Goldman E. 1909. Die äussere und innere Sekretion des gesunden und kranken Organismus im Lichte der “vitalen Färbung.” Beitr Klin Chirurg 64:192–265.

Guerin C, Laterra J, Hruban R, Brem H, Drewes LR, Goldstein GW. 1990. The glucose transporter and blood-brain barrier of human brain tumors. Ann Neurol 28:758–765.

Guerin C, Laterra J, Drewes L, Brem H, Goldstein GW. 1992. Vascular expression of glucose transporter in experimental brain neoplasms. Am J Pathol 140:114–125.

Hansen AJ, Lund-Andersen H, Crone C. 1977. K+- permeability of the blood-brain barrier, investigated by aid of a K+-sensitive microelectrode. Acta Physiol Scand 101:438–445.

Jennett B, Teasdale G. 1981. Management of Head Injuries. Philadelphia, PA: Davis.

Lal B, Indurti RR, Couraud P-O, Goldstein GW, Laterra J. 1994. Endothelial cell implantation and survival within experimental gliomas. Proc Natl Acad Sci U S A 21:9695–9699.

Reese TS, Karnovsky MJ. 1967. Fine structural localization of a blood-brain barrier to exogenous peroxidase. J Cell Biol 34:207–217. P.1301

Resnick L, Berger JR, Shapshak P, Tourtellotte WW. 1988. Early penetration of the blood-brain barrier by HIV. Neurology 38:9–14.

Rubin LL, Hall DE, Porter S, Barbu K, Cannon C, Horner HC, Janatpour M, Liaw CW, Manning K, Morales J, Tanner LI, Toamselli KJ, Bard F. 1991. A cell culture model of the blood-brain barrier. J Cell Biol 115:1725–1735.

Schinkel AH, Smit JJM, Vantellingen O, Beijnen JH, Wagenaar E, Vandeemter L, Mol CAAM, Vandervalk MA, Robanusmaandag EC, Teriele HPJ, Berns AJM, Borst P. 1994. Disruption of the mouse mdr1a P-glycoprotein gene leads to a deficiency in the blood-brain barrier and to increased sensitivity to drugs. Cell 77:491–502.

Shivers RR, Betz AL, Goldstein GW. 1984. Isolated rat brain capillaries possess intact, structurally complex, interendothelial tight junctions; freeze-fracture verification of tight junction integrity. Brain Res 324:313–322.

Spector R, Johanson CE. 1989. The mammalian choroid plexus. Sci Am 261(5):68–74.

Stewart PA, Wiley MJ. 1981. Developing nervous tissue induces formation of blood-brain barrier characteristics in invading endothelial cells: a study using quail-chick transplantation chimeras. Dev Biol 84:183–192.

Svengaard N, Bjorklund A, Hardebo JE, Stenevi U. 1975. Axonal degeneration associated with a defective blood-brain barrier in cerebral implants. Nature 255:334–336.

Wahl M, Unterberg A, Baerthmann A, Schilling L. 1988. Mediators of blood-brain barrier dysfunction and formation of vasogenic brain edema. J Cereb Blood Flow Metab 8:621–634.

Wolburg H, Neuhaus J, Kniesel U, Kraub B, Schmid E-M, Ocalan M, Farrell C, Risau W. 1994. Modulation of tight junction structure in blood-brain barrier endothelial cells: Effects of tissue culture, second messengers, and cocultured astrocytes. J Cell Sci 107:1347–1357. P.1302

Appendix C Circulation of the Brain John C.M. Brust THE BRAIN IS HIGHLY vulnerable to disturbance of its blood supply. Anoxia and ischemia lasting only seconds cause neurological symptoms and when they last minutes they can cause irreversible neuronal damage. Blood flow to the central nervous system must efficiently deliver oxygen, glucose, and other nutrients and remove carbon dioxide, lactic acid, and other metabolic products. The cerebral vasculature has unique anatomical and physiological features that protect the brain from circulatory compromise. When these protective mechanisms fail, the result is a stroke. Broadly defined, the term stroke, or cerebrovascular accident, refers to the neurological symptoms or signs, usually focal and acute, that result from diseases involving blood vessels.

The Blood Supply Of The Brain Can Be Divided Into Arterial Territories Each cerebral hemisphere is supplied by an internal carotid artery, which arises from a common carotid artery beneath the angle of the jaw, enters the cranium through the carotid foramen, traverses the cavernous sinus (giving off the ophthalmic artery), penetrates the dura, and divides into the anterior and middle cerebral arteries (Figure C-1). The large surface branches of the anterior cerebral artery supply the cortex and white matter of the inferior frontal lobe, the medial surface of the frontal and parietal lobes, and the anterior corpus callosum. Smaller penetrating branches—including the so-called recurrent artery of Heubner—supply the deeper cerebrum and diencephalon, including limbic structures, P.1303 P.1304 the head of the caudate, and the anterior limb of the internal capsule.

Figure C-1 The blood vessels of the brain. The circle of Willis is made up of the proximal posterior cerebral arteries, the posterior communicating arteries, the internal carotid arteries just before their bifurcations, the proximal anterior cerebral arteries, and the anterior communicating artery. Dark areas show common sites of atherosclerosis and occlusion.

Figure C-2 Cerebral arterial areas.

The large surface branches of the middle cerebral artery supply most of the cortex and white matter of the hemisphere's convexity, including the frontal, parietal, temporal, and occipital lobes, and the insula. Smaller penetrating branches (the lenticulostriate arteries) supply the deep white matter and diencephalic structures, such as the posterior limb of the internal capsule, the putamen, the outer globus pallidus, and the body of the caudate. After the internal carotid emerges from the cavernous sinus, it also gives off the anterior choroidal artery, which supplies the anterior hippocampus and, at a caudal level, the posterior limb of the internal capsule. Left and right vertebral arteries arise from the subclavian arteries and enter the cranium through the foramen magnum. Each gives off an anterior spinal artery and a posterior inferior cerebellar artery. The vertebral arteries join at the junction of the pons and the medulla to form the basilar artery, which at the level of the pons gives off the anterior inferior cerebellar artery and the internal auditory artery and at the midbrain the superior cerebellar artery. The basilar artery then divides into the two posterior cerebral arteries, which supply the inferior temporal and medial occipital lobes and the posterior corpus callosum. The smaller penetrating branches of these vessels (the thalamoperforate and thalamogeniculate arteries) supply diencephalic structures, including the thalamus and the subthalamic nuclei, as well as parts of the midbrain. These arterial territories are shown schematically in Figure C-2. Infarctions in the territories of the anterior, middle, and posterior cerebral arteries are shown in Figures C-3, C-4, and C-5. Interconnections between blood vessels (anastomoses) protect the brain when part of its vascular supply is blocked (Figure C-6). At the circle of Willis the two anterior cerebral arteries are connected by the anterior communicating artery, and the posterior cerebral arteries are connected to the internal carotid arteries by the posterior communicating arteries. The circle of Willis provides an overlapping blood supply. A congenitally incomplete circle, which is common in the general population, is much more frequent among patients who have had strokes. Other important anastomoses include connections between the ophthalmic artery and branches of the external carotid artery through the orbit, and connections at the brain surface between branches of the middle, anterior, and posterior cerebral arteries (sharing border zones or watersheds). The small penetrating vessels arising from the circle of Willis and proximal major arteries tend to lack anastomoses. The deep brain regions they supply are therefore referred to as end zones.

Figure C-3 CT scan showing infarction (dark area) in the territory of the anterior cerebral artery. (Courtesy of Dr. Allan J. Schwartz.)

Figure C-4 CT scan showing infarction (dark area) in the territory of the middle cerebral artery. (Courtesy of Dr. Allan J. Schwartz.)

P.1305

The Crebral Vessels Have Unique Physiological Responses Although the human brain constitutes only 2% of total body weight, it receives about 15% of the cardiac output and consumes approximately 20% of the oxygen used by the entire body. These values reflect the high metabolic rate and oxygen requirements of the brain. The total blood flow to the brain is about 750–1000 ml/min; about 350 ml of this amount flows through each carotid artery and about 100–200 ml flows through the vertebrobasilar system. Flow per unit mass of gray matter is approximately four times that of white matter. Cerebral vessels are capable of altering their own diameter and can respond in a unique fashion to altered physiological conditions. Two main types of autoregulation exist. Brain arterioles constrict when the systemic blood pressure is raised and dilate when it is lowered. These adjustments help to maintain optimal cerebral blood flow. The result is that normal individuals have a constant cerebral blood flow between mean arterial pressures of approximately 60–150 mm Hg. Above or below these pressures cerebral blood flow rises or falls linearly. The second type of autoregulation involves blood or tissue gases and pH. When arterial CO2 is raised, brain arterioles dilate and cerebral blood flow increases; with hypocarbia, vasoconstriction results and cerebral blood flow decreases. The response is very sensitive: inhalation of 5% CO2 increases cerebral blood flow by 50%; 7% CO2 doubles it. Changing arterial O2 causes an opposite and less pronounced response: Breathing 100% O2 lowers cerebral blood flow by about 13%; 10% O2 raises it by 35%. The mechanism of these responses is uncertain. The vasodilatory action of arterial CO2 is probably mediated by alterations in extracellular pH. Local concentrations of K+ and adenosine, both of which cause vasodilation in animals, may play a role. Whatever the mechanism, these responses protect the brain by increasing the delivery of oxygen and the removal of acid metabolites in the presence of hypoxia, ischemia, or tissue damage. They also allow nearly instantaneous adjustments of regional cerebral blood flow to meet the demands of rapidly changing oxygen and glucose metabolism that accompany normal brain activities. For example, viewing a complex scene will increase oxygen and glucose consumption in the visual P.1306 cortex of the occipital lobes. The resulting increased CO2 concentration and lowered pH in the area cause an immediate local increase in blood flow.

Figure C-5 CT scan showing infarction (dark area) in the territory of the posterior cerebral artery. (Courtesy of Dr. Allan J. Schwartz.)

A Stroke Is the Result of Diseases Involving Blood Vessels Diseases of the blood vessels are among the most frequent serious neurological disorders, ranking third as a cause of death in the adult population in the United States and probably first as a cause of chronic functional incapacity. Approximately two million people in the United States today are impaired by the neurological consequences of cerebrovascular disease. Many of them are between 25 and 64 years of age. Strokes are either occlusive (due to closure of a blood vessel) or hemorrhagic (due to bleeding from a vessel). Insufficiency of blood supply is termed ischemia; if it is temporary, symptoms and signs may clear with little or no pathological evidence of tissue damage. Ischemia is not synonymous with anoxia, for a reduced blood supply deprives tissue not only of oxygen but also of glucose. In addition, it prevents the removal of potentially toxic metabolites such as lactic acid. When ischemia is sufficiently severe and prolonged, neurons and other cellular elements die; this condition is called

infarction. Hemorrhage may occur at the brain surface (extraparenchymal), for example, from rupture of congenital aneurysms at the circle of Willis, causing subarachnoid hemorrhage. Alternatively, hemorrhage may be intraparenchymal —for example, from rupture of vessels damaged by long-standing hypertension—and may cause a blood clot or hematoma within the cerebral hemispheres, in the brain stem, or in the cerebellum. Hemorrhage may result in ischemia or infarction. The mass effect of an intracerebral hematoma may limit the blood supply of adjacent brain tissue. By mechanisms that are not understood, subarachnoid hemorrhage may cause reactive vasospasm of cerebral surface vessels, leading to further ischemic brain damage. Although most occlusive strokes are due to atherosclerosis and thrombosis and most hemorrhagic strokes are associated with hypertension or aneurysms, strokes of either type may occur at any age from many causes, including cardiac disease, trauma, infection, neoplasm, blood dyscrasia, vascular malformation, immunological disorder, and exogenous toxins. Diagnostic strategies and treatment should vary accordingly; however, in this appendix we examine the anatomical and physiological principles relevant to any occlusive or hemorrhagic stroke.

Clinical Vascular Syndromes May Follow Vessel Occlusion, Hypoperfusion, Or Hemorrhage Infarction Can Occur in the Middle Cerebral Artery Territory Infarction in the territory of the middle cerebral artery (cortex and white matter) causes the most frequently encountered stroke syndrome, with contralateral weakness, sensory loss, and visual field impairment (homonymous hemianopsia), and, depending on the hemisphere involved, either language disturbance or impaired spatial perception. Weakness and sensory loss affect the face and arm more than the leg because of the somatotopy of the motor and sensory cortex (pre- and postcentral gyri). The face- and arm-control areas are on the convexity, whereas the leg-control area is on the medial surface of the hemisphere. Motor and sensory loss are greatest in the hand, for the more proximal limbs and the trunk tend to have greater representation in both hemispheres. Paraspinal muscles, for example, are P.1307 rarely weak in unilateral cerebral lesions. Similarly, the facial muscles of the forehead and the muscles of the pharynx and jaw are represented in both hemispheres and therefore are usually spared. Tongue weakness is variable. If weakness is severe (plegia), muscle tone is usually decreased at first but gradually increases over days or weeks to spasticity with hyperactive tendon reflexes. A Babinski sign, reflecting upper motor neuron disturbance (see Chapters 33 and 38), is usually present from the outset. When weakness is mild, or during recovery, there may be clumsiness or slowness of movement out of proportion to loss of strength; such motor disability may resemble parkinsonian bradykinesia or even cerebellar ataxia.

Figure C-6 Angiograms demonstrating the importance of anastomoses in that they allow retrograde filling after occlusion of the middle cerebral artery. A. Occlusion of the middle cerebral artery results in no filling in the middle cerebral distribution. B. Retrograde filling of the middle cerebral artery has begun via distal anastomotic branches of the anterior cerebral artery. C. Retrograde filling of the middle cerebral artery continues at a time when little contrast material is seen in the anterior cerebralartery. (Courtesy of Dr. Margaret Whelan and Dr. Sadek K. Hilal.)

Acutely, paresis of contralateral conjugate gaze often occurs as a result of damage to the convexity of the cortex anterior to the motor cortex (the frontal eye field). The reason this gaze palsy persists for only 1 or 2 days, even when other signs remain severe, is not clear. Sensory loss tends to involve discriminative and proprioceptive modalities more than affective modalities. Pain and temperature sensation may be impaired or altered but are usually not lost. Joint position sense, however, may be severely disturbed, causing limb ataxia, and there may be loss of two-point discrimination, astereognosis (inability to recognize a held object by tactile sensation), or extinction (failure to appreciate a touch stimulus if a comparable stimulus is delivered simultaneously to the unaffected side of the body). Homonymous hemianopsia is the result of damage to the optic radiations, the deep fiber tracts connecting the thalamic lateral geniculate body to the visual (calcarine) cortex. If the parietal radiation is

primarily affected, the visual field loss may be an inferior quadrantanopia, whereas in temporal lobe lesions quadrantanopia may be superior. In more than 95% of right-handed persons and in the majority of those who are left handed, the left hemisphere is dominant for language. Destruction of left opercular (perisylvian) cortex in leftdominant individuals causes aphasia, which may take several forms deP.1308 pending on the degree and distribution of the damage. Frontal opercular lesions tend to produce particular difficulty with speech output and writing with relative preservation of language comprehension (Broca aphasia), whereas infarction of the posterior superior temporal gyrus tends to cause severe difficulty in speech comprehension and reading (Wernicke aphasia). When opercular damage is widespread, there is severe disturbance of mixed type (global aphasia). Left-hemisphere convexity damage, especially parietal, may also cause motor apraxia, a disturbance of learned motor acts not explained by weakness or incoordination, with the ability to perform the act when the setting is altered (see Chapters 19 and 59). For example, a patient unable to imitate lighting a match might be able to perform the act normally if given a match to light. Right-hemisphere convexity infarction, especially parietal, tends to cause disturbances of spatial perception. Patients may have difficulty in copying simple pictures or diagrams (constructional apraxia), in interpreting maps or finding their way about (topographagnosia), or in putting on their clothing properly (dressing apraxia). Awareness of space and the patient's own body contralateral to the lesion may be particularly affected (hemi-inattention or hemineglect). Patients may fail to recognize their hemiplegia (anosognosia), left arm (asomatognosia), or any external object to the left of their own midline. Such phenomena may occur independently of visual field defects and in patients otherwise mentally intact (see Chapter 20). Particular types of language or spatial dysfunction tend to follow occlusion not of the proximal stem of the middle cerebral artery but of one of its several main pial branches. In such circumstances other signs (eg, weakness or visual field defect) may not be present. Similarly, occlusion of the rolandic branch of the middle cerebral artery may cause motor and sensory loss affecting the face and arm without disturbance of vision, language, or spatial perception.

Infarction Can Occur in the Anterior Cerebral Artery Territory Infarction in the territory of the anterior cerebral artery causes weakness and sensory loss qualitatively similar to that of convexity lesions, but infarction in this territory affects mainly the distal contralateral leg. Urinary incontinence may be present, but it is uncertain whether this is because of a lesion of the paracentral lobule (medial hemispheric motor and sensory cortices) or of a more anterior region necessary for the inhibition of bladder emptying. Damage to the supplementary motor cortex may cause speech disturbance, considered aphasia by some and a type of motor inertia by others. Involvement of the anterior corpus callosum may cause apraxia of the left arm (sympathetic apraxia), which is attributed to disconnection of the left (languagedominant) hemisphere from the right motor cortex. Bilateral anterior cerebral artery territory infarction (occurring, for example, when both arteries arise anomalously from a single trunk) may cause a severe behavioral disturbance, known as abulia, consisting of profound apathy, motor inertia, and muteness, and attributable to destruction, in variable combinations, of the inferior frontal lobes (orbitofrontal cortex), deeper limbic structures, supplementary motor cortices, and cingulate gyri.

Infarction Can Occur in the Posterior Cerebral Artery Territory Infarction in the territory of the posterior cerebral artery causes contralateral homonymous hemianopsia by destroying the calcarine cortex. Macular (central) vision tends to be spared because the occipital pole, where macular vision is represented, receives blood supply from the middle cerebral artery. If the lesion is on the left and the posterior corpus callosum is affected, alexia—inability to read—may be present without aphasia or agraphia. A possible explanation for the alexia is the disconnection of the seeing right occipital cortex from the language-dominant left hemisphere. If infarction is bilateral (eg, following thrombosis at the point where both posterior cerebral arteries arise from the basilar artery), there may be cortical blindness with failure of the patient to recognize that he cannot see (Anton syndrome), or memory disturbance may occur as a result of bilateral damage to the inferomedial temporal lobes. If posterior cerebral artery occlusion is proximal, the lesion may include, or especially affect, the following structures: the thalamus, causing contralateral hemisensory loss and sometimes spontaneous pain and dysesthesia (thalamic pain syndrome); the subthalamic nucleus, causing contralateral severe proximal chorea (hemiballism); or even the midbrain, with ipsilateral oculomotor palsy and contralateral hemiparesis or ataxia from involvement of the corticospinal tract or the crossed superior cerebellar peduncle (dentatothalamic tract).

The Anterior Choroidal and Penetrating Arteries Can Become Occluded Anterior choroidal artery occlusion can cause contralateral hemiplegia and sensory loss from involvement of P.1309 the posterior limb of the internal capsule and homonymous hemianopsia from involvement of the thalamic lateral geniculate nucleus. As mentioned earlier in this chapter, the deeper cerebral white matter and diencephalon are supplied by small penetrating arteries, variously called the lenticulostriates, the thalamogeniculates, or the thalamoperforates, which arise from the circle of Willis or the proximal portions of the middle, anterior, and posterior cerebral arteries. These end-arteries lack anastomotic interconnections, and occlusion of individual vessels, usually in association with hypertensive damage to the vessel wall, causes small (less than 1.5 cm in diameter) infarcts (lacunes), which, if critically located, are followed by characteristic syndromes. For example, lacunes in the pyramidal tract area of the internal capsule cause pure hemiparesis, with arm and leg weakness of equal severity and with little or no sensory loss, visual field disturbance, aphasia, or spatial disruption. Lacunes in the ventral posterior nucleus of the thalamus produce pure hemisensory loss, with involvement of pain, temperature, proprioceptive, and discriminative modalities and with little motor, visual, language, or spatial disturbance. Most lacunes occur in redundant areas (eg, nonpyramidal corona radiata) and so are asymptomatic. If bilateral and numerous, however, they may cause a characteristic syndrome (état lacunaire) of progressive dementia, shuffling gait, and pseudobulbar palsy (spastic dysarthria and dysphagia, with lingual and pharyngeal paralysis and hyperactive palate and gag reflexes, plus lability of emotional response, with abrupt crying or laughing out of proportion to mood). Infarction restricted to structures supplied by the recurrent artery of Heubner or other deep penetrating branches of the anterior cerebral artery (the anterior caudate nucleus and less predictably the anterior putamen and anterior limb of the internal capsule) results in varying combinations of psychomotor slowing, dysarthria, agitation, contralateral neglect, and, when left hemispheric, language disturbance.

The Carotid Artery Can Become Occluded Atherothrombotic vessel occlusion often occurs in the internal carotid artery rather than the intracranial vessels. Particularly in a patient with an incomplete circle of Willis, infarction may include the territories of both the middle and anterior cerebral arteries, with arm and leg weakness and sensory loss equally severe. Alternatively, infarction may be limited to the distal shared territory (border zones of these vessels), producing, by destruction of the motor cortex at the upper cerebral convexity, weakness limited to the arm or the leg. Another cause of leg weakness and sensory loss in association with a convexity syndrome is occlusion of the middle cerebral artery at its proximal stem; the internal capsule and other diencephalic structures supplied by the middle cerebral artery's lenticulostriate branches are then affected in addition to the cortex of the cerebral convexity.

The Brain Stem and Cerebellum Are Supplied by Branches of the Vertebral and Basilar Arteries Branches of the vertebral and basilar arteries consist of three sets: (1) Paramedian branches, including the anterior spinal artery, supply midline structures; (2) short circumferential branches supply more lateral structures, including the inferior, middle, and superior cerebral peduncles; and (3) long circumferential arteries—the posterior inferior, anterior inferior, and superior cerebellar arteries—also supply lateral brain stem structures and the cerebellar peduncles, as well as the cerebellum itself. Most of the midbrain is supplied by branches of the posterior cerebral artery. The interpeduncular branches, the most medial branches located between the basilar artery bifurcation and the posterior communicating arteries, supply paramedian midbrain structures. Lateral to this group are the thalamoperforate branches, which supply the inferior, medial, and anterior thalamus and the subthalamic nucleus. Further laterally are the thalamogeniculate branches, which supply lateral and dorsal structures in the midbrain and thalamus. In some people the midbrain also receives blood from the superior cerebellar, posterior communicating, and anterior choroidal arteries. After the posterior cerebral artery passes around the midbrain, it enters the middle fossa to supply the occipital and inferior temporal lobes. It does not supply the cerebellum. Various syndromes resulting from damage to specific brain stem structures have been defined (Figure C-7). With the exception of the lateral medullary syndrome of Wallenberg, however, most of the original descriptions were based on patients with neoplasms. Brain stem infarction more often follows occlusion of the vertebral or basilar arteries themselves than of their medial or lateral branches; resulting syndromes and signs tend to be less stereotyped than classical descriptions imply. Generally speaking, a lesion of the posterior fossa is suggested by (1) bilateral long tract (motor or sensory) signs, (2) crossed (eg, left face and right limb) motor or sensory signs, (3) cerebellar signs, (4) stupor or coma (from involvement of the ascending reticular activating system), (5) disconjugate eye movements or nystagmus, and (6) involvement of cranial nerves not usually affected by unilateral hemispheric infarcts (eg, unilateral P.1310 deafness or pharyngeal weakness). Sometimes a lesion involving only a single tiny structure can be localized accurately by symptomatology. For example, internuclear opthalmoplegia implicates a lesion of the median longitudinal fasciculus. Other lesions produce more ambiguous symptoms. For example, infarction limited to the upper pontine corticospinal tract can produce contralateral face, arm, and leg weakness indistinguishable from that caused by a small infarct in the internal capsule.

Figure C-7 Syndromes of brain stem vascular lesions (indicated on the left in each figure).

Figure C-8 Magnetic resonance imaging shows a white highlight in the ventral portion of one half of the pons. The lesion stops abruptly at the midline, suggesting unilateral occlusion of one or more paramedian vessels.

P.1311

Infarcts Affecting Predominantly Medial or Lateral Brain Stem Structures Produce Characteristic Syndromes Infarction of the lateral medulla follows occlusion of the vertebral artery or less often the posterior inferior cerebellar artery. Symptoms and signs include (1) vertigo, nausea, vomiting, and nystagmus (from involvement of the vestibular nuclei); (2) ataxia of gait and ipsilateral limbs (inferior cerebellar peduncle or the cerebellum itself); (3) decreased pain and temperature (but not touch) sensation on the ipsilateral face (descending tract and nucleus of the trigeminal nerve) and the contralateral body (spinothalamic tract); (4) dysphagia, hoarseness, ipsilateral weakness of the palate and vocal cords, and ipsilaterally decreased gag reflex (nucleus ambiguus, or glossopharyngeal and vagus outflow tracts); and (5) ipsilateral Horner syndrome (descending sympathetic fibers). Involvement of the nucleus solitarius can cause ipsilateral loss of taste, and hiccups are often present (Table C-1). Infarction of the medial medulla causes contralateral hemiparesis (from involvement of the corticospinal tract), ipsilateral tongue weakness with dysarthria and deviation toward the paretic side (hypoglossal nucleus or outflow tract), and contralateral impaired proprioception and discriminative sensation with preserved pain and temperature sensation (medial lemniscus).

Infarction of the lateral pons affects caudal structures when the anterior inferior cerebellar artery is occluded and rostral structures when the superior cerebellar artery is occluded (Figure C-8). Symptoms of caudal damage resemble those of lateral medullary infarction, with vertigo, nystagmus, gait and ipsilateral limb ataxia, crossed face-and-body pain and temperature loss, Horner syndrome, and ipsilateral loss of taste. There is also unilateral tinnitus and deafness (from involvement of the cochlear nuclei). Involvement of more medial structures can cause ipsilateral gaze paresis or facial weakness. Symptoms of rostral damage include gait and ipsilateral limb ataxia, Horner syndrome, and crossed sensory loss, which at this level includes touch, pain, and temperature sensation on the ipsilateral face (from involvement of the primary sensory nucleus or entering sensory fibers of the trigeminal nerve). There may also be ipsilateral jaw weakness with deviation to the paretic side (trigeminal motor nucleus and outflow tract). Vertigo, deafness, and face weakness are not present. Infarction of the medial pons, whether caudal or rostral, causes contralateral hemiparesis (from involvement of the corticospinal tract). Caudal lesions affecting the facial nucleus or outflow tract cause ipsilateral facial weakness. Rostral lesions result in contralateral facial weakness. There may also be ipsilateral gaze paresis (paramedian pontine reticular formation or abducens nucleus, together comprising the pontine gaze center) or abducens paresis (sixth nerve outflow tract); internuclear ophthalmoplegia and limb and gait ataxia are often present. Contralateral impairment of proprioception and discriminative touch is most prominent with caudal lesions. Rapid involuntary movements of the palate—so-called palatal myoclonus—has been attributed to involvement of the central tegmental tract; theinvoluntary movements may spread to include the pharynx, larynx, face, eyes, or respiratory muscles. Table C-1 Signs That indicate the Level of Brain Stem Vascular Syndromes Syndrome

Artery affected

Structure involved

Manifestations

Medial syndromes Medulla Inferior pons

Paramedian branches Paramedian branches

Emerging fibers of twelfth nerve Pontine gaze center Emerging fibers of sixth nerve

Ipsilateral hemiparalysis of tongue Paralysis of gaze to side of lesion Ipsilateral abduction paralysis

Superior pons Lateral syndromes

Paramedian branches

Medial longitudinal fasciculus

Internuclear ophthalmoplegia

Medulla

Posterior inferior cerebellar

Emerging fibers of ninth or tenth nerves Vestibular nuclei Descending tract

Dysphagia; hoarseness; ipsi-lateral paralysis of vocal cord; ipsilateral loss of pharyngeal reflex Vertigo;

Inferior pons Mid pons

Anterior inferior cerebellar

and nucleus of fifth nerve Solitary nucleus and tract Emerging fibers of seventh nerve Solitary nucleus and tract Cochlear nuclei Motor nucleus of fifth nerve Emerging sensory fibers of fifth nerve

nystagmus Ipsilateral facial analgesia Taste loss on ipsilateral half of tongue posteriorly Ipsilateral facial paralysis Taste loss on ipsilateral half of tongue anteriorly Deafness; tinnitus Ipsilateral jaw weakness Ipsilateral facial numbness

P.1312 Syndromes of midbrain infarction are more conveniently characterized as peduncular (ventral), tegmental, or pretectal/tectal (dorsal) (Figure C-9). Unilateral peduncular lesions cause Weber syndrome, characterized by ipsilateral paresis of adduction and vertical gaze and pupillary dilation (involvement of oculomotor nerve outflow tract) and contralateral face, arm, and leg paresis (corticospinal and corticobulbar tracts). Unilateral tegmental lesions cause Claude syndrome, characterized by oculomotor paresis (oculomotor nucleus) and contralateral ataxia and tremor (often referred to as rubral tremor but probably the result of damage to the brachium conjunctivum). Lesions affecting both the peduncle and tegmentum produce combinations of oculomotor paresis, ataxia, and weakness (Benedikt syndrome). Dorsal midbrain lesions, which are infrequently vascular and rarely unilateral, cause Parinaud syndrome, characterized by impaired vertical gaze—especially upward (posterior commissure and the rostral interstitial nucleus of the median longitudinal fasciculus)—and loss of the pupillary light reflex (pretectal structures).

Bilateral Brain Stem Lesions Can Have Devastating Consequences Bilateral paramedian infarction of the upper brain stem can involve the reticular activating system and cause obtundation or coma. Bilateral damage of the proximal posterior cerebral artery produces altered consciousness and various combinations of mesencephalic, diencephalic, and cortical signs (top of the basilar artery syndrome), affecting eye movements, pupils, vision P.1313 (including, even without visual loss, vivid formed hallucinations), sensation, coordination, memory, and behavior (including agitated delirium). Bilateral corticospinal tract infarction causes quadriparesis or quadriplegia; additional cranial weakness depends on how rostral or caudal the lesion is. Bilateral infarction of the rostral basis pontis (with sparing of the tegmentum) produces paralysis of all muscles except eye movements, the so-called locked-in state. Such a patient may appear comatose yet is awake and able to communicate through eye movements. Less severe damage to the corticospinal tracts in the rostral brain stem can cause pseudobulbar palsy, with spastic quadriparesis, dysarthria, dysphagia, a hyperactive gag reflex, and for reasons unclear, labile emotional responses with explosive crying or laughing.

Infarction Can Be Restricted to the Cerebellum Infarcts of the inferior cerebellum, which has extensive vestibular connections, can cause vertigo, nausea, and nystagmus without other symptoms, suggesting disease of the inner ear or vestibular nerve. (Similar symptoms, with or without tinnitus or deafness, can occur following occlusions of the internal auditory artery, arising from the basilar artery and supplying the peripheral labyrinth.) More superior cerebellar infarcts produce gait and ipsilateral limb ataxia.

Infarction Can Affect the Spinal Cord The ventral spinal cord is supplied by a single anterior spinal artery; the dorsal spinal cord is supplied by two or more posterior spinal arteries (Figure C-10). Except most rostrally, where the anterior spinal artery arises from the joining of two vertebral artery branches, the anterior and posterior spinal arteries are fed along their course by several radicular arteries, which arise from segmental branches of the aorta and iliac arteries. Moreover, whereas the posterior spinal arteries are longitudinally continuous and anastomotic, the anterior spinal artery's continuity is tenuous, making the anterior spinal cord more dependent on its segmental supply. The upper thoracic spinal cord is especially vulnerable in this regard. Vascular anatomy explains the characteristic pattern of spinal cord infarction. Vessel occlusion is usually in a proximal segmental artery; because of the anastomotic continuity of the posterior spinal arteries, infarction tends to be limited to the anterior spinal artery territory. There is paraparesis or quadriparesis (corticospinal tracts), loss of bladder and bowel control, and loss of pain and temperature sensation below the lesion (spinothalamic tracts), but proprioception and discriminative touch (dorsal columns) are spared. If the cervical or lumbar spinal cord is involved, atrophic weakness of upper or lower extremity muscles (anterior horns) can occur. Because the anterior spinal artery gives off sulcal arteries that alternately enter the left and right halves of the spinal cord, infarction can sometimes produce a Brown-Séquard syndrome, with ipsilateral weakness and contralateral loss of pain and temperature sensation.

Figure C-9 The three midbrain syndromes.

Diffuse Hypoperfusion Can Cause Ischemia or Infarction Brain ischemia or infarction may accompany diffuse hypoperfusion (shock). In such circumstances the most vulnerable regions are often the border zones between large arterial territories and the end

zones of deep penetrating vessels. Whatever the cause of reduced cerebral perfusion, signs tend to be bilateral. Paralysis and sensory loss may be present in both arms (from bilateral infarction of the cortex at the junction of the middle and anterior arterial supply, affecting the arm-control area of the motor and sensory cortex). Disturbed vision or memory may result (from infarction of the occipital or temporal lobes at the junction of the middle and posterior cerebral arterial supply). There may also be ataxia (from cerebellar border-zone infarction) or abnormal movements such as chorea or myoclonus (presumably from involvement of the basal ganglia). Such signs may exist alone or in combination and may be accompanied by a variety of aphasic or other cognitive disturbances. P.1314 Hypotension can also cause spinal cord infarction, most often upper thoracic, affecting either the territory of the anterior spinal artery or the border zone between the anterior and posterior spinal arteries.

Figure C-10 Diagram of the major sources of blood supply to the spinal cord. Anterior spinal rami are not shown

Cerebrovascular Disease Can Cause Dementia Cerebral infarction causes dementia by a number of mechanisms, including:

●

Infarcts may be critically located. For example, thalamic or inferomedial temporal damage (posterior cerebral artery, usually bilateral) can cause amnesia; hemispheric convexity damage (middle cerebral artery) can cause cognitive or behavioral impairment not explained by disruption of language or spatial discrimination; and bilateral inferomedial frontal lobe damage (anterior cerebral artery) can cause abulia and impaired memory. ●

Multiple scattered infarcts, none sufficient to cause significant cognitive loss, can produce additive effects culminating in dementia. In such patients at least 100 cc of brain volume has usually been destroyed. ●

Small vessel disease, affecting especially the deep cerebral white matter, can cause either scattered lacunes or more diffuse ischemic lesions. When such lesions are severe enough to cause dementia— so-called Binswanger disease—altered behavior, pseudobulbar palsy, pyramidal signs, disturbed gait, andurinary incontinence usually occur.

P.1315

The Rupture of Microaneurysms Causes Intraparenchymal Stroke The two most common causes of hemorrhagic stroke, hypertensive intra-axial hemorrhage and rupture of a saccular aneurysm, tend to occur at particular sites and to cause recognizable syndromes. Hypertensive intercerebral hemorrhage is the result of damage to the same small penetrating vessels that, when occluded, cause lacunes; in the case of hemorrhage, however, the damaged vessels develop weakened walls (Charcot-Bouchard microaneurysms) that eventually rupture. The most common sites are the putamen, thalamus, pons, internal capsule and corona radiata, and cerebellum. Large diencephalic hemorrhages tend to cause stupor and hemiplegia and have a high mortality rate. With lesions of the putamen the eyes are usually deviated ipsilaterally (because of disruption of capsular pathways descending from the frontal eye field), whereas with thalamic hemorrhage the eyes tend to be deviated downward and the pupils may not react to light (because of involvement of midbrain pretectal structures essential for upward gaze and pupillary light reactivity). Small hemorrhages may not impair alertness, and, with small thalamic hemorrhages, the motor sensory loss may exceed the weakness. Moreover, computerized tomography has shown that small thalamic hemorrhages may cause aphasia when on the left and hemi-inattention when on the right. Figures C-11 and C-12 show a large putamenal and a small thalamic hemorrhage, respectively. Pontine hemorrhage, unless quite small, usually causes coma (by disrupting the reticular activating system) and quadriparesis (by transecting the corticospinal tracts). Eye movements, spontaneous or reflex (eg, to ice water in either external auditory canal) are absent, and pupils are pinpoint in size, perhaps in part from transection of descending sympathetic pathways and in part from destruction of reticular inhibitory mechanisms on the Edinger-Westphal nucleus of the midbrain. Pupillary light reactivity, however, is usually preserved, for the pathway subserving this reflex, from the retina to midbrain, is intact. Respirations may be irregular, presumably because of reticular formation involvement. These strokes are nearly always fatal. Cerebellar hemorrhage, which tends to occur in the region of the dentate nucleus, typically causes a sudden inability to stand or walk (astasia-abasia), with ipsilateral limb ataxia. There may be ipsilateral abducens palsy, or horizontal gaze palsy, or facial weakness, presumably from pontine compression. Long-tract motor and sensory signs, however, are usually absent. As swelling increases, further brain stem damage may cause coma, ophthalmoplegia, miosis, and irregular respiration, with fatal outcome.

Figure C-11 CT scan showing hemorrhage (white area) in the putamen. (Courtesy of Dr. Allan J. Schwartz.)

The Rupture of Saccular Aneurysms Causes Subarachnoid Hemorrhage Congenital saccular aneurysms (not to be confused with hypertensive Charcot-Bouchard microaneurysms) are most often found at the junction of the anterior communicating artery with an anterior cerebral artery, at the junction of a posterior communicating artery with an internal carotid artery, and at the first bifurcation of a middle cerebral artery in the sylvian fissure. Each aneurysm, upon rupture, tends to cause not only sudden severe headache but also a characteristic syndrome. By producing a hematoma directly over the oculomotor nerve as it traverses the base of the brain, a ruptured posterior communicating artery aneurysm often causes ipsilateral pupillary dilation with loss of light reactivity. A middle cerebral artery aneurysm may, by either hematoma or secondary infarction, cause a clinical picture resembling that of middle cerebral artery occlusion. After rupture of an anterior communicating artery aneurysm, there may be no focal signs but only decreased alertness or behavioral changes.

Figure C-12 CT scan showing thalamic hemorrhage. Hematoma is the white area surrounded by a darker zone of edema or infarction. (Courtesy of Dr. Allan J. Schwartz.)

P.1316 Posterior fossa aneurysms most often occur at the rostral bifurcation of the basilar artery or at the origin of the posterior inferior cerebellar artery. They cause a variety of cranial nerve and brain stem signs. Rupture of an aneurysm at any site may cause abrupt coma; the reason is uncertain but may be related to sudden increased intracranial pressure and functional disruption of vital pontomedullary structures.

Stroke Alters the Vascular Physiology of the Brain After a stroke, cerebral blood flow and cerebrovascular responses to changes in blood pressure or arterial gases are altered. The term luxury perfusion refers to the frequent appearance of hyperemia relative to demand after brain infarction. Red venous blood may be seen draining infarcts (reflecting decreased oxygen extraction), and regional cerebral blood flow may or may not be absolutely increased. In addition, there may be vasomotor paralysis with loss of autoregulation to blood pressure changes and then blunted responses to alterations in arterial O2 or CO2. This kind of physiological abnormality occurs both within and around ischemic lesions. In such patients CO2 (or other cerebral vasodilators) may produce a paradoxical response, increasing cerebral blood flow in brain regions distant from the infarct without affecting the vessels around the lesion. Blood may therefore be shunted from ischemic to normal brain (intracerebral steal). In contrast, cerebral vasoconstrictors, by decreasing cerebral blood flow in normal brain without affecting the vessels of ischemic brain, may shunt blood into the area of ischemia or infarction (inverse intracerebral steal). There is controversy about the frequency of these phenomena. Hyperperfusion is not invariable in infarcted brain, and it may coexist with adjacent hypoperfusion with increased oxygen extraction. Similarly, intracerebral steal, while probably most frequent with very large infarcts, is quite unpredictable (particularly in duration) in any single patient. It is also not clear whether increasing cerebral blood flow to infarcted or ischemic areas improves matters by increasing oxygen delivery and the removal of tissue-damaging metabolites or makes matters worse by increasing edema, mass effect, and anastomotic compromise.

Selected Readings Adams RD, Victor M, Ropper AH. 1996. Principles of Neurology, 6th ed., pp. 777–873. New York: McGraw-Hill.

Brust JCM. 1995. Cerebral infarction. In: LP Rowland (ed). Merritt's Textbook of Neurology, 9th ed., pp. 246–256. Philadelphia, PA: Lea & Febiger.

Feinberg TE, Farah MJ (eds). 1997. Behavioral Neurology and Neuropsychology. NewYork: McGraw-Hill.

Pulsinelli WA. 1996. Cerebrovascular diseases. In: JC Bennett, F Plum (eds). Cecil Textbook of Medicine, 20th ed., pp. 2057–2080. Philadelphia, PA: Saunders. P.1317

Appendix D Consciousness and the Neurobiology of the Twenty-First Century

James H. Schwartz With the demise of behaviorism and the development of computers in the middle of the twentieth century, consciousness became increasingly interesting as a phenomenon for possible scientific analysis. As we enter the twenty-first century, discussion of consciousness amongst neuroscientists as well as philosophers has become popular, with a large number of papers, books, seminars, and even a journal (Journal of Consciousness Studies) devoted to the subject. The purpose of this appendix is to provide a guide to the most relevant literature about consciousness. As discussed in Chapter 20, we predict that cognitive neuroscientists will soon be designing and carrying out experiments to explain various aspects of the phenomenon. It would therefore be useful for the readers of this text to become familiar with the defining concepts.

Early Ideas About Consciousness Were Dualistic Although the ancient Greek philosophers, notably Plato (circa 427–347 BC) and Aristotle (384–322 BC), developed important ideas about the nature of mind and soul (psyche), it is convenient to date modern discussions of consciousness to René Descartes (1596–1650). To arrive at certainty, Descartes discarded all ideas about which he could not be sure, and concluded that he could be absolutely certain only that he was a thinking being: cogito, ergo sum. Thus the only thing he could be certain of was the awareness of his own thoughts. Modern philosophers describe this introspective view of consciousness as a drama taking place in a personal Cartesian theater. The British empiricists John Locke (1632–1704) and George Berkeley (1685–1753) and the Prussian philosopher Immanuel Kant (1724–1804), while contributing enormously to understanding the relationship between the external world and how we know it (epistemology), added very little to Descartes's basic concept of consciousness. They clearly assumed that the substance of mind is different from the substance of brain or of any other physical organ. This presumption, called dualism, was taken for granted in all accounts of consciousness until the nineteenth century. While these philosophers provided quite specific descriptions of consciousness, they were not concerned with explaining the way in which it worked. Thus no clear idea was offered about how the mental or spiritual component interacts with physical matter to result in mind and consciousness.

The Modern View of Consciousness Arose in the Nineteenth Century The possibility of a physical explanation of consciousness became evident during the mid-nineteenth century with the rise of experimental psychology (Wilhelm Wundt [1832–1920]) and psychophysics (Gustav Fechner [1801–1887]; see Chapter 21), which presumed that P.1318 mental activity correlates with distinct physical states (psychophysical parallelism). In 1890, William James (1842–1910) summarized the accomplishments of experimental psychology in his influential textbook The Principles of Psychology, and defined consciousness as a continuous stream that, although accessible only to the subject experiencing it, might be experimentally approached by analyzing its several functions. Thus the stream of consciousness is a continuous activity of the brain that involves attention, intentionality, and selfawareness. Self-awareness includes both perception per se and the awareness of experiencing perceptions, often referred to as “qualia.”

Modern Thinking About Consciousness Is Materialistic Most neuroscientists and philosophers now take for granted that all biological phenomena, including consciousness, are properties of matter. This physicalist stance breaks with the tradition of dualism stemming from ancient Greek philosophy. The break with the tradition that mind and consciousness arise from a mysterious interaction of spirit with body actually focused the problem of consciousness for the twentieth century neuroscientist. Philosophically disposed against dualism, we are obliged to find a solution to the problem in terms of nerve cells and neural circuits. Is the problem of consciousness real, however? Some philosophers and many neuroscientists believe that consciousness is an illusion. This viewpoint is an example of radical functionalism, crudely illustrated by the assertion that mind and consciousness is to the brain as walking is to the legs. Patricia Churchland makes the argument that “electrical current in a wire is not caused by moving electrons; it is moving electrons. Genes are not caused by chunks of base pairs in DNA; they are chunks of base pairs.” This point of view, called “eliminative materialism,” is magisterially explicated in Daniel Dennett's Consciousness Explained. Although the field of artificial intelligence has greatly influenced cognitive neuroscience, John Searle argues that consciousness cannot be reduced to a machine that can think, a physical computer with mind as a software program and consciousness as an emergent property. He maintains that the mind is not analogous to software being processed by the hardware of the brain. He argues that programs consist entirely of a set rules, no matter how complex, is not sufficient for semantics. Searle pleads for a scientific study of consciousness, rather than a denial of its evident existence. Certain neurological disorders have cast some light on the problem of consciousness, as they have on other aspects of brain function as the aphasias added to our understanding of language. Especially influential is the phenomenon of blindsight as studied by Lawrence Weiskrantz and his colleagues at Oxford. Patients with lesions of the primary visual cortex (V1) are blind; but when forced to make a choice on the basis of what is shown before their eyes, they can make decisions almost as if they can see. Nevertheless, these patients insist that they cannot see. Thus, they perceive but are not conscious of perceiving. Martha Farah has reviewed these curious disorders—blindsight, prosopagnosia, and neglect—and their relevance to consciousness. Two serious theoretical explanations derived from the known properties of neurons and neural circuits have been offered. Francis Crick and Christof Koch proposed that consciousness is an integration of neural activity similar in mechanism to the binding of different aspects of sensation that occurs to produce a unified perception. Like binding, consciousness would also depend on the synchronous firing of cortical neurons at frequencies around 40 Hz. Gerald Edelman has proposed that consciousness results from several crucial functions of brain activity: memory, learning, distinguishing self from nonself, and most important, reentry —the recursive comparison of information by different brain regions. Giulio Tononi and Edelman suggest that this re-entry mechanism is localized in circuits of the thalamocortical system.

Can Consciousness Be Explained? In a classic paper, Thomas Nagel argued that consciousness is first-person specific and unlike any other natural phenomenon. Because of its inherently subjective character, it poses a unique problem for scientific analysis. Colin McGinn took this argument a step further. Even though a materialist, McGinn believes that the human mind lacks the cognitive ability to understand the nature of consciousness, just as monkeys cannot understand particle physics. We agree that the problem of consciousness is difficult, perhaps the most difficult one that neuroscience has to face. As Crick and Koch and many others presume, consciousness must have a neural correlate. We are optimistic that future cognitive P.1319 neural scientists will identify the neurons involved and characterize the mechanisms by which consciousness is produced.

Selected Reading Block N, Flanagan O, Güzeldere G (eds). 1997. The Nature of Consciousness. Cambridge, MA: MIT Press.

Churchland PM, Churchland PS. 1998. On the Contrary: Critical Essays, 1987–1997. Cambridge, MA: MIT Press.

Churchland PS. 1986. Neurophilosophy: Toward a Unified Science of the Mind-Brain. Cambridge, MA: MIT Press.

Churchland PS, Sejnowski T. 1992. The Computational Brain: Models and Methods on the Frontier of Computational Neuroscience. Cambridge, MA: MIT Press.

Crick F, Koch C. 1990. Towards a neurobiological theory of consciousness. Seminars in the Neurosciences 2:263–275.

Crick F, Koch C. 1998. Consciousness and neuroscience. Cerebral Cortex 8:97–107.

Dennett DC. 1991. Consciousness Explained. New York: Little Brown.

Descartes R. [1641] 1993. Meditations on First Philosophy. Cress DA (transl). Indianapolis, IN: Hackett Publishing Company.

Edelman GM. 1989. The Remembered Present: A Biological Theory of Consciousness. New York: BasicBooks.

Farah M. 1995. Visual perception and visual awareness after brain damage: A tutorial overview. In: C Umiltà, M Moscovitch (eds). Attention and Performance XV: Conscious and Nonconscious Information Processing, pp. 37–75. Cambridge, MA: MIT Press.

James W. 1890. The Principles of Psychology, Chap. IX. New York: Henry Holt and Company.

McGinn C. 1997. The Character of Mind: An Introduction to the Philosophy of Mind, 2nd ed. New York: Oxford Univ. Press.

Nagel T. 1974. What is it like to be a bat? Philosophical Review 83:435–450.

Searle JR. 1984. Minds, Brains and Science. Cambridge, MA: Harvard Univ. Press.

Searle JR. 1997. The Mystery of Consciousness. New York: A New York Review Book.

Shear J. 1997. Explaining Consciousness: The Hard Problem. Cambridge, MA: MIT Press.

Tononi G, Edelman GM. 1998. Consciousness and complexity. Science 282:1846–1851.

Weiskrantz L (ed). 1988. Thought Without Language. Oxford: Oxford Univ. Press.

Weiskrantz L. 1997. Consciousness Lost and Found. Oxford: Oxford Univ. Press.

Zeki S. 1993. A Vision of the Brain, pp. 321–336. Oxford: Blackwell Scientific Publishers. P.1320

Symbols

C Cin

Capacitance (measured in farads). Total input capacitance of a cell.

cm

Capacitance per unit length of membrane cylinder.

Cm

Specific capacitance of a unit area of membrane (measured in F · cm-2).

E

Equilibrium (or nernst) potential of an ion species, e.g., ENa, or reversal potential for current through an ion channel.

F

Faraday's constant (9.5 × 104 coulombs per mole).

G g

Condu ctance (measured in siemens). Condutance of a population of ion channels to one or more ion species, e.g., gNa.

gl

Resting (leakage) conductance; total conductance of a population of resting (leakage)ion channels.

I Ic

Current (measured in amperes). The flow of charge per unit time, ∆Q/∆t. Ohm's law, I = V · G, states that current flowing though a conductor (G) is directly proportional to the potential difference (V) imposed across it. Capacitive current; that changes the charge distribution on the lipid bilayer.

Ii

Ionic current; the resistive current that flows through ion channels.

Il

Leakage current; the current flowing through a population of resting ion channels.

Im

Total current crossing the cell membrane.

i Q R

Current flowing through a single ion channel. Excess positive or negative charge on each side of a capacitor (measured in coulombs).

R Rin

Gas constant (1.99 cal · °K-1 · mol-1). Resistance (measured in ohms). The reciprocal of conductance, 1/G. Total input resistance of a cell.

Rm

Specific resistance of a unit area of membrane (measured in Ω · cm2).

r ra

Resistance of a single ion channel.

rm

Membrane resistance, per unit length (measured in Ω · cm).

Vm

Membrane potential, Vm = Q/C

Vr

Resting membrane potential.

Vt

Threshold of membrane potential above which the neuron generates an action potential.

Vin

Potential on the inside of the cel membrane.

Vout

Potential on the outside of the cell membrane.

Z

Valence.

γ

Conductance of a single ion channel, e.g., γNa.

λ

Cell membrane length constant (typical values 0.1–1.0 mm). λ =

τ

Cell membrane time constant; the product of resistance and capacitance of the membrane (typical values 1–20 ms). τ = Rm · Cm.

Axial resistance of the cytoplasmic core of an axon, per unit length (measured in Ω/cm).

in

(measured in volts).

.

Units of Measurement

A Å

Ampere, measure of electric current (SI base unit). One ampere of current represents the movement of 1 coulomb of charge per second. Ångström, measure of length (10-10 m, non-SI unit). Coulomb, measure of quantity of electricity, electric charge (expressed in SI base units s · A).

C F

Farad, measure of capacitance (expressed in SI base units m2 · kg-1 · s4 · A2).

Hz M mol mol wt S

Hertz, measure of freqnency (expressed in S-1). Molar, measure of concentration of a solution (mole of solute per liter of solution). Mole, measure of amount of substance (SI base unit). Molecular weight.

V

Siemens, measure of conductance (expressed in SI base units m-2 · kg-1 · S3 · A2). Volt, measure of electric potential, electromotive force (expressed in SI base units m2 · kg · s-3 · A-1). One volt is the energy required to move 1 coulomb a distance of 1 meter against a force of 1 newton. Measurements in cells are in the range of millivolts (mV).

Ω

Ohm, measure of electric resistance (expressed in SI base units m2 · kg · s-3 · A-2).

P.1321 Index Following page numbers: d = definition, f = figure, t = table

A A kinase attachment proteins 235 a priori knowledge 412 A-alpha fibers, effect of blocking conduction in 474–475 A-beta fibers, effect of blocking conduction in 474–475 A-delta fibers, carry information from thermal and mechanical nociceptors 474

A-type K+ channel 159 A1 See Primary auditory cortex A1-A7 cell groups See Noradrenergic cell groups A8-A17 cell groups See Dopaminergic cell groups Abducens cranial nerve (VI) in developing hindbrain 1031 function and dysfunction 874–875 877 innervation of extraocular muscle 787 lesion of 787–788 origin at brain stem 876 877 vestibulo-ocular reflex 811 Abducens interneurons, vestibulo-ocular reflex 812 Abducens nuclei, location 883 Abducens nucleus 881 motor circuit for horizontal saccades 791 vestibulo-ocular reflex 811 Abduction eye movement 785 muscles involved 787 Absence seizure 913 childhood, neuronal cell activity during 922–923 similarity of EEG activity to sleep spindles 923 Absolute refractory period 157 Abulia, after infarction of anterior cerebral artery 1308 Acceleration angular 805 measurement by vestibular labyrinth 802 See also Vestibular system Accessory nerve (XI), origin at brain stem 876 877 Accessory nucleus 881 Accessory oculomotor nucleus See Edinger-Westphal nucleus Accessory olfactory bulb olfactory information processing 633 in vomeronasal system 634 Accessory olfactory system 634 Accommodation 243 adjusting eye lens curvature for focus on retina 785 Acetylcholine (ACh) activation of G-protein-coupled inward rectifying ion channels 247 binding in postsynaptic muscle cell 199 biosynthesis and structure 282 biosynthetic enzymes 281 chemical signal 175–176 co-release with CGRP 290 294 with VIP 290 duration of action increased by neostigmine 299 300 300 effect on heat 967 postsynaptic cells 184 hyperpolarization of cardiac muscle cells 247 isolation of 966 muscle neurotransmitter 676 neurotransmitter in autonomic nervous system 970 efferent synapses with hair cells 623 and nociceptor sensitization 477–478 receptors for, in autonomic nervous system 971 release from axon growth cone in synaptic differentiation 1090 nerve terminal impaired by botulinum toxin 307 preganglionic terminals 970 release of and reduction in EEG voltage during REM sleep 942 removal from synaptic cleft 190 role in fasciculations 701 See also Acetylecholine receptor small-molecule neurotransmitter 282 in terminals of motor neuron 1089 used by nerve to repress expression of acetylcholine receptor genes 1096 1098 Acetylcholine pore, large diameter 192 Acetylcholine receptor 188 189 antibodies to 300–301 produced in myasthenia gravis 201 antibody binds to alpha-subunit of, in myasthenia gravis 303–304 autoimmune reaction against in myasthenia gravis 305 -channel nicotinic, structure 220 opening abnormally prolonged in slow-channel syndrome 307 phosphorylation mechanism 248 -channel complex 189 clustering on muscle surface triggered by agrin 1092–1094 at neuromuscular junction during synapse formation 1091 on postsynaptic membrane 258 density in denervated muscle 1096 reduced in muscle fibers in myasthenia gravis 301 302 expression in nonsynaptic areas regulated by neural activity 1096 1096–1098 factors directing clustering on muscle surface 1092 genes, transcription regulated by calcium influx 1096 1098 -inducing activity See Neuroregulin P.1322 muscarinic, G protein-coupled receptor family 241

neuroregulin stimulates synthesis of 1094–1096 1095 nicotinic type 189 antibodies produced against in autoimmune myasthenia gravis 298 modulation 248 normal versus myasthenic neuromuscular junction 303 rate of destruction in myasthenia gravis 304 structure 118 1091–1092 substrate for PKA, PKC, and tyrosine kinase 248 subunit, nicotinic, mutation in noctural frontal lobe epilepsy 931 three-dimensional model 199–201 200 types 189 Acetylcholinesterase 676 anchored to collagen fibrils at neuromuscular junction 189 deficiency of at end plate in congenital myasthenia gravis 306 Achaete-scute genes determining neuronal cell fate 1045 and Notch signaling in nerve cell specification 1042 ACh See Acetycholine AChE See Acetylcholinesterase Achromatic mechanism, in cones 580 Achromatic vision 579 Achromatopsia 499 500 563 585 case history 585 optokinetic reflex in 813 Acidity, as chemical intermediary for pain 442 Acoustic nerve tumor 879 Acoustic neuroma 877 Acoustic stimuli, hair cells tuned to specific frequencies 620–622 Acoustical information, parallel pathways for processing 606 See also Auditory information; Auditory pathways ACPD See trans-(1S, 3R)-1-amino-1,3-cyclopentanedicarboxylic acid ACTH See Adrenocorticotropic hormone Actin in axon growth cone filopodia 1071 1073 filaments as tracks for molecular motors in cell 75 overlap with myosin filaments affects number of muscle fiber cross bridges 681–682 in microfilaments 74 motors, myosins 75 movement by faster component of slow axonal transport 103 muscle contraction 679 in muscle fibers 677 678 Actin-binding proteins movement by faster component of slow axonal transport 103 network with actin filaments 74 Action internal cellular representation required for 381–403 See also Movement selection, in lateral premotor areas 774–777 sensory information for, role of cerebrocerebellum 845–848 Action potential 21 28 30 126 abolishes balance of ion fluxes that gives rise to resting membrane potential 132 all-or-none behavior 21 31 158 amplitude boosted by nodes of Ranvier 148 148 in presynaptic cell 253 reduced by lower external concentration of sodium ions 151 and amount Ca2+ that flows into presynaptic terminal 256 and density of voltage-sensitive sodium channels 30 and ionic conductance 151 central neuron, role of summation 227 changes in membrane potential during 105 characteristics 31 compound 146 299 conducted at different rates by afferent fibers of different receptors 444 447 conversion of end-plate potential into at neuromuscular junction 190 density of Na+ channels and velocity of 160 difficulty for electrically coupled cells to fire 180 effect of axial resistance and membrane capacitance on rate of spread of depolarization 147–148 Ca2+ influx during 159 slowing down conduction of 148 electrotonic conduction role in propagation 145 events following 157 factors limiting duration 157 first intracellular recording 23 frequency of conveys information 31 generation 29–30 flow of ions through voltage-gated channels 150–158 ligand-gated channel 196 sequential opening of voltage-gated Na+ and K+ channels 158 how do they give rise to meaning 398 importance of rapid propagation 147 increase of ion conduction across cell membrane during 150–151 increased permeability for K+ in falling phase 151 inhibited by inhibitory synpatic potentials in motor neuron 209 initiated by integration of many EPSPs in motor neuron 209 initiation 169 large- and small-diameter motor neurons 686 membrane permeability to Na+ during 133 membrane potential approaches Na+ equilibrium potential 132 message of determined by neural pathway 31 motor units 685

muscle fiber 676 681 factor in amount of active force 682 number of conveys information 31 opens Ca

+

channels in nerve terminal at chemical synapse 183

passive conduction of depolarization along axon and propagation of 146 passive electrical properties of neuron influence speed of conduction 140 presynaptic, effect of tetrodotoxin 253 propagation in sensory fibers and perception of pain 473 properties affecting velocity of propagation 147–148 reconstruction from properties of Na+ and K+ channels 155–158 in reflex 32 regeneration 22 regulation of calcium influx during modulates amount of neurotransmitter released 274–276 repolarization at nodes of Ranvier 160 saltatory conduction in myelinated axon 148 selectivity of ion channels for Na+ during 107 sensory nerves frequency of encodes stimulus intensity 421–23 sensory nerves, series of conveys sensory message to brain 421 sequence of events 156–158 by skin mechanoreceptors in response to vibration 437 termination by repolarization of membrane 132 train of 32 triggered at axon hillock in myelinated axon 148 waveform 146 Action tremor 849 Activation gate, Na+ channels 155 Active fixation system, eye 784 P.1323 Active state, ion channels 114 Active zone 182 188 189 1089 presynaptic terminal, all-or-none transmitter release 261 secretory machinery of neuron 183 Activity-dependent synaptic modification, mediated by NMDA receptor 213 Actomyosin, role in muscle contraction 75 Acute intermittent porphyria, chronic neuropathy 702 Acute organic brain syndrome 901 Adams, Paul 241 Adaptation hair cells 619–620 621 movement, role of primary motor cortex 764–770 prism glasses, adjustment of eye-hand coordination during 847 sensory neurons 424 424–425 vestibulo-ocular reflex 825–828 Adaptive adjustment, vestibulo-ocular reflex, hypotheses of 826–827 Addiction, opioid peptides 489 Addictive states 998–1013 Adduction, eye movement 785 muscles involved 787 Adenosine extracellular actions 970 hyponogenic properties 943 neurotransmitter 285 Adenosine monophosphate (AMP), role in sensitization 1250–1251 Adenosine triphosphate (ATP) as chemical intermediary for pain 442 converted into mechanical energy in myosin head of muscle fiber 678 co-release 294 extracellular actions 970 hydrolysis, setup of initial concentration gradients and maintenance 129 muscle contraction 679 as neurotransmitter 285 receptors structure 220 transmitter-gated ion channel 222 required for movement of protein through nuclear pores 93 transfer of polypeptides into endoplasmic reticulum 94 role in anterograde transport to axon 101 conjugation of ubiquitin 93 sensitivity of ion channel gating to 114 -ubiquitin-proteasome pathway, selective and regulated proteolysis of cytosolic proteins 93 Adenylyl cyclase in activity-dependent facilitation 1252 role in sensitization 1250–1251 type III, in olfactory signal transduction 629 629 Adequate stimulus 414 Adhesion molecules 1078 also promote neurite outgrowth 1074–1075 1076 cell-surface, effect of endocytosis on 97–98 guidance cues for axon growth cone guidance 1071 organization of presynaptic differentiation 1100 Adolescents, pattern of sleep 943 ADP, muscle contraction 679 Adrenal gland, enlargement of in patients with unipolar depression 1220 Adrenaline See Epinephrine Adrenergic 280 Adrenergic cell groups in medulla and pons 890 890 891–892 Adrenergic receptors, types 970 971 Adrenocorticotropic hormone, excessive secretion in unipolar depression 1220

Adrenogenital syndrome See Congenital adrenal hyperplasia Adrian, Edgar 12 31 421 430 695 842 Advanced sleep phase syndrome 954 Affect 1209 Affective behavior, role of serotonergic neurons 896 Affective functions See Emotion Afferent axon terminals, site of modification of reflex pathway 724 725 Afferent fiber groups, in peripheral nerves 444 Afferent fibers conduct action potentials at different rates for different receptors 444 447 crossing of in medulla and pons in ascending somatosensory pathway 448 distinct terminal patterns in spinal cord and medulla for somatic sensory information 447–449 nociceptive neurotransmitters 477 and non-nociceptive, gate-control theory of pain 482–483 terminate on neurons in dorsal horn of spinal cord 475–477 Afferent neurons 25 Afferent pathways, nociceptor, integrated with descending pathways by local-circuit dorsal horn interneurons 488 After-potential 157 Afterhyperpolarization, paroxysmal depolarizing shift, and onset of clinical seizure 919 Aggregate-field view, brain function 7 11 Agressive behavior See Behavior, aggressive Aggressive behavior, and serotonergic transmission 50 Aging behavioral changes associated with 1151 brain 1149–1161 changes in brain structure and function 1150–1151 and genomic instability 1150 molecular mechanisms 1149–1150 and number of cell doublings 1150 premature See Werner syndrome See also Alzheimer disease; Elderly Agnosia 355 498 apperceptive, drawings by patient with 1235 associative, drawings by patient with 1235 produced by damage to posterior parietal lobe 392–393 types 498–499 visual 500 Agraphia, acquired disorder of writing 1183–1184 Agrin aggregation of acetylcholine receptors in postsynaptic membrane 1112 mechanism for aggregating acetylcholine receptors at synaptic sites in muscle fiber 1093 1094 in postsynaptic differentiation 1098 release by nerve terminals at neuromuscular junction 1093 1094 triggers clustering of acetylcholine receptors on muscle surface 1092–1094 Aguayo, Albert 1112 AKAP See protein kinase A attachment proteins Akinetic mutism, damage to anterior cingulate region causes 866 Alar plate, neural tube 880 Albus, James 848 Alcohol, targets GABA-gated channels 219 Alcoholism chronic neuropathy 702 genetic component 58–59 58 Alert state 400 Alertness, nature of 400 Alexander, Garret 357 Alexia 355 acquired disorder of reading 1183–1184 after infarction of posteral cerebral artery 1308 All-or-none opening of ACh-gated ion channels 195 197 release of neurotransmitters from active zones of presynaptic terminal 261 response, muscle fiber 676 Alleles 38 dominant and recessive 38 single gene, encode normal behavioral variations in worms and flies 42 P.1324 Allelic polymorphism 38 Allman, John 496 Allodynia 475 Allometry 817 Alpha motor neurons coactivation with gamma motor neurons in voluntary movements 29 rate of firing in voluntary movements 28–729 site of modification of reflex pathway 24 725 Alpha waves activity during sleep apnea syndrome 952 EEG activity during sleep 937–938 electroencephalogram 916 Alpha-2-macroglobulin, mutation in gene encoding, genetic risk factor in Alzheimer disease 1156 1157 Alpha-amino-3-hydroxy-5-methylisoxazole-4-proprionic acid, activates ionotropic glutamate receptors 212 Alpha-bungarotoxin action in voltage-gated versus ligand-gated channels 197 blockage of nicotinic ACh-gated channel 114 used to isolate and purify ACh receptors 300 used to detect acetylcholine receptors 1092 Alpha-fetoprotein high postnatal titers in rat 1138 source of estrogen postnatally 1140 Alpha-gamma coactivation 725 Alpha-mating factor, precursor structure 291 Alpha-melanocyte-stimulating hormone, neuroactive peptide 289

Alpha-neoendorphin, amino acid sequence 487 5-Alpha-reductase deficiency cognitive and psychosexual aspects 1143 and sexual differentiation 1134 1135 Alzheimer, Alois 1151 Alzheimer disease animal models 1157–1158 classical pathology 1151–1152 cytoskeletal abnormalities in neurons 1154 differential diagnosis 1152 early pathological changes in entorhinal cortex 1232 early-onset, genetic risk factors 1156 genetic component 58 genetic risk factors 1156–1157 late-onset, genetic risk factors 1156–1157 neurofibrillary tangle characteristic of 74 neuronal systems vulnerable in 1153 prevalence 1152 risk factors, pathogenic processes, and clinical signs 1152 role of microglia 20 structural abnormalities in brain 153–1155 structures involved in behavioral and emotional disturbances 1154 memory impairment 1154 symptoms and abnormalities 1152 treatment 1158 Alzheimer type dementia 1149–1161 Amacrine cell fire action potentials 521 retina 520 GABA as major transmitter 285 structure 515 Amaral, David 1233 American Sign Language 612 chimpanzees and gorillas 1173 depends on left hemisphere 1175 2-Amino-5-phosphonovaleric acid, blocks NMDA glutamate receptor 212 Amino acids transmitters 284–285 transport across blood-brain barrier 1291 Aminophosphorobutyrate, antagonism of transmission from photoreceptors 520 4-Aminopyridine, study of synaptic vesicles during exocytosis 264 Amitriptyline, antidepressant, structure 1213 Amnesia and damage to hippocampus 1233 and frontal lobe damage 1237 retrograde 1244 word recall in 1230 amnesiac, Drosophila learning mutant 1257 Amorphogenesis 355 Amotrophic lateral sclerosis, and motor neurons 33 AMPA receptor activation of during excitotoxicity 930 receptor-channels, conduct Ca2+ 221 AMPA See Alpha-amino-3-hydroxy-5-methylisoxazole-4-proprionic acid Amphetamine depletes vesicles of amine transmitters 286 positive reinforcement action 1010 treatment, narcolepsy 951 uptake by dopamine transporter 295 Amplification, property of chemical transmission 182 Ampulla 802 cochlea 592 semicircular canal, organization 804 806 Amygdala 332 855 987 abnormalities in Alzheimer disease 1153 in autonomic response control pathway 975 brain mapping by blood flow, role in emotional responses 989 central nucleus, connections with hypothalamic and brain stem areas and tests for fear and anxiety 993 of cerebral hemispheres 322 and context conditioning 992 coordinating role in emotion 988 evaluative and peripheral components of emotion 985 damage, dissociation between autonomic responses to emotive stimuli and cognitive evaluation of stimuli 994 effects of ablation 991 emotion 323 experience 988–993 expressed by faces, learning cues for 989 989 kindling, experimental model of hyperexcitability 931–932 lesions effect on emotion 985 effect on response to fear 990 mediation of autonomic expression and cognitive experience of emotion 992–993 emotions 980 nuclei in 331 992–993 olfactory information processing 633 pathway of visceral sensory information 974 processes learned emotional responses 990–992 reciprocal connections with neocortex, incorporation of learning and experience into cognitive aspects of emotion 993–994 role in

emotion 15 872 implicit memory 1243 pleasurable and fearful repsonses to stimuli 992 social cognition 990 Urback-Wiethe disease 988–989 in vomeronasal system 634 Amygdalohippocampectomy, treatment, temporal lobe epilepsy 928–929 Amygdaloid complex, conditioned behavioral responses 973 Amygdaloid nuclei, function 8 Amyloid deposits See Senile plaques Amyloid peptide, A-beta, synthesis and processing 1155 Amyloid precursor protein, synthesis and forms 1155 Amyloidosis, chronic neuropathy 702 Amyotrophic lateral sclerosis 696–697 700 neurogenic disease of motor neuron 701 P.1325 Anaclitic depression 1128 Analgesia by direct electrical stimulation of brain 482 induction by stress 489 mechanism 482 opiate-induced, pathways of 483 production of 490 Anaphora 1171 Anastomoses 1304 and retrograde filling of middle cerebral artery after occlusion 1307 Andersen, Per 1259 Anderson, Richard 401 Androgen insensitivity syndrome cognitive and psychosexual aspects 1142 and sexual differentiation 1134 1135 Anesthesia dolorosa 473 Aneurysms saccular, and subarachnoid hemorrhage 1315–1316 See also Microaneurysms Angel dust See Phencyclidine Angina, referred pain in 475 Angiotensin II and drinking behavior 1006 neuroactive peptide 289 Angular gyrus, language 1174 and visual and somatosensory input 355 Anhedonia 1210 Anions 108 126 ion channels selective for 110–111 organic, distribution across cell membrane 128 neuronal cell membrane at rest 128 Anlagen 1133 Anomalous trichromacy 584 Anoxia 1306 Antagonist muscles 687 Anterior association area, cerebral cortex 350 Anterior cerebral artery 1303 branches, effects of occlusion 1309 cortex, frontal and parietal lobes, and corpus callosum 1302 infarction 1308 PET scan of infarction 1305 Anterior choroidal artery hippocampus and internal capsule 1304 occlusion 1308–1309 Anterior cingulate circuit, basal ganglia, role in motivated behavior and procedural learning 866 Anterior cingulate cortex, activation in perception of thermal pain 484 485 Anterior cingulate region damage to causes akinetic mutism 866 language 1174 Anterior commissure 987 midsagittal cross-sectional area, larger in homosexual men than in heterosexual men 1145 Anterior communicating artery 1303 Anterior hypothalamic nucleus 976 Anterior inferior cerebellar artery 1304 Anterior insulafrontal operculum, taste information pathway 642 Anterior insular cortex, topographic map of internal organ systems 974 Anterior language area, damaged in global aphasia 1181 Anterior nuclei, thalamus 343 Anterior olfactory nucleus, olfactory information processing 633 Anterior pituitary See Pituitary, anterior Anterior radicular artery 1314 Anterior spinal artery 1303 1304 1314 Anterior thalamic nuclei 987 Anterograde 100 Anterograde axonal transport 103 kinesin as motor molecule for 101 See also Slow axonal transport Anterolateral cordotomy 480 Anterolateral system 732 mediates sensations of pain and temperature 448–449 pathway of sensory information 446 Anterolateral tract ascending pathways of 449 axons arranged somatotopically 448 direct and indirect pathways to thalamus 449 Anteroventral periventricular nucleus, gonadal hormones induce apoptosis in 1140–1141 Anti-accommodation 243

Antibiotics, aminoglycoside, toxic effect on hair cells 617 Antibodies to ACh receptor in myasthenia gravis 300–301 method for testing proposed ion channel structure 117–118 Anticholinesterase inhibitors, treatment, congenital myasthenia gravis and slow-channel syndrome 307 Anticholinesterases, treatment of symptoms of autoimmune myasthenia gravis 306 Anticipatory control 657 Anticipatory mechanisms, effect on motivational states 1007 Anticipatory motor action, response to postural disturbance 818 819 Anticonvulsant drugs, use as mood stabilizers 1216 Antidepressant drugs 1214–1216 action on cholinergic and GABA-ergic systems 1219–1220 effects on serotonergic and noradrenergic neurons 1218–1219 long-term effects on serotonergic system 1217 1217 types and structure 1213 Antipsychotic drugs atypical 1198 1198 See also specific names treatment of schizophrenia 1197–1200 1198 Antipyretic area, brain and body temperature 1001–1002 structure 1001–1002 Anton disturbance, after infarction of posterior cerebral artery 1308 Anxiety disorders 1209–1226 major types 1220–1224 tests for, connections between central nucleus of amgydala and hypothalamic and brain stem areas 993 Apaf-1 See Apoptosis activating factor-1 APB See Aminophosphorobutyrate Aperture problem and middle temporal area 553–556 solution of 554 Aphagia 1002 Aphasia 10 1169–1187 after middle cerebral artery infarction 1307–1308 conduction 11 differential diagnosis 1176 difficulty with affective aspects of language 14–15 in deaf people 13 location of brain areas related to language 1174–1181 receptive versus expressive malfunction 11 role in study of localization of language 10–11 spontaneous speech, auditory comprehension, and repetition in 1178 Aplysia gill-withdrawal reflex cellular mechanisms of habituation 1248 1249 1249 classical conditioning in 1252–1253 1253 long-term sensitization 1254–1255 sensitization 1250–1251 serotonergic neurons and food intake 1005 Apnea See Obstructive sleep apnea syndrome; Sleep apnea Apneusis, in coma 903 ApoE alleles, genetic risk factor in Alzheimer disease 1156 1157 Apomorphine, effect on feeding responses 1004 Aponeuroses store mechanical energy during muscle contraction 678 transmit force of muscle fibers to connective tissue 682 P.1326 Aponeurosis 675 Apoptosis activating factor-1 1060 caspase pathway in 1059–1060 compared with necrotic cell death 1058 induction in anteroventral periventricular nucleus by gonadal hormones 1140–1141 neuronal, activated by removal of neurotrophic factors 1058–1061 possible role in Huntington disease 865 role in excitotoxic damage of neurons 928 See also Programmed cell death sexually dimorphic nucleus of the preoptic area, estradiol prevents 1140 study of in C. elegans during development 1058–1061 suppressed by testosterone 1140 APP See Amyloid precursor protein APP gene, genetic risk factor for Alzheimer disease 1156 Apparent motion 552 Apperceptive agnosia 355 Apperceptive visual agnosia 1236 Appetitive conditioning 1240 Appraisal theory, emotion 985 Apprehension, amygdala 988–989 Aprosodias 15 APV See 2-Amino-5-phosphonovaleric acid Aqueduct of Sylvius 1294 1295 site of obstruction of cerebrospinal fluid pathways 1299–1300 Arachidonic acid actions of metabolites 237 as transcellular synaptic messengers 238 hydrolyzed phospholipid 236 mechanism of release 238 metabolites of action at synapses 262 open same channels closed by cAMP 243–244 other second messengers 236–238 second messenger in synaptic transmission 230 system 231 Arachnoid granulation, absorption of cerebrospinal fluid 1296

Arachnoid membrane, cerebrospinal fluid 1294 Arachnoid villus 1294 transport of cerebrospinal fluid 1295 1296 Architectonic, feature of complex biological systems 65 Arcuate nucleus 976 hypothalamus, origin of dopaminergic tract 283 Aristotle 1317 Arm muscles, activation by stimulation of motor cortex 758 Armstrong, Clay 163 Arnold, Magda 986 Arnold theory, emotion 985–986 Arousability, level of, evaluation of in structural coma 903–904 Arousal 871–1013 basal nucleus of Meynert modulatory role in 334 behavioral, role of histaminergic neurons 896 brain stem modulatory role in 334 confusional, from non-REM sleep, dysfunctional behaviors 956 958 cortical, role of cholinergic neurons 896 from sleep, disorders of 955–958 general and specific 983 influence of locus ceruleus 896 modulated by ascending projections from brain stem 896–900 promoted by different neural system than that of sleep 939 stimulation of posterior hypothalamus 939 role of central nucleus of amygdala 992 Arousal level affects performance 983 influenced by reticular formation in brain stem 320 Arousal system ascending components 900 damage to impairs consciousness 899–900 injuries to 897 pathways for eye movement in 904 Arrestin, interaction with phosphorylated rhodopsin in phototransduction 514 Arterial blood pressure, control by parasympathetic and sympathethic systems 967–968 Articulatory loop, working memory 360 1239 Artificial intelligence 34 and consciousness 1318 Ascending arousal system, components 900 Ascending pathways, nociceptive information 480–482 482 Ascending tract of Deiter's, vestibulo-ocular reflex 811 Ascending tracts, spinal cord See Dorsal column-medial lemniscal system; Lateral spinothalamic tracts; Spinocerebellar tracts Aserinsky, Eugene 936 945 Aspartate, neurotransmitter in pyramidal and spiny stellate cells of primary visual cortex 533 Association, cells involved in vision 502 Association areas brain 1165 cerebral cortex 349–380 higher-order areas of cortex 349 interaction among and comprehension, cognition, and consciousness 362–363 multimodal in cerebral cortex 326 integrate sensory modalities and link to action 350–352 pathways to 354 principles of function 352–362 Association cortex 11 damaged in transcortical motor aphasia 1180 function illustrated by prefrontal association areas 356–362 Association cortexes and consciousness 363 and language 1175 lesions, effect on memory 1233 stores explicit memory 1233–1239 Association, cells involved in vision 502 Association regions, relationship to primary sensory and motor cortices 352 Associational connections, neocortex 327 Associative agnosia 355 Associative learning 777 eyeblink reflex, role of cerebellum 849 Associative visual agnosia 1236 Associativity, long-term potentiation 1260 Astasia-abasia, cerebellar hemorrhage 1315 Astereognosis 393 after middle cererbal artery infarction 1307 Asthma, as multigenic disease 55 Astrocyte, structure 21 electrical stimulation and rise of intracellular Ca2+ in 180 functions 20 type of glial cell 20 Astroglia, perivascular, source of signals that induce expression of blood-brain barrier properties in endothelial cells 1293–1294 Asymbolia for pain 482 Ataxia 753 cerebellar infarction 1313 cerebellar abnormality 849 diffuse hypoperfusion 1313 infarcts of medial or lateral brain stem structures 1311 Ataxic 844 Athetosis 861 Ativan See Benzodiazepines Atonia 896

during REM sleep 938 ATP See Adenosine triphosphate ATPase, microtubule-associated, motor molecule for retrograde fast transfer 103 P.1327 Atrial naturetic peptide, neuroactive peptide 289 Atropy 696 Attention on elements in visual field and construction of visual image 502 increase in firing rate of neurons related specifically to 401 role in creating coherent visual image 504 See also Selective attention selective limits amounts of information reaching cortex 504–505 and spatial location 504 visual brain centers involved in 505 changes in cellular activity 566 and conscious awareness 504–505 controlled by parietal cortex 794 coordination between separate visual pathways 501–504 coordination between separate visual pathways 565–566 linked with saccades 794 multimodal sensory association cortex 354 Attentional control system, working memory 1239 Attentive process, visual perception 503 Attenuation, in signal propagation 144 Atypical depression 1210–1211 Auditory association cortex, left, damage in Wernicke aphasia 1179 Auditory cortex formation of tonotopic maps on neurons in 1127 language 1174 Auditory information neural processing 601–608 processing in bat cerebral cortex 609 processing in many areas of cerebral cortex 608–610 Auditory input, and processing of emotional information 990 Auditory nerve fiber firing pattern 603 projections 603 tonotopic organization 597 Auditory pathways cochlear nucleus to auditory cortex 604 tonotopic organization 601 Auditory system components of in midbrain 322 early-warning system 610 refinement or modification of connections by sensory experience 1127 role of posterior nuclei of thalamus 343 Auditory transduction, hair cells 590 Auerbach's plexus See Myenteric plexus Aura preceding partial seizures 913 with seizure 920 Auricle, as reflector 591 591 Autism, genetic component 58 Autocoid 281 Autogenic excitation 721 Autogenic inhibition 722 Autoimmune diseases See Myasthenia gravis; Lambert-Eaton syndrome Autoimmune reaction, molecular basis of in mysasthenia gravis 304–306 Autonomic division, peripheral nervous system 335 Autonomic function coordinated by central autonomic network 972–978 role of hypothalamus 8 medulla oblongata 8 Autonomic ganglia fast and slow synaptic transmission in 242 sympathetic and parasympathetic motor systems 962 Autonomic motor neurons 962 Autonomic nervous system 960 acts in parallel with somatic motor system 979–980 anatomical organization 962–965 compared with somatic nervous system 960 control of visceral and ocular reflexes 966–969 divisions of 961 features 980 and hypothalamus 960–981 neurotransmitters in 970 organization of motor pathways 961 pharmacology 971 receptors in and drugs that act at 971 See also Parasympathetic system; Sympathetic system sensory inputs 965–969 sympathetic and parasympathetic divisions 964 balance between 961–962 unipolar neurons in 24 visceral sensory and motor system 961–962 Autonomic neurons chemical transmitters in 969–970 combinatorial release of chemical mediators 980 neuropeptides in 970 972 peptides released by 980

small molecular transmitters released by 980 Autonomic reflexes, slow and rapid visceral responses 966–969 Autonomic regulation, role of dopaminergic neurons 896 Autonomic responses, pathways of control 975 Autoradiography, tracing neural projections 98 Autoreceptors 281 Autoregulation, cerebral blood vessels 1305 Autosomes 38 Awareness consciousness as state of 396 of self and place in environment as consciousness 897 spatial, perceptual abilities involved 418 Axes, of central nervous system 321 Axial resistance 144 intercellular, as passive electrical property of neuron 140 Axis, secondary, generation in amphibian embryos, organizer graft experiment 1023 Axo-axonic synapses 225 226 on presynaptic terminals, regulate intracellular free calcium 275–276 Axodendritic synapses 223 225 Axolemma, sensory neurons 77 Axon 22 chemospecificity hypothesis of target recognition 1065–1066 cooperation and competition and formation of ocular dominance columns 1120–1121 cytoskeletal structure 72 damage to affects neurons and cells around them 1108–1109 1109 diameter of affects velocity of action potential propagation 147–148 endocytosis occurs at nerve terminals 99 excitatory terminal fiber 22 growth cone 1070–1074 attracted and repelled by soluble factors 1081 guidance cues 1071 inhibitory signals provided by ephrins and semaphorins 1081 integrins, on interact with laminins in extracellular matrix 1074 release of acetylcholine in synaptic differentiation 1090 sensory and motor structure 1070 1073 structure 1071 1072 growth divided into short segments 1069 guidance 1063–1086 contrasting theories of 1063–1064 growth-promoting cues 1069 molecular clues 1063–1066 See also Growth cone guided by molecules of different families 1081–1085 hillock 21 22 membrane potential is readout for integrative action of neuron 222 motor neuron 78 summation 227 inhibitory terminal fiber 22 initial segment 21 P.1328 injury see Axotomy large dense-core vesicles targeted to 97 kinesin as motor molecule for anterograde transport 101 myelin sheath 75 myelination effect on increasing conduction velocity 147–148 navigation along gradients 1069 neuron 70 neuronal 21 passive conduction of depolarization along and propagation of action potential 146 peripheral nervous system, factors contributing to regenerative capacities 1110–1111 pioneers 1069 reach destinations in series of steps 1067–1070 receptor, as modality-specific line of communication 416 recurrent collateral branches in motor neuron 78 reflex, nociceptor sensitization 477 regenerated, new functional nerve endings 1109 regeneration after injury 1112–1113 in central nervous system promoted by therapeutic interventions 1110–1111 retinal course correction to reach optic tectum 1068 path followed by to optic tectum 1067 ribosomes absent from 90 signaling role 159–160 size and excitation by extracellular current stimuli 146 specificity of recognition of synaptic targets 1105–1108 structure 71 terminals, synapses on often modulatory 226 transport of proteins and organelles along 99–103 Axonal guidance, contrasting theories of 1063–1064 Axonal transport 99–103 movement of cytosolic and cytoskeletal proteins 103 and neuroanatomical tracing 98 slow, for cytosolic proteins and cytoskeletal elements 103 Axoplasmic flow 100 Axosomatic synapses 225 Axotomy effect on inputs to injured neurons 1108 postsynaptic neurons 1108 effects of 1108 1109 reversible in peripheral nervous system 1109

Azathioprine, treatment, autoimmune myasthenia gravis 306

B B1-B9 cell groups See Serotonergic cell groups Babinski, Jean 846 849 Background, and foreground in visual image 497 Back propagation 919 Baclofen, treatment, spasticity 730 Bacterial meningitis, altered blood-brain barrier in 1294–1295 Bacteriorhodopsin, membrane protein, structure 116 Baddeley, Alan 357 360 Bag cell peptides, neuroactive peptide 289 Balance brain stem is site of entry for information from 320 loss of with defects in vestibular labyrinth 824 regulation by vestibulocerebellum 841 See also Vestibular system voluntary movement preceded by counterbalancing movement 818 Balint's syndrome 794 Ball joints 687 Ball-catching, feed-forward and feedback controls 656 Ballism 861 See also Hemiballism Baltimore Longitudinal Study of Aging 1151 Bandwidth 416 Barbiturates, target GABA-gated channels 219 Bard, Philip 12 385 984 Bargmann, Cori 635 636 Bargmann, Cornelia 42 Barlow, Horace 561 Barnes maze, study of spatial memory 1273 Baroreceptor neurons 967 reflex 967 and water intake 1006–1007 Barrels 462 developmental organization in somatosensory cortex of rodents 1037 1037 See also Whiskers Barrington's nucleus 968 Bartlett, Frederick 382 1239 Basal forebrain in ascending arousal system 900 cholinergic neurons in 896 Basal ganglia 347 853–867 of cerebral hemispheres 322 cognitive and behavioral role 853 contribution to variety of behaviors 857 control of fine movement 323 damaged in global aphasia 1181 direct and indirect pathways, imbalances in caused movement disorders 861–864 disturbance of in obsessive-compulsive disorder 1224 dopamine level decreased in Parkinson disease 864 dysfunction, Huntington disease 864–866 function 8 and inferotemporal cortex, hallucinations in schizophrenia 1190 1190 influence cortical and brain stem motor systems 663–665 inhibit superior colliculus 793 inputs to premotor areas and primary motor cortex 761 left, language 1174 1175 locus for Tourette syndrome 1224 motor functions 853 in motor system 667 nuclei in 331 input and output 854–857 parallel circuits linking thalamus and cerebral cortex 857–861 pyramidal system mediates motor actions 854 relationship to motor system 854 roles in cognition, mood, and nonmotor behavior 866 and surrounding structures 855 and thalamus, positive feedback and indirect pathway negative feedback 857 types of motor distrurbances associated with 853 Basal ganglia-thalamocortical circuit frontal lobe targets of 857 normal and in disease 860–861 parallel direct and indirect pathways 856 serial processing 859 Basal ganglia-thalamocortical motor circuit, somatotopic organization 859 Basal lamina 1089 components at synaptic site organize nerve terminal 1097 laminins as major component of 1098 Basal nucleus of Meynert, modulatory role in arousal and selective attention 334 Basal plate, neural tube 880 Basal stem cell, olfactory epithelium 627 Basement membrane 188 Basilar artery 1303 1304 branches supply blood to brain stem and cerebellum 1309 P.1329 Basilar membrane 595 as mechanical frequency analyzer 597 cochlea 592 592 596 mechanical analyzer of sound frequency 593–597 motion of 595 organ of Corti 596

and stimulation of hair cells 598 tuned to a progression of sound frequencies 594 Basis pedunculi 876 877 Basket cells 331 cerebellar cortex 836 cerebellum and hippocampus, GABA as major transmitter 285 in cerebral cortex 922 923 dendrites of excited by beams 837 GABA-ergic interneuron 329 Basolateral complex, amygdala, association of place cues with reward value 992 Basolateral nuclei, amygdala, connections 992 lesions, effect 992 Battery 134 concentration gradients of ions as 134 in equivalent circuit model of cell membrane 138 Bayliss, William 108 Bcl-2 family, in cell death pathway 1059 1060–1061 BDNF See Brain-derived growth factor Becker muscular dystrophy 710 low levels of distrophin in 707 See also Distrophin gene Bedwetting, parasomnia 955 Behavior adaptability of related to modifiability of specific connections among nerve cells 34 adaptation of postural control to 819–820 aggressive and decreased activity of serotonergic neurons 50 effect of social stressors 50 and X-linked mental retardation 50 and brain 5–18 combination of biological and psychological concepts, history 6–7 complex modulatory systems of brain underlying 334 single gene defects can affect in mice 47 50 contributions of genes and learning 1165 control of, and sex differences in brain 1141–1143 directed by sensory representations 653 disturbance See Abulia effects of slowing down conduction of action potential 148 executive functions, anterior association cortex 352 fusiform system activity levels in different types, cat walking example 727 and genes 36–62 guided by interactions between posterior and anterior association areas 363 human genotype as determinant of 40–42 influence of single genes 51–55 impulsive, effect of mutation in gene encoding serotonergic receptor 50 inheritable components 37 instantaneous, and electrical transmission 180 181 integration of autonomic and endocrine functions with, by hypothalamus 974–977 learned, some involve both implicit and explicit forms of memory 1243–1244 locomotor, disrupted by deletion of gene encoding enzyme important for dopamine 50–51 motivated, role of anterior cingulate circuit of basal ganglia 866 neurobiology 3–62 nonmotor, role of basal ganglia 866 novel, processing 779 novelty-seeking, human, and gene that encodes D4 dopamine receptor 51 planning, tests of 358 psychological investigation of, history 6 reflexive 873–888 relationship with brain, opposing views 6–7 result of genetic and developmental mechanisms acting in brain 1277 pattern of signaling between appropriately interconnected cells 317 role of dopaminergic system in 50–51 See also Learning; Memory sex differences in 1136–1137 shared and nonshared environmental contribution 41–42 simple, uses many parts of the brain, pathway of processing 317–319 318 specific, mediated by specific signaling networks of nerve cells 25–27 symbolic 364 unification of study of with neural science 5 use of twin studies to evaluate contributions of genes and environment 40–42 voluntary, law of effect 1242 Behavioral activation, role of limbic dopaminergic neurons 1009–1010 Behavioral context, and neuronal responses in S-II 468 Behavioral disorders, complex, genetic component 58 Behavioral homeostasis 871–1013 Behavioral responses, role of dopaminergic neurons 896 Behavioral traits complex, multigenic in humans 55–59 genome analysis 59 60 Behaviorism, empirical school of psychology 382 Behaviorist psychology 412 Bell's palsy, injury of facial cranial nerve 878 Belt desmosome 614 615 Benedikt syndrome, midbrain infarction 1312 Benzer, Seymour 44 1257 Benzodiazepines effect on GABA receptor 1223 target GABA-gated channels 219 treatment generalized anxiety disorder 1222 parasomnias 958

periodic limb movement disorder 955 prolonged repetitive seizures 919 Bereavement, compared with depression 1211 Berger, Hans 897 911 922 Berkeley, George 411 493 1317 Bernard, Claude 6 871 961 Beta efferents 725 Beta waves, electroencephalogram 916 Beta-endorphin amino acid sequence 487 interaction with opioid receptors 485–486 neuroactive peptide 289 Beta2-adrenergic receptor, structure 232 Betz, Vladimir 758 Bezanilla, Francisco 163 Binding mechanism, vision 502 Binding problem and synchrony of cells 567 visual system 566–567 Binocular circuits, development in visual cortex and postnatal neural activity 1117–1122 Binocular disparity 560 Binocular interaction, ocular dominance columns in 539 Binocular zone 525 visual field 524 Binswanger disease, cerebrovascular disease 1314 Biochemical cascase 229 Biochemical processes, use of PET for imaging 375 Biogenic amine system, abnormalities in and panic attacks 1221 P.1330 Biogenic amine transmission abnormality of in disorders of mood 1216–1220 neurotransmitters biosynthesis and structure 282 as small-molecule neurotransmitters 282 Biogenic amine uptake blockers, antidepressants, structure 1213 Biogenic amines, magnitude and timing of motor neuron activity in locomotor networks in spinal cord 751 Bipolar affective disorder see Bipolar mood disorder Bipolar cell center-surround receptive field 518 structure of 521 convey cone signals to ganglion cells 520–521 excitatory connections 521 passive transmission of signals 520–521 receives input from rods and cones 509 retina 508 structure 515 Bipolar mood disorder functional abnormality in prefrontal cortex ventral to genu of corpus callosum 1212 in families of adoptees 1212 genetic component 58–59 models of transmission 59 in twin pairs 1212 See also Depression; Mania symptoms 1211 Birds, sleep patterns 944 Birthday, neuronal 1049 Bishop, Peter 561 Bisiach, Edoardo 394 Bitemporal hemianopsia 544 545 Bitter tastant mechanims of transduction 639 response of taste cells to 640 taste quality 639–640 Bladder, autonomic reflexes and voluntary control 968 Blakemore, Collin 561 Blalock, Alfred 300 Bleuler, Eugen 1192 Blind spot 524 525 eye 508 Blindsight 528 lesions of primary visual cortex, relevance to consciousness 1318 Bliss, Timothy 1259 Blobs 540 541 545 location of color processing 545 in primary visual cortex 501 532 537 539 549–550 striate cortex, double-opponent cells in 583 Blocking molecules, ion channels 112 Blood oxygen level detection, use of in functional MRI 374–375 Blood pressure, hypothalamic control 974 Blood supply, brain 1302–1304 Blood vessels, brain 1303 Blood-brain barrier 1288–1295 anatomy 1288–1289 developmental disorder of 1295 disorders of 1294–1295 metabolic 1293 movement of water-soluble compounds and ions across 1292 role of astrocytes 20 selectivity 1289–1293 transport of amino acids across 1291 transport properties 1290–1292

Blood-cerebrospinal fluid barrier, epithelial cells of choroid plexus regulate molecular flow across 1297 BMP See Bone morphogenetic proteins Body image, role of parietal lobe 9 Body maps cortical, modifiable by experience 388–391 orderliness of in cortex are basis of clinical neurological examinations 388 See also Body surface maps; Somatotopic map in superior colliculus 792 Body representation, related to representation of visual space 402 Body resource conservation, parasympathetic system of peripheral nervous system 335 Body surface complete representation in each area of primary somatosensory cortex 389 for each submodality of sensation in primary somatosensory cortex 387–388 map of multiple in somatic sensory cortex 469 neural, maintained at each stage of information processing 342 primary somatic cortex, variation among individuals 1274 produced by arrangement of central axons or dorsal root ganglion neurons 340–341 representation in brain by somatotopic arrangement of sensory inputs 458–461 touch and pressure, somatic division of peripheral nervous system 335 two-point discrimination for stimuli 436 Body temperature, hypothalamic control 974 Body weight, set point 1002 alteration by hypothalamic lesions 1002 1002 Body-centered frame of reference 498 Bogen, Joseph 364 Bolshakov, Vadim 1264 Bombesin, neuroactive peptide 289 Bone morphogenetic proteins (BMP) and development of neuronal identity 1048–1049 neural crest cell fate 1047 neural induction 1024 1024 patterning of dorsal neural tube 1025 1029–1030 Bonhoeffer, Friedrich 1081 Bony labyrinth 802 Botulinum toxin 271 A, B, and C, target SNARE proteins 270 Botulism, disorder of neuromuscular transmission 307–308 Bouquet cell, double, in cerebral cortex 922 Bowman's glands 626 Bradykinesia 861 Bradykinin activation of nociceptors 480 as chemical intermediary for pain 442 effect on nociceptors 481 neuroactive peptide 289 and nociceptor sensitization 477–478 Braille dots and mechanoreceptors 438 role of inhibitory interactions in reading 461 See also Letters, embossed Brain a priori knowledge 412 activities of as biological processes 1277 adult structural changes caused by gonadal hormones 1141 transient effects of gonadal hormones 1136 aggregate-field view of function 7 aging of 1149–1161 all behavior emanates from 6 alteration of vascular physiology after stroke 1316 anatomy 9 abnormalities in schizophrenia 1195–1196 organization 337 areas without blood-brain barrier 1293 association areas 1165 and behavior 5–18 blood oxygen level as index of activity, PET 375 supply divided into arterial territories 1302–1304 vessels of 1303 blood-brain barrier 1288–1295 cellular connectionism view 7 circulation 1302–1316 cognitive capabilities 349–380 P.1331 complexity of connections within 34 consciousness as function of 396 See also Consciousness coronal sections 332 damage to by prolonged seizures 927–930 death, bilateral forebrain damage 900 development 1017–1162 1139 1140 distinct functional regions of 7 9 diverging and converging neuronal connections 26 edema, types 1299 estradiol as masculinizing hormone for sexually dimorphic characteristics 1138–1140 experience modifies 1274–1275 functional systems on one side control other side of body 324 high expression of total genetic information encoded in DNA 89 homosexual versus heterosexual 1145 hormonally dependent sexual differentiation 1134–1140 idea of distributed processing 11 individual neurons as signaling units of 7

individuality of 1274–1275 information conveyed by action potentials 22 integrates perception produced by nerve cells wired together according to general plan 382 tactile information about an object 452 language-related areas 1174 localization of complex functions 365 mental functions in specific regions 3 neural basis of language 13 major modulatory systems 890–894 894 mass action theory of function 12 mental processes represented by elementary processing operations 15–17 modulatory systems influence motivation, emotion, and memory 65 333–334 MRI image 9 network properties of functional circuits 384 neural maps in create representation of outside world 33–34 nonhuman primates, cellular abnormalities 1157 number of neurons in 19 parallel processing in 34 See also Parallel processing personal space, orderly representation of studied at cellular level 384–388 positron emission in 376–377 rate of blood flow to 1305 reconstruction of object pattern by analysis of which nerve fibers have been excited 452 relationship with behavior, opposing views 6–7 See also names of parts of brain and pathways separate areas activated by motion and color 552 significant inhibitory input on neuron cell bodies in 224 specific sex differences and control of behavior 1141–1143 structural abnormalities in Alzheimer disease 1153–1155 study of lesions that interfere with mental functioning, cognitive neural science approach 383–384 single cells in intact and behaving animals, cognitive neural science approach 383 using clinical lesions 10 synaptic connections, morphological types 202 212 tabula rasa 411 theories of development 1139 1140 topographical maps in 323 unique modification of by experience 1274–1275 Brain-derived growth factor, binding by receptor tyrosine kinases 238 Brain-derived neurotrophic factor 1055 1056 blocks formation of ocular dominance columns 1124 1125 candidate for organization of presynaptic differentiation 1100 Brain death, as result of bilateral forebrain damage 900 Brain hemispheres, bilaterality, personal neglect syndrome 393–394 Brain imaging techniques, and monitoring progress of psychotherapy 1275 1277 Brain slice hippocampal 918 preparation for electrophysiological studies 918 918 recording from neurons in, set up 918 Brain stem 320 873–888 ascending projections from monoaminergic cell groups increase wakefulness and vigilance 896–897 ascending projections modulate arousal and consciousness 896–900 bilateral lesions, effects 1312–1313 blood supplied by vertebral and basilar artery branches 1309 cell groups with long projections defined by their neurotransmitters 889–896 cholinergic cell groups in 894 894 circuits for repetitive rhythmic motor patterns 656 connections with central nucleus of amygdala and tests for fear and anxiety 993 cranial nerve nuclei at various levels 884 descending motor systems modulated by spinocerebellum 843–844 descending pathways initiate walking and control speed 750–751 descending pathways to spinal cord modulate sensory and motor pathways 896 differences in organization from spinal cord 885 division of central nervous system 320 dopaminergic neurons in 892 effects of damage to 871 function 8 8 320 identifying sites of lesions 886 886 infarction, characteristic syndromes produced 1311–1312 injury locations and loss of normal reflex eye movements 905 intact, ocular reflexes characteristic 907 lateral, emergence of cranial nerves from 877 lesions in and characteristic deficits of eye movements 789 792 lower, effect of injuries to 900–901 medial and lateral descending pathways 669 mediation of emotions 980 memory of adaptive learning in vestibulo-ocular reflex 828 midline, serotonergic neurons 893 893 modulates action of spinal motor circuits 668–669 arousal and selective attention 334 sensation, movement, and consciousness 889–909 monoaminergic nuclei, abnormalities in Alzheimer disease 1153 motor areas, somatotypical organization 648 motor circuits 663 for horizontal saccades 791 motor neurons corticalbulbar tract is pathway for cerebral cortex action on 671 modulated by cerebral cortex 669–671 motor nuclei, in motor system 667 nuclei, contain preganglionic cells of parasympathetic nervous system 963 motor circuits for saccades 789–792

ocular motor nuclei in 788 organization of stereotyped behaviors 900 P.1332 pathway of descending signals from and stepping 750 posterior fossa, lesion, symptoms of 1309–1310 raphe nuclei of, REM-off cells regulation PGO-on cells 942 regions of that control sleep 941 relay nuclei mediate localization of sound 606–698 reticular formation in 320 coordinates reflexes and behaviors mediated by cranial nerves 885–887 at level of medulla 887 and sleep 936 same developmental plan as spinal cord 883 See also Medulla; Pons; Reticular formation stereotyped motor responses 873 structure 873 transection 739 variety of reflex circuits 663 vascular syndromes 1312 ventral, origins of cranial nerves 876 Breathing, in obstructive sleep apnea syndrome 951–952 Brightness component function of reflectance function 578 variations in carry visual information 579 vision 572 Brikmayer, Walter 862 Broca aphasia 1177 after middle cerebral artery infarction 1308 characteristics 1176 difficulty understanding grammatically complex sentences 1177–1179 frontal lobe lesion 1175–1177 MRI of lesion 1177 spontaneous speech, auditory comprehension, and repetition in 1178 and working memory 1179 Broca's area activation when words are seen 13 Brodmann's areas included 1175 and category-specific knowledge 1236 language 1174 1175 and speech 10 11 Broca, Paul 986 Broca, Pierre Paul 10 325 1166 1228 Brodie, Bernard 1217 Brodmann, Korbinian 11 327 Brodmann's areas 328 cerebral cortex 12 Brodmann's area 1 effect of lesions 468 receptive fields of cells comprising column in 456 See Somatic sensory cortex Brodmann's area 2 effect of lesions 468 See Somatic sensory cortex Brodmann's area 3 See Somatic sensory cortex Brodmann's area 3b, effect of lesions 468 Brodmann's areas 3, 2, and 1, origination of lateral corticospinal tract 670 Brodmann's areas 3a, 3b, 1, and 2, primary somatic cortex 452 Brodmann's areas 3b, 3a, 1, and 2, effects of lesions 468 Brodmann's areas 4 and 6, origination of lateral corticospinal tract 670 Brodmann's area 4 primary motor cortex 671 See Primary motor cortex; Motor cortex Brodmann's area 5 See Posterior parietal cortex Brodmann's areas 5 and 7, posterior parietal cortex 452 Brodmann's area 6 origination of lateral corticospinal tract 670 premotor cortex 671 See Premotor areas; Prefrontal cortex Brodmann's Brodmann's Brodmann's Brodmann's Brodmann's

area area area area area

7 See Posterior parietal cortex 11 see Limbic cortex 17 See Striate cortex; Primary visual cortex 18 see Secondary visual cortex 20 See Visual inferotemporal area

Brodmann's Brodmann's Brodmann's Brodmann's

area area area area

21 22 39 40

See See See See

Visual inferotemporal area Auditory cortex Parietal-temporal-occipital cortex Parietal-temporal-occipital cortex

Brodmann's area 41 See Auditory cortex Brodmann's area 42 See Auditory cortex Brodmann's areas 1–5 457 Brodmann's areas 41 and 42, primary auditory cortex 609 Bronk, Detlev 695 Brown, David 241 Brown, Graham 742 Brown, Thomas Graham 740 Brown-Sequard syndrome hemisection of spinal cord 733 spinal cord infarction 1313 Bruce, Charles 357 Brucke, Ernst 108 Buccalines, neuroactive peptide 289 Bucy, Paul 988 Bueker, Elmer 1056 Burst cells in pontine reticular formation 789 types 790 Burst neurons, motor circuit for horizontal saccades 791

Bushy cell, cochlear nucleus 605 606

C C See Capacitance C fiber carry information from polymodal nociceptors 474 localization of substance P in terminal of 476 memory of input 479 wind-up phenomenon 479 c-fos, activation by seizures 933 C-terminal recognition sequence, membrane-anchored protein in endoplasmic reticulum 96 C/EBP activated by CREB in long-term facilitation 1254–1255 in long-term facilitation 1256–1257 C1-C2 cell groups See Adrenergic cell groups Ca2+ /calmodulin-dependent protein kinase, role in correlated firing of pyramidal cells in hippocampus 1267 Cacineurin 249 Cacosmia 635 Cade, John 1216 Cadherin, and neurite outgrowth 1074 1076 1077 Caenorhabditis elegans mechanisms for discriminating among chemicals 635–636 sequencing of genome, genes for channels 120 solitary versus social strains, singles genes and social behavior 42 study of apoptosis during development in 1058–1061 Cahill, Lawrence 992 Calcarine cortex, effects of infarction of posterior cerebral artery 1308 Calcarine fissure 368 Calcarine sulcus 324 and category-specific knowledge 1236 Calcineurin, dephosphorylation and inactivation of channels 159 Calcitonin gene-related peptide (CGRP) co-release with ACh in efferent synapses with hair cells 623 co-release with ACh 290 294 effect on nociceptors 481 neuroactive peptide 289 in sympathetic neurons 972 Calcitonin, neuroactive peptide 289 Calcium signaling, glial networks, and seizure foci 919 Calcium and axon growth cone motility 1074 causes vesicle fusion and transmitter release at chemical synapse 183 P.1333 conducted by AMPA receptor-channels 221 and cross bridge formation in muscle fibers 680–681 determinants of permeability in AMPA-type glutamate receptors 221 effect of changes in membrane potential at synaptic terminal 274 excess in Huntington disease 866 and fusion pore 264 266 influx of in long-term potentiation in mossy fiber pathway 1260 of in long-term potentiation in Schaffer collateral pathway 1260 at presynaptic nerve terminals triggers transmitter release 160 into presynaptic sensory neuron in conditioned stimulus pathway 1252 1253 regulates transcription of acetylcholine receptor genes 1096 1098 triggers transmitter release 255–258 intracellular concentration, modulatory influences on gating of ion channels 159 in excitotoxicity 928 free, regulated by axo-axonic synapses on presynaptic terminals 275–276 mechanism affecting transmitter release 260–261 regulation of influx during action potential modulates amount of neurotransmitter released 274–276 second messenger in synaptic transmission 230 levels of and neural activity in retina 1124 and light adaptation 514 mobilization of synaptic vesicles to active zone 277 in nucleus reticular cells during non-REM sleep 940 regulation of store of in smooth endoplasmic reticulum 71 residual as form of cellular memory 275 effect on synaptic transmission 274 retinal ganglion neurons 1121 role in neuronal function 276–277 See also Calcium ions Calcium-activated K+ channel 158 Calcium/calmodulin-dependent protein kinase 226 activation 236 regulation 235 Calcium binding, and refractory state of voltage-gated ion channels 115 Calcium carbonate See Otoconia Calcium gluconate, treatment botulism 307 Lambert-Eaton syndrome 307 Calcium ions (Ca +) as blocking molecules in ion channels 112 concentration at active zone 255 control of synaptic vesicle mobilization, docking, and fusion 272 enhanced influx of and presynaptic facilitation 275–276 muscle contraction 679 NMDA receptor-channel permeable to 212 role in mechanoelectrical transduction in hair cells 617 620 622–623

role in producing contractile force of muscle fibers 678 Calnexin, chaperone protein 95 Calreticulin, chaperone protein 95 CAM kinase II 271 cAMP See Cyclic adenosine monophosphate cAMP-response element binding (CREB) protein, activator, and memory in Drosophila 1259 Campbell, Kevin 707 708 Cannon, Walter B. 871 961 984 Cannon-Bard theory, emotion 984 Capacitance (C) 138 as passive electrical property of neuron 140 circuit analysis 1284 current flow in circuits with 1285–1286 electrical equivalent circuit for 142 electrical parameter 1281–1282 measurements of and components of membrane recovery 269 membrane 138 effect on membrane potential 143 effect on rate of spread of depolarization during action potential 147 and time course of electrical signals 142–143 study of exocytosis and endocytosis 266 and voltage response 142 Capacitive current 153 Capacitive membrane current 142 Capacitor ability of cell membrane to store charge 134 membrane to store charge in electrical equivalent circuit 134 electric potential difference across 138 in equivalent circuit model of cell membrane 138 time course of charging 1285 in parallel with a resistor 1286 in series with a resistor 1286 Capgras syndrome 994 Capsaicin receptor, in nociceptors 474 Capsule, specialized end-organ surrounding mechanoreceptor nerve terminal 432–133 Caramazza, Alfonso 13 Carbamazepine, treatment, prolonged repetitive seizures 919 Carbon dioxide, induction of panic attacks 1221 Carbon monoxide action at synapses 262 second messenger in synaptic transmission 230 stimulates cGMP synthesis 239–240 transcellular messenger 239 Carboxypeptidase, B, biosynthesis of neuroactive peptides 288 Carcinomas, chronic neuropathy in 702 Cardiac arrhythmia caused by ion channel malfunction 105 methods for documenting 949 Cardiac muscle 674 Cardiovascular reflexes, mechanism 967–968 Carlsson, Arvid 862 1198 1201 Carnosine 284 Caron, Marc 1011 Carotid artery, occlusion 1309 Carrier model, selectivity of ion channels 108 Cartesian view of consciousness 1317 Caspases activation triggered by neurotrophic factor deprivation 1060 in cell death pathway 1059 role in apoptotic cell death 1059–1060 Cataplexy 943 949 neurophysiological similarity to atonia of REM sleep 950 symptom of narcoleptic syndrome 949 treatment 951 Cataracts, early-versus late-forming, effect on vision 1116 Catatonic schizophrenia 1193 Catechol-O-methyltransferases, degradation of biogenic amines 294 Catecholamines as small-molecule neurotransmitters 282 biosynthesis and structure 282 Cation channel, cyclic nucleotide-activated, molecular structure 168 Cations 108 126 ion channels selective for 110 Caudal 321 Caudate nucleus 325 332 333 347 368 369 833 basal ganglia 331 855 855 hyperactivity in obsessive-compulsive disorder 1224 inhibitory input to substantia nigra in saccades 793 in oculomotor circuit 861 P.1334 Cavernus sinus 877 ced genes, C. elegans 1058–1059 Ced-4 family, in cell death pathway 1059 Celican ganglion 964 Cell body 22 location of synthesis of neuronal proteins 103 neuron, synthesis of proteins 88–92 neuronal 21 67 retrograde transport to 102–103 Cell death

genes, C. elegans 1058–1059 genetic pathway for in C. elegans and vertebrates 1059 inhibitors of 1059 pathway, evolutionary conservation 1059 1059 program, neurons, activated by removal of neurotrophic factors 1058–1061 promoters of 1059 See also Apoptosis; Programmed cell death Cell fate, factors determining 1023 Cell membrane determination of ionic permeability properties 106–107 distribution of ions across 128 on either side of 126 equivalent circuit model of 138 flux of K+ across 129 forces driving ions across 128 high capacitance 148–149 hydrolysis of phospholipids in and activation of second-messenger cascades 237 increase of ion conduction across during action potential 150–151 lipid bilayer as insulator separating two conducting solutions 138 contributes to determination of ionic permeability properties of cell membrane 106–107 maintains separation of charges 126 passive properties affect velocity of action potential propagation 147–148 rate of transfer of ions across 108 Cell motility, role of actin motors 75 Cell theory 23 Cells, electrically coupled require large synaptic current to depolarize 180 triggered in all-or-none manner 180 Cellular connectionism, view of brain function 7 Center-surround antagonism 519 Central axons, permissive environment for regeneration provided by peripheral nerves 1112 Central lateral nucleus, thalamic 482 Central nerve terminals, subject to elimination 1101–1103 Central nervous system 335 adult subdivision 1022 anatomical but not functional distinction from peripheral nervous system 334–335 anatomical organization 317–336 ascending pathway preserve sensory specialization of dorsal root ganglion neurons 447 axonal regeneration promoted by therapeutic interventions 1110–1111 blood-brain barriers 1288–1295 cerebrospinal fluid 1288–1301 circuits, activity-dependent refinement of connections in 1125–1127 damage produces characteristic alterations in reflex responses and muscle tone 730–735 development 1017–1062 permanent effects of gonadal hormones 1136 differentiation of glial cells in 1049 embryonic subdivisions 1022 EPSPs in 226 excitatory synpatic actions regulated by glutamate receptors 213 functional systems of 323–324 glutamate as excitatory transmitter 226 hierarchical organization of functional systems 324 human, structural sex differences 1143 lesser capacity for nerve regeneration 1109–1110 main parts 7 8 8 major divisions 319–323 320 MRI of major regions of 367 neuronal cell death 1054–1055 neurons studies with extracellular recordings 454 notch signaling regulates neuronal cell fate 1045 pathways in 323 rat, structural sex differences 1138 See also Central neurons; specific regions sensory information processed in stages 428 sex differences in, produced by exposure to testicular hormones during development 1136–1137 stretch reflex circuit of quadriceps muscle 208 survival of neurons in and neurotrophin 1057–1058 synapse formation similar to that at neuromuscular junction 1101–1104 synapse ultrastructure 1100 synaptic connections compared with neuromuscular junction 207 synaptic transmission 207–228 three major axes of 321 zones of contrasting activity 427 Central neuron contain little laminin and low amounts of trophic molecules 1110 cytoplasmic proteins mediate clustering of receptors at synapses 1104 integrates excitatory and inhibitory signals into single response 222–223 myelin inhibits regeneration of axons 1110 neurotransmitter receptors cluster at synapses 1102–1103 pre- and postsynaptic membrane linked by macromolecular complexes at synapse 1105 receive excitatory and inhibitory inputs 207 209 See also Central nervous system; Spinal neurons synapses on dendritic spines often excitatory 224–225 grouped according to function 223–226 synaptic cleft compared with that at neuromuscular junction 1103–1104 variety of inputs mediated by different neurotransmitter types 1103 Central nucleus, amygdala connections with hypothalamic and brain stem areas and tests for fear and anxiety 993 lesions 992 projections 992 Central pain 481 Central pain syndrome, stroke 484

Central pattern generator 754 characteristics 744 neurons in 744 postinhibitory rebound in 744 spinal cord, methods of revealing 743 Central sensitization 479 Central sulcus 9 324 457 cerebral cortex 325 Centromedian nucleus, thalamus 343 Cephalic flexure 1021 1022 Cerebellar artery, posterior inferior and anterior inferior 1303 Cerebellar ataxia 665 Cerebellar cortex 347 cerebellum 833 dendritic architecture in 72 lateral, Purkinje neurons of project to dentate nucleus 845 layers 835 836 use of herpes simplex virus to trace projections of cells in primary motor cortex to 99 Cerebellar flocculus, neural integration of velocity signal in saccade 790 P.1335 Cerebellar glomeruli 835 Cerebellar hemisphere, projections to contralateral red nucleus and motor cortex 842 Cerebellar nuclei, somatotopic organization 843 Cerebellar peduncles 877 cerebellum 833 cranial nerve nuclei at level of 884 Cerebellum 9 320 324 332 367 761 832–852 afferent inputs 835–839 anterior lobe lesions, affect anticipatory postural control 821 821 basic circuit of 837 837 blood supplied by vertebral and basilar artery branches 1309 effect of thiamine deficiency on 850 elimination of synapses after birth 1103 fine-tuning of locomotor pattern 753 folia 834 function 7 8 8 322 functional regions 833–835 hemorrhage, effects 1315 increased blood flow in cocaine craving 1008 infarction, effects 1313 influence on motor systems 832 influences cortical and brain stem motor systems 663–665 inputs to motor cortex 761 and outputs 835 intermediate, lesion of 850 lateral hemispheres, input from cerebral cortex 845 lesions 795 affect limb movement 843 effect on motor learning 848–849 in right hemisphere 849 lobes of 834 and mental operations 850 in motor learning 848–849 850 in motor system 667 and movement anticipatory actions 850 internal feedback signals compared with external feedback signals 850 nuclei 833 organization 832 regions of 832 833 required for adaptive postural control 820–821 right lateral and medial, and category-specific knowledge 1236 role in adapting vestibulo-ocular control 825–828 control of smooth pursuit 795–796 implicit memory 1243 signs and symptoms of diseases 849–850 849 tracts connecting to brain stem 833 Cerebral aqueduct 367 Cerebral arteries See Anterior cerebral artery; Middle cerebral artery; Posterior cerebral artery Cerebral blood flow, correlation of increases with cocaine craving 1008 Cerebral blood vessels, unique physiological responses 1305–1306 Cerebral cortex 320 acts on brain stem motor neurons through corticobulbar tract 671 affective aspects of language in right hemisphere 14–15 areas dedicated to processing of visual information 499 anatomy 9 324 in ascending arousal system 900 and ascending pathway of nociceptive information 480–482 482 association areas of 349–380 associative capabilities, anatomical basis 331 auditory information in bats 609 processed in many areas of 608–610 auditory regions 591 basal ganglia parallel circuits link with thalamus 857–861 Brodmann's areas 12 cell types in 922 of cerebral hemispheres 322 chromatic channels in 581–582

and cognitive functioning 9–13 324–329 columnar organization and pattern of neuronal connections in different layers 458 control of saccades 792–795 cytoarchitectonic characterization 11 descending motor systems modulated by spinocerebellum 843–844 dominance of left hemisphere 10 establishment of neuronal layers in 1049 evaluative component of emotion 985 eye movements 797 four lobes of 325 functional regions 325–326 351 experimental localization 12 generation and migration of neurons in 1050–1051 highest level of information processing in 344–346 inhibition mediated by GAB A 923 injuries to and study of function of association areas 351 353 input to lateral hemispheres of cerebellum 845 interactions among areas to produce visual image 505 intrinsic connections 457 language areas, experimental confirmation 12–13 layers of neurons in 326 levels of electrical activity 897 location for unimodal and multimodal association areas to communicate regarding sensory signals 382 mediation of feelings 980 modulates action of brain stem and spinal cord motor neurons 669–671 motor areas of 756 758 somatotopic organization 757 somatotypical organization 648 motor centers 648 neuronal cell fate controlled by timing of cell differentiation 1049–1051 neuronal cell types 329–331 neurons defined by receptive fields and modalities 454–456 neurotransmitters in cells of 922 nonuniformity of layers in 327 organization of 9–10 327 PET identification of regions involved in language processing 14 plane of division of progenitor cells influences fate 1052 processing of olfactory information in several areas 633 pain 481–482 sensory information 345 prominence of particular cell layers 328 pyramidal neurons of have more extensive dendritic trees than spinal motor neurons 85 regional differentiation 1036–1037 regional properties during development 1038 relay of taste information to 642–644 role in cognition, history 10–13 control of smooth pursuit 795–796 See also Cortex; Neocortex; specific regions sensory illusion of pain in 484 484 sensory information from unimodal areas converges in multimodal areas 354–355 sensory modalities conveyed to in ascending pathways 449 separate operations in each hemisphere 16 specialized regions 337 specific regions control specific functions 6 structure 8 summated activity of as consciousness 897 synapses eliminated after birth 1103 synaptic inhibition 922 time course of K+ concentration 1291 topography of neurofibrillary tangles and senile plaques in Alzheimer disease 1153 P.1336 translation of peripheral signals into specific feelings 985 transmission of taste information from taste buds 642 two pathways for visual processing centers 501 use of extracellular recording to create three-dimensional functional maps 454 vestibular projection, perception of rotation and vertical orientation 813 visual information, local changes in blood flow by PET in processing 378 vision processing, different areas make different contributions 497–500 Cerebral hemispheres 9 blood supply 1302 1304 consciousness and sensory processing streams not distributed symmetrically in 363–365 function 7 8 8 functional differentiation of in movement 364 involvement of each in aspects of speech 364 MRI scan coronal section 369 horizontal section 368 nondominant, effect of damage to 364 See also Cerebral cortex structure and function 322–323 structures 325 test of independent function in split-brain patient 365 Wada test for distinguishing dominance 364 Cerebral penduncle 346 Cerebral ventricles, increase in volume causes hydrocephalus 1299–1300 Cerebrocerebellum 834 cognitive functions 846–848 lesions, disrupt motor planning and prolong reaction time 846 part of feedback circuit regulating cortical motor programs 845–846 perceptual and cognitive functions 845

planning movement and evaluating sensory information for action 845–848 Cerebrospinal fluid alteration of composition in disease 1297–1298 comparison with serum 1296 distribution 1294 functions 1295–1299 increased intracranial pressure 1298–1299 1298 transport within arachnoid villi 1295 1296 ventricular organization 1288–1301 Cerebrovascular accident See Stroke Cerebrovascular disease cause of dementia 1314 See also Aneurysm; Hemorrhage; Infarction; Occlusion; Stroke Cerebrum, arterial areas 1303 Cervical flexure 1021 1022 Cervical region, spinal cord 338–340 339 Cervical ventral roots 876 Cervicocollic reflex, stabilizes head relative to trunk 822 Cervicospinal reflexes, collaboration with vestibulospinal reflexes to maintain postural stability 823–824 823 Cervicothalamic tract, ascending pathway for nociceptive information 480–482 cGMP See Cyclic guanosine monophosphate CGRP See Calcitonin gene related peptide Ch1-Ch6 cell groups See Cholinergic cell groups Chandelier cells 331 in cerebral cortex 922 GABA-ergic interneuron 329 Chang, C.C. 300 Changeux, Jean-Pierre 197 300 Channel-receptors, pore properties 220–221 Channels See Gap-junction channel; Ion channels Chaperones folding of proteins 103 import of proteins into mitochondria 93 role in protein folding 91–92 protein glycosylation in endoplasmic reticulum 95 Charcot-Bouchard microaneurysms 1315 Charcot-Marie-Tooth disease 710 chronic neuropathy 702 demyelination results from mutation in connexin 32 gene in Schwann cell 182 duplication of PMP22 gene causes 83–84 gene duplication in chromosome 17 84 genetic defects in 709 nerve biopsies 84 phenotype 84 Chemical coding, combinatorial release of chemical mediators by autonomic neurons 980 Chemical driving force contribution to current flow 133 and flux of ion across cell membrane 131 ions 128 Chemical ligands, effect on ion channel gating 114 Chemical messengers as metabolites 295 histochemical detection within neurons 292–293 pheromones 633–634 See also Neurotransmitters Chemical receptors 416 Chemical senses 625–647 Chemical signals, carry information 125 Chemical synpases, plasticity of 34 Chemical transmission, diseases of at nerve-muscle synapse 298–309 Chemical transmitters bind to postsynaptic receptors 183–185 common biochemical features of receptors for 185 criteria for 280–281 different among neurons 33 Chemoattractant molecule, guidance cue for axon growth cone guidance 1071 Chemoreceptors nociceptors as 442 transduction of stimulus energy into neural activity requires intracellular second messengers 417 Chemorepulsion, guidance cue for axon growth cone guidance 1071 Chemosensory information, vertebrate and invertebrate strategies for processing 635–636 Chemosensory receptors, in viscera 443–444 Chemospecificity hypothesis, axon target recognition 1065–1066 Chemotaxis, and axon growth 1078 1080 Cheyne-Stokes respiration, in coma 902–903 Chiaroscuro, depth perception 558 Childhood absence seizure, neuronal cell activity during 922–923 Children confusional arousals in 956 organized dreams in 945 pattern of sleep 943 spontaneous development of language in 1171–1172 Chimeric mice 49 Chloride channels, gene family 119 Chloride ions (Cl-) distribution 138 distribution across cell membrane 128 neuronal cell membrane at rest 128 GABA- and glycine-gated channels that conduct, mediate inhibitory synpatic action 214–219 gradient controlled by chloride transporter 132 ion channels selective for and inhibitory actions at chemical synapses 216 P.1337

nerve cells permeable to at rest 129 passive distribution 131–132 across cell membrane 131 resting ion channels in nerve cells selective for, in addition to Na+ and K+ ions 129–131 role in generalized anxiety disorder 1222–1223 1223 secondary active transport 132 selectivity of anion-selective channels for 111 Chloride pathway, included in equivalent circuit model 137 Chloride transporter, integral membrane protein controlling Cl- gradient 132 Chlorporthixene, structure 1198 Chlorpromazine blocks dopamine receptors 1199 structure 1198 treatment, schizophrenia 1197 Choice effect, voluntary movement 661 Cholecystokinin effect on feeding 1004 neuroactive peptide 289 Cholinergic 280 Cholinergic cell groups, in brain stem and forebrain 894 894 Cholinergic neurons destroyed in Alzheimer disease 1154 in midbrain and basal forebrain 896 Cholinergic system, basal forebrain, target for treatment of Alzheimer disease 1158 Chomsky, Naom 382 1171 1173 Chopper cell, cochlear nucleus 605 606 Chopper response, cochlear nucleus 606 Chorda tympani fibers, hamster, response profiles 643 Chorda tympani nerve (VII) innervation of taste buds 637 643 taste information pathway 642 Chordin, neural induction 1024 Chorea 861 basal ganglia-thalamocortical circuit in 860–861 See also Huntington chorea Choroid plexus epithelial cells regulate molecular flow across blood-CSF barrier 1297 secretes cerebrospinal fluid 1295–1297 Chromatic aberration 580–581 Chromatolytic reaction, after axotomy 1108 Chromatolysis, after axotomy 1109 Chromosomes 37 38 human, map at metaphase 39 See also X chromosome sex 38 store genetic information 37–38 Chronic granulomatous disease, molecular genetics of 705 Chronic insufficient sleep syndrome 953–954 Chronic neuropathies 702 Chronic peripheral neuropathy, neurogenic disease of peripheral nerve 701 Chronic sensorimotor polyneuropathy, muscle fiber distribution in 698 Churchland, Patricia 398 1318 Ciliary ganglion 964 Ciliary neurotrophic factor, candidate for organization of presynaptic differentiation 1100 Cingulate bundle 893 Cingulate cortex of cerebral cortex 325 and emotion 992–994 in hallucinations in schizophrenia 1190 infralimbic area, pathway of sensory information 974 mediation of feelings 980 storage of emotional memory 991 Cingulate gyrus 324 325 367 369 evaluative component of emotion 985 in limbic lobe 986 987 perception of feeling and emotion 988 role in processing pain 481–482 Cingulate motor areas 760 Cingulate sulcus 324 Cingulum 987 Circadian clock features of 44 in flies 44 Circadian cycle, disturbance of in unipolar depression 1220 Circadian pacemaker neurons, resetting 937 Circadian rhythm disturbed in insomnia 954–955 in elderly 955 flies, molecular polymorphisms in period gene 42 for homeostatic functions 1007 in mammals 45 role of period gene in flies 45 and sleep 937 946 regulation by suprachiasmatic nucleus of hypothalamus 322 Circle of Willis 1303 overlapping blood supply in brain 1304 Circuit analysis, rules for 1282–1284 See also Electrical equivalent circuit model with capacitor 1285 with resistor and capacitor in parallel 1285–1286 in series 1285 Circular vection 828

destabilizing effect 829 Circulation, brain 1302–1304 Circumvallate papillae, on tongue 636 637 Circumventricular organs 975 absence of blood-brain barrier 1293 Cis -9, 10-Octadecenoamide, hypnogenic properties 943 11-Cis-retinol 573 Cisterna magna 367 Cisternae, Golgi complex 96–97 CK See Creatinine kinase Clapham, David 248 Classical conditioning association of two stimuli 1240–1242 associative learning 1240 capacity of conditioned stimulus to produce conditioned response 1241 gill-withdrawal reflex in Aplysia 1252–1253 1253 long-term storage of implicit memory 1254–1259 presynaptic facilitation of synaptic transmission 1252 timing of stimuli is critical 1252 Clathrin coat generation of transport vesicles 96 mediates endocytosis of synaptic vesicles 99 -coated vesicles, in endocytic traffic 98 movement by faster component of slow axonal transport 103 pits coated with 273 role in recycling of synaptic vesicles 269 Claude syndrome, midbrain infarction 1312 Claustrum 333 855 and visual attention 505 Climbing fibers activity produces long-lasting effect on synaptic efficacy of parallel fibers 840–841 cerebellar afferent input 835–839 836 837 encoding of peripheral and descending information 839–840 induction of long-term depression 840 system, compared with mossy and parallel fiber systems 838 Clinical neurological examinations, reliance on orderliness of cortical maps of body 388 Clock mutation, mice, regulation of circadian rhythm 45 Clock protein, circadian rhythm 45 Clonazepam See Benzodiazepines Clonic phase, partial seizure 913 Clonidine, treatment, post-traumatic stress disorder 1222 Clostridial neurotoxins, SNARE proteins as target of 270 Clozapine structure 1198 treatment for some cases of schizophrenia 1206 CNQX See 6-Cyano-7-nitroquinoxaline-2, 3-dione P.1338 CNTF and diversification of glial cells in rat optic nerve 1048 induction of switch from noradrenergic to cholinergic neurotransmitter phenotype 1051–1052 neurotrophic receptor 1057 CO See Carbon monoxide Coated pits, in exocytosis 265 Cocaine blocks uptake of norepinephrine 295 voltage-gated Na+ channel 154 craving correlation with increases in cerebral blood flow 1008 elicited by environmental cues reminiscent of usage 1008 1008 effect on rate of electrical self-stimulation of brain 1010 positive reinforcement action 1010 structure 154 Cochlea 590 591 802 807 amplies sound energy 599–600 601 cellular architecture of Organ of Corti 596 deconstruction of sound 594 evoked otoacoustical emissions 600 functional anatomy 593–600 See also Organ of Corti structure 592 595 Cochlear duct 802 See Scala media Cochlear nerve 591 592 802 807 encodes stimulus frequency and intensity 601–602 Cochlear nuclei 590 auditory pathway 604 cranial nerve nuclei at level of 884 location and function 882 sound processing 603–606 Cochlear nucleus 881 dorsal, layers 605 formation of tonotopic maps on neurons in 1127 representation of stimulus frequency in 605 types of cells in 605–606 606 ventral, neurons in 605 Cochlear prosthesis, treatment, hearing loss 610–612 611 Codeine, analgesia 483

Coeliac ganglion 963 Cognition age-associated alterations 1151 disciplines used to study 313 effects of sleep 944 and integrative actions of brain 382 interaction among association areas 362–363 internal cellular representation required for perception and action 381–403 neural basis of 313–403 role of basal ganglia 866 use of sterognosis to study 452 Cognitive abilities, genetic component 58 Cognitive function approaches to study 383–384 localized within cerebral cortex 9–13 role of cerebral cortex 324–329 cerebral hemispheres 322 use of functional imaging to determine 366–379 Cognitive map, of spatial environment in hippocampus 1264 1266 Cognitive neural science 313–314 382 1165 five major approaches of 383–384 study of neural representations of mental acts 382–383 Cognitive performance, sex differences 1142 Cognitive psychology 4 382–383 402 convergence with neural science 1227 Cohen, Monroe 1092 Cohen, Stanley 1055 1056 Cold mediated by thermal receptors 444–445 -sensitive neurons, hypothalamus 1001 Cole, Kenneth 150 152 Collapsin-1, semaphorin that causes axon growth cones to collapse 1080 1081 Color agnosia 500 anomia 500 appearance influenced by context 572 574 areas of brain activated by 552 blindness congenital versus acquired 583–585 mutations causing 51–52 cells in inferior temporal cortex respond to 565 constancy 563 contrast 531 sensitivity of P and M cells 530 information bound up with analysis of other object attributes 588 carried by P cell system 579 pathway for 583 neural basis of perception without accounting for subjective qualities 398 not an isolated attribute 581–582 -opponent neurons, in V4 588 -opponent signals, retina 588 perception, effect of mutations in opsin genes 51–52 processing in blobs 545 in cerebral cortex 497–500 signals about conveyed to temporal lobe 583 television, confusion of color visual system by 577 theory of multistage processing 587 vision 572–589 achromatopsia case history 586 affected by disease or injury 585 dichromatic system 573 effects of lesions in lateral geniculate nucleus on 530 530 531 531 loss of after damage to ventral occipital cortex 563–564 mediated by cones 509 opponent mechanisms 578 P pathway 545 and properties of surfaces 573 See also Color blindness three classes of cone photoreceptors 585 588 trichromatic 584 types of photoreceptors 573–575 versus brightness vision 572 and visual perception 573 wavelengths of light 572 Colors, synthesis of wide range with three primary lights 579 Columns computational modules of neocortex 331 distribution of neurons in neocortex 329–331 functional modules of cortical processing 457 functional organization of cortical neurons 469 in inferior temporal cortex 565 in neocortex 325 organization of cranial nerve nuclei 880–885 881 in primary visual cortex 537–539 545 linked by horizontal connections 540–543 542 See also Ocular dominance columns; Orientation columns somatic sensory cortex inputs to 456–58 organization 456–58

summation, in primary auditory cortex 609 suppression, in primary auditory cortex 609 Coma after lesion of paramedian reticular formation in midbrain 899 after transection of ascending arousal system rostral to level of inferior colliculus 899 bilateral forebrain damage 900 bilateral lesions of brain stem 1312–1313 blocked thalamocortical transmission 899 emergency care of patient 905 907 P.1339 examination of patient 901–908 metabolic encephalopathy, common causes 901 nature of eye movements and level of brain dysfunction in 907 pupillary response and level of nervous system dysfuncion in 906 pontine hemorrhage 1315 posterior fossa aneurysm 1316 respiratory pattern 902 structural evaluation of eye movements 904–905 pupillary light response 904 level of arousability 903–904 motor responses 903–904 respiratory pattern 902–903 Comatose 901 Command cells 33 Commissurotomy 365 two hemispheres of cerebral cortex operate independently 16 Commisures 323 365 Communication systems, in nonhuman animals 1173 Compartmentalization, neuronal cell functions 67 Competence, response to inductive signals 1023 Complex cells, primary visual cortex 533–534 receptive field 536 Complex spike, Purkinje cells 839 Complex stimuli, response of neuron in inferior temporal cortex 566 Component direction-sensitive neurons 554 Compound action potential 146 299 Comprehension, interaction among association areas 362–363 Compulsions 1223 Computational neurobiology 34 Computational power, degree of associated with number of columns in cerebral cortex 331 Computers See Artificial intelligence Comte, Auguste 411 Concentration gradient ions 126 K+, gives rise to electromotive force 133 Conceptual system, language 1175 Concordance 1193 Conditional bursters, in central pattern generator 744 Conditioned flexion-withdrawal reflex 715 Conditioned response 1240 1241 Conditioned stimulus 1240 1241 Conditioning classical, and prediction of events in environment 1240 context, role of amygdala 992 food-aversion 1243 Conductance (g) 135 acetylcholine-gated ion channels 196 synaptic, determination of time course of end-plate potential 204 calcium-dependent K+, contribution to primary generalized seizures 925 chloride, increase in results in inhibitory IPSP 217 circuit analysis 1282–1283 electrical parameter 1281 end-plate 202 ion channel 111–112 K+, mechanism of in inward rectifying K+ channel 121–122 leakage 153 membrane 135 of rectifying ion channel 112 single-channel 193 194 two states of in voltage-gated channels 162 voltage-gated Na+ and K+, calculated from current 154–155 Conductile component, nerve cell signaling 31 Conducting signal 27 Conduction aphasia characteristics 1176 damage to left superior temporal gyrus and inferior parietal lobe 1180 phonemic paraphasias and problems with confrontation naming 1180 spontaneous speech, auditory comprehension, and repetition in 1178 Conduction block 703 Conduction, methods for increasing velocity 147 Conduction velocity according to axon diameter and myelination 444 in demyelinated motor neurons 703–704 measurement in peripheral nerves 444 Conductor in equivalent circuit model of cell membrane 138 ion channels as 134

single K+ channel as 133 Cones desensitization during light adaptation, role of calcium 514 differences from rods 509 functional regions 510 glutamate neurotransmitter in 518 mediate color vision 509 membrane potential during light adaptation 515 and on-center and off-center bipolar cells 518 opsins, common precursor gene 576 photoreceptors 585 588 pigments of 573 preferential response to particular wavelengths of light 574 retinal photoreceptor 508 509–510 See also Color blindness; Color vision signals conveyed to ganglion cells by bipolar cells 520–521 mechanisms for combination of 579 transformed early in visual pathway 577–581 spectral sensitivities 577 structure 510 515 three types in retina 575–577 transformation of signals from 580 types of 509 510 visual pigments in 512 Congenital adrenal hyperplasia cognitive and psychosexual aspects 1143 and sexual differentiation 1134 1135 Connectins, in muscle fibers 678 Connectional specificity, principle of neural organization 23 Connectionist models, computational neurobiology 34 Connections, among nerve cells, convey information 33–34 Connections, among nerve cells, modifiability of and adaptability of behavior 34 Connexins 178 gene family 180 mutation in gene for causes demyelination in Charcot-Marie-Tooth disease 182 structure 179 Connexon 178 structure 179 Conscious thought, multimodal association areas of cerebral cortex as anatomical substrate for 350 Consciousness accessibility to neurobiological study 396–400 and association cortices 363 binding mechanism 1318 and blindsight studies 1318 Cartesian view 1317 content of, evaluation 901 emergent property of brain 397 forms of 400 function of brain 396 history of ideas about 1317–1319 illusion 1318 impaired by damage to ascending arousal system 899–900 intentionality of 396 interaction among association areas 362–363 loss of identifying site of impairment 901–908 P.1340 injury to ascending arousal system 897 structural or metabolic 901–902 modulated by ascending projections from brain stem 896–900 brain stem 889–909 neural representation 16–17 not distributed symmetrically in cerebral hemispheres 363–365 not a unitary process 16 questions of accessibilty to empirical study 397 reductionist approach to study 398–400 selective attention as testable component of 400–402 state of awareness 396 evaluation 901 study of neural correlates of 400 subjectivity of 396 397 summated activity of cerebral cortex 897 unitary nature of 396 400 and visual attention 504–505 Conservation, evolutionary, of ion channel structure and function 117 Consolidation processing of explicit knowledge 1237–1238 short-term into long-term memory 1254 1256 Constant-frequency emissions, echolocation 610 Constantine-Paton, Martha 1121 Contact inhibition, guidance cue for ax on growth cone guidance 1071 Context, affects appearance of color 573 574 Context conditioning 992 Contextual effect 543 Contractile force, muscle fiber, produced by cross bridges 678

Contralateral hemianopsia 544 Contralateral olfactory bulb, olfactory information processing 633 Contralateral precentral gyrus, primary motor cortex 758 Contralaterality, cerebral cortex hemispheres 9–10 Contrast sensitivity 531 Contrasts, visual pattern of detected by ganglion cells 519–520 Control systems analysis of feeding behavior 1002 analysis of homeostatic processes in terms of 999 Controlled variable 1000 Convergence 26 Convergence, depth of field 561 Convulsions, benign familial neonatal, novel potassium channel gene linked to 931 Cooperativity, in long-term potentiation 1260 Cornea chromatic aberration 580–581 eye 508 Coronal plane 321 Coronary artery disease, as multigenic disease 55 Corpus callosum 9 16 323 324 332 364 367 369 855 connection of somatosensory cortical areas 452 damage after infarction of anterior cerebral artery 1308 and infarction of posterior cerebral artery 1308 interconnects cerebral hemispheres 322–323 Cortex in autonomic response control pathway 975 altered development as cause of epilepsy 931 cerebellar 322 developing forebrain 1036 pathway of visceral sensory information 974 representation of feeling 986–988 See also Cerebral cortex spread of seizure activity from seizure focus through normal circuitry of columns and fiber pathways 920 training expands existing representation of fingers in 1274 Cortical cells, patterns of activity during REM sleep 940 Cortical neuron collective behavior recorded in electroencephalogram 913–917 final position correlates with birthday 1049 functional organization into columns 469 generation and migration in cerebral cortex 1050–1051 receptive fields altered by experience 460–461 inhibitory surround 461 magnification 460–461 spatial arrangement of presynaptic inputs and stimulus features 467 supplements optokinetic response 813 vulnerable in Alzheimer disease 1153 Corticobasal ganglia-thalamocortical circuit, disorders of action associated with 866 Corticobulbar fibers, location 671 Corticobulbar pathway, cerebral control of motor neurons through 672 Corticobulbar tract, pathway for cerebral cortex action on brain stem motor neurons 671 Corticomotoneuronal cell, activity depends on motor task 772 Corticomotoneuronal cells and individual finger movements 769 primary motor cortex 765 Corticospinal axon activity correlates with direction and amplitude of muscle force 766 direct and indirect connections to spinal motor neurons 763–764 Corticospinal fibers, location 671 Corticospinal neurons, terminations of 778 Corticospinal pathway, cerebral control of motor neurons through 672 Corticospinal projections inhibitory effects on spinal motor neurons 764 motor cortex reflex circuits 765 Corticospinal synapse, features 763 Corticospinal tracts 346 axons in 347 bilateral lesions, effects 1313 degeneration of axon myelin in spinal muscular atrophy 700–701 monosynaptic connections with motor neurons 347 scarring in amyotrophic lateral sclerosis 700 synapses with interneurons 347 Corticosteroids, treatment, autoimmune myasthenia gravis 306 See also specific names Corticotropin-releasing hormone hypersecretion in unipolar depression 1220 hypothalamic 980 neuroactive peptide 289 neurons releasing 979 980 Cotranslational transfer, protein 94 Cotransmission 294 Cotzias, Georhe 862 Covergent excitation 463 CPG See Central pattern generator

Cranial muscles, affected in myasthenia gravis 299 299 Cranial nerve IX, innervation of taste buds 643 Cranial nerve nuclei 8 at various levels of brain stem 884 motor general somatic motor column 883 884–885 special visceral motor column 883–884 organization into longitudinal columns 880–885 881 of motor and sensory columns 881 relationship to sulcus limitans 881 sensory general somatic afferent column 880–882 specific somatic afferent column 882 visceral afferent column 882–883 Cranial nerve VII, innervation of taste buds 643 P.1341 Cranial nerves 873–888 964 assessment in neurological examination 876 carries sensory and motor output of brain stem 320 control of extraocular muscles of eye 787–788 development 883 emergence from brain stem 877 cerebellopontine angle 879 skull in groups 876–877 function 874–875 877–880 functional classes 882 injury 876–877 origins of at brain stem 876 passing through superior orbital fissure 878 reticular formation of brain stem coordinates reflexes and behaviors mediated by 885–887 role homologous to spinal nerves 876 use of to identify sites of brain stem lesions 886 886 CRE See cAMP response elements Cre/loxP system, restriction of region of gene knockout 1268 1269 Creatinine kinase, diagnosis of myopathic diseases 699 CREB See cAMP-response element binding protein CREB-1 activation and growth of new synaptic connections 1257 in long-term sensitization 1256 CREB-2 in long-term facilitation 1256 repressor, blocks long-term memory in Drosophila 1259 Cribriform plate, olfactory bulb 626 Crick, Francis 401 1318 Cross bridges 678 organizations unit of muscle fibers 676–683 See also Muscle filaments Cross-innervation, muscles 1107 1108 Cross-talk 248 during visual processing in cerebral cortex 505 Crossed-extension reflex 715 muscles involved 716 Crossing over, chromosomal 40 Crus commune 802 CT scanning See X-ray computerized tomography CTRH See Corticotropin-releasing hormone Culmen, cerebellum 833 Cuneate fascicle 342 dorsal column 447–448 pathway of sensory information 446 Cuneate fasciculus, spinal cord 338 Cuneate nucleus 342 448 pathway of sensory information 446 Cupula, semicircular canals 804 806 Curare blockade of nicotinic ACh-gated channel 114 blocks ACh receptors and inhibits action of ACh at neuromuscular junction 299 isolation of end-plate potential 190 Current (I) capacitive 153 characterization of in single ion channel 110 circuit analysis 1283–1284 direction of flow 157 electrical parameter 1280–1281 end-plate, calculation 196 end-plate See End-plate current extracellular, larger axons more easily excited by 146 flow across cell membrane 126 in chemical and electrical synapses 176 circuits with capacitance 1285–1286 contribution of chemical and electrical forces 133 controlled by ion channels in cell membrane 125 during EPSP, calculation 202 follows path of least resistance 144 in neurons 1280–1287 ion channels, as nonlinear function of driving force 111–112 neuron, modeling with electrical equivalent circuit 135 patch-clamp recording of in ion channels 111 through NMDA-type glutamate receptor-channel 214

generator in equivalent circuit model of cell membrane 138 voltage clamp as 152 graded inward calcium, activated by graded depolarizations at presynaptic terminal 255 leakage 153 oppositely directed, determination of separate time courses of in voltage-clamp experiments 153 passive flow in neuron 135 recording of through GABA- and glycine-gated channels 217 relationship with voltage 141 saturating 112 See also Equivalent electrical circuits; Ion flux single-channel comparison of glutamate-activated versus GABA- and glycine-activated 218 depends on electrochemical driving force 193 through ACh-activated channel, relationship to voltage is linear 109–110 through gramicidin ion channel varies with membrane potential in linear manner 109 through ion channel, depends on concentration of ions 112 Current-voltage relationship, K+ channel 133 Curtis, Howard 150 Cutaneous innervation, map of 734 Cutaneous nerve, afferent fiber groups in 444 Cutaneous receptors, in motor system 667 Cuticular plate, hair cell 615 6-Cyano-7-nitroquinoxaline-2,3-dione, blocks AMPA and kainate receptors 212 Cyclic adenosine monophosphate (cAMP) cascade activation results in phosphorylation of ACh receptor-channel 248 defects in learning mutants in Drosophila 1257 cycle 232–233 -dependent protein kinase closes potassium channels 243 mediation of serotonin effects on S-type K+ channel 243 regulation 235 substrates 235–236 target of action of cAMP 234 235 in long-term sensitization 1256 in long-term facilitation 1254–1255 pathway 234 mechanism 231–236 -PKA-CREB pathway in implicit memory storage for implicit memory 1257–1259 in long-term storage of implicit memory for sensitization and classical conditioning 1254–1259 -response element binding protein (CREB), synthesized during long-term facilitation 1254–1255 See also cAMP-response element binding protein system 231 second messenger in synaptic transmission 230 Cyclic guanosine 3′-5′-monophosphate (cGMP) cytoplasmic concentration reduced after activation of photoreceptor pigment molecules 512–514 cascade, role in LTD of synaptic transmission 240 phosphodiesterase, during phototransduction 512 production stimulated by NO 295 role in phototransduction 521 second messenger in photoreceptors 510–511 P.1342 Cyclic nucleotides, and axon growth cone motility 1074 Cystic fibrosis, caused by ion channel malfunction 105 Cysts, spinal cord 733 Cytoarchitectonic method, characterization of cerebral cortex 11 Cytoarchitectonic regions brain 328 cerebral cortex 327 See also Brodmann's areas Cytochrome oxidase, staining of blobs in primary visual cortex 549 Cytokeratins, in neurofilaments 73 Cytology, of neurons 67–87 Cytoplasm as poor conductor 149 extent of in neuron 71 neuron 69 Cytoskeletal elements, movement by slow axonal transport 103 Cytoskeletal proteins, manufactured on free ribosomes 103 Cytoskeleton abnormalities in brain areas affected by Alzheimer disease 1153 1154 muscle, proteins associated with 708 708 neuron 72–75 protein transport in the cell 75 role in protein synthesis 91 vesicles bound to by synapsin 271 277 Cytosol location of protein synthesis 89 90 some proteins synthesized in actively imported by nucleus, mitochondria, and peroxisomes 93–94 Cytosolic enzymes, movement by faster component of slow axonal transport 103 Cytosolic proteins manufactured on free ribosomes 103 movement by faster component of slow axonal transport 103 slow axonal transport 103 Cytotoxic edema, brain 1299

D D4 dopamine receptor, gene encoding, role in novelty-seeking human behavior 51 da Vinci, Leonardo 558 Dacey, Dennis 579 DAG See Diacylglycerol

Dale, Henry 176 184 299 966 Damasio, Antonio 985 995 1213 Damasio, Hannah 994 Dandy-Walker syndrome 1300 Dark current, photoreceptor 513 513 Darkness, photoreceptor membrane potential during 513 513 Darwin, Charles 6 989 1171 Davies, Kay 705 Davis, Michael 985 Day vision, role of cones 509–510 See also Cones De Valois, Russel 579 Deafferented preparations, study of stepping 738–739 Deafness 593 aphasia in 13 See also Hearing loss and speech development, 610 deBono, Mario 42 Decerebrate animals 654 stepping 754 Decerebrate cat 816–817 immobilized, complex motor pattern 746 walking, motor patterns 746 Decerebrate posturing, in structural coma 903 Decerebrate preparation 717 study of stepping 738–739 Decerebrate rigidity 817 Declarative memory See Memory, explicit Declive, cerebellum 833 Decorticate posturing, in structural coma 903 Decussation 324 See also Commissures; Corpus callosum; Optic chiasm Defensive conditioning 1240 Deiters' cells See Phalangeal cells Deja vu, ictal phenomenon 15 Dejerine, Jules 1183 Dejerine-Roussy syndrome 481 Dejerine-Sottas disease 709 del Castillo, Jose 255 Del Castillo, Ricardo 257 260 262 Delay, John 1197 Delayed attention task 356 Delayed rectifier channel 158 Delayed response task 356 oculomotor, recordings from one neuron during 362 Delayed sleep phase syndrome 954 Delirium 901 Delivery hypothesis, brain development 1140 Delta protein, role in determining neuronal cell fate 1043 1046 Delta receptors, opiates 484 Delta sleep-inducing peptide 943 Delta waves EEG activity during sleep 938 high-amplitude activity during parasomnias 956 Delusions, in schizophrenia 1193 Dement 945 Dement, William 936 Dementia 901 1149 AIDS-related, role of microglia 20 Alzheimer type 1149–1161 caused by cerebrovascular disease 1314 causes of in elderly 1152 See also Alzheimer disease; Huntington disease senile, affecting elderly 1151–1153 Dementia praecox 1192 Demyelinating diseases, genetic basis 82–83 Demyelination in Charcot-Marie-Tooth disease 182 in experimental allergic encephalomyelitis 82 in Guillain-Barré disease 148 in multiple sclerosis 148 slows conduction velocity 703–704 Dendrites apical 22 basal 22 cytoskeletal structure 72 neuronal 21 67 70 polyribosomes in 90 postsynaptic 22 signaling role 159–160 spines on in pyramidal cells in CA1 region of hippocampus 80 structure in spinal motor neuron 76 synaptic potential in can generate action potential at axon hillock 223 223 Dendritic spines central neurons, synapses on often excitatory 224–225 postsynaptic neurons, transmitters act through second messenger to stimulate local protein synthesis in 250 Dendritic trees, more extensive in cerebral cortex pyramidal neurons than in spinal motor neurons 85 Dendrodendritic synapses 223–224 Denervation supersensitivity 1096 Deniker, Pierre 1197 Dennett, Daniel 397 1318 Dentate gyrus 1232 gatekeeper of excitability in hippocampus 931–933 932 hippocampus 78 Dentate nucleus 332 842

activity during evaluation of sensory information 848 mental activity and movement 845 cerebellum 833 833 effect of inactivation of 844 inactivation of and disruption of agonist/antagonist activation following perturbation 843 Dentatorubral-pallidoluysian atrophy, trinucleotide repeats in 55 56 2-Deoxy glucose detection of horizontal connections in primary visual cortex 540 542 detection of orientation columns in living cortex 537 P.1343 Dependence, drug 1011 Dephosphorylation post-translational protein modification 93 and refractory state of voltage-gated ion channels 115 Depolarization 28 126 127 127 127 calculation of magnitude 141 rate of spread 147 in cochlear hair cells 601 different conformations of Na+ channels 154–155 differing rates of Na+ and K+ channel opening in response to 154 during action potential 156–157 effects of near resting potential 242 end-plate 190 201 end-plate potential 203 enhances steady-state Ca

+

influx 274

inactivation of Na+ channels after end of 156 and increase in membrane permeability for Na+ 132 K+ efflux throughout 132 long-term, different responses of K+ and Na+ channels 156 in mechanoreceptors 415 membrane potential 131 more efficient in larger-diameter ax on 146 neuron as simple resistor during 141 in olfactory sensory neurons 629 opening of CI- channels 219 voltage-gated Na+ channels 132 presynaptic terminal, regulates neurotransmitter release 253–255 and transmitter release 253 and release of neurotrophic factors in central nervous system 1124 in sensory neuron, caused by serotonin 244 Depolarizing currents, transmitted by electrical synapses 178 Depolarizing receptor potential, compared to excitatory postsynaptic potential 416 Depression 1209–1226 abnormality in function of subgenual region of frontal cortex 1212–1213 bipolar, symptoms 1211 See also Bipolar mood disorder and corticobasal ganglia-thalamocortical circuits, 866 drugs effective in treatment act on serotonergic and noradrenergic pathways 1216 eye movement 785 genetically determined defects in chemical synaptic transmission 1224 major, polygenic nature 1212 and panic attacks 1222 role of serotonin and possibly norepinephrine 283 sleep distrubances in 948 treatment 1213–1220 unipolar clinical features 1210 disturbance of circadian cycle in 1220 disturbances of neuroendocrine function 1220 exclusion criteria 1210 functional abnormality in prefrontal cortex ventral to genu of corpus callosum 1212 types 1210 Depth agnosia 499 of field, role of visual cortex in focusing eyes at 561 perception 548–571 far-field, monocular cues 558 559 near-field, stereoscopic cues 560 processing in cerebral cortex 497–500 vision, monocular cues and binocular disparity 558–562 Dermatomal maps 445 Dermatomes 447 distribution 445 pain 445 spinal, correspond to cortical map of body 458 tactile 445 Dermatomyositis, acquired myopathic disease 701 704–705 Descartes, René 6 1317 Descending inhibitory neurons, and analgesia 482 Descending lateral corticospinal pathway 346 Descending pathways inhibitory, nociceptive projection neurons 486 initiation and adaptive control of walking 750–753 750 to spinal cord, interruption produces spasticity 730 Desensitization ligand-gated channels entering refractory state 114 transmitter receptors 248 Designer genes 43

Desimone, Robert 566 Detwiler, Samuel 1054 Deuteranomaly 584 Deuteranopia 584 Development brain delivery hypothesis 1140 protection hypothesis 1139 death of neurons as normal occurrence during 1054 early, effects of exposure to testosterone during 1136–1137 functional properties of ion channels can change over course of 120 120 nervous system 1017–1162 spatial and temporal pattern of gene expression 1017 neuromuscular junction 1088 1089 neuronal, study of apoptosis during in C. elegans 1058–1061 secondary axis, amphibians 1023 sexual differentiation of reproductive system 1131–1134 of nervous system 1131–1134 Developmental injury, causative agent for schizophrenia 1196 Developmental signals, evolutionary conservation 1036 Dexamethasone suppression test, diagnosis of depression 1220 Diabetes chronic neuropathy 702 as multigenic disease 55 56 diabetic gene, located on same chromosome region as leptin receptor 47 Diacetyl receptor, in C. elegans 636 Diacylglycerol hydrolyzed phospholipid 236 second messenger in synaptic transmission 230 Diameter axon, largest have lowest threshold for extracellular current 146 nerve process, effect on axial and membrane resistance 145 3, 4-Diaminopyridine, treatment, congenital myasthenia gravis and slow-channel syndrome 307 Diazepam effect on GAB A receptor 1223 See also Benzodiazepines treatment, prolonged repetitive seizures 919 Dichromatic system, color vision 573 Dichromats 584 Diencephalon 9 320 development 1021 1022 function 7 8 8 MRI scan coronal section 369 horizontal section 368 See also Hypothalamus; Thalamus structure and function 322 Diener, Hans 821 Difference limen 421 Differentiation, neural cells, inductive signals for 1022–1027 Digital pulse code, change in membrane potential produced by sensory stimulus transformed into 421 P.1344 Digits See Fingers Dihydropyridines, block L-type Ca2+ channel 257 Dihydrotestosterone 1134 Dimerization, tyrosine kinases 239 Diploid 37 Diplopia 787 797 Direction sensitivity, convergence of relay neurons 467 Direction-sensitive neurons area 2, primary somatic sensory cortex 466 in somatic sensory cortex 464 465 Discriminative touch 430 Discs, in out segment of photoreceptors 510 Disease 1188 central nervous system, use of stretch reflex in diagnosis 730 multigenic 55–56 of motor unit 695–712 See also Myopathic diseases; Neurogenic diseases; specific names nervous system See specific names Dishabituation, nonassociative learning 1240 Disorganized schizophrenia 1193 Dissociation constant 112 Distal stump, periperhal nerve 1109 Distributed processing theory of brain function 11 visual system 496 505 distrophin gene, deletion in and severity of muscular dystrophy 707 Divergence, depth of field 561 DLX-1 and -2, homeodomain proteins in forebrain development 1035 DNA, encodes information for protein synthesis 88 DNA See Genes Dodge, Raymond 783 Dogs, narcolepsy in 951 Dolphin, non-REM sleep patterns 944 Domoic acid, shellfish contaminated by, neurological damage if ingested 930 Doniach, Tabitha 42 Dopamine in basal ganglia-thalamocortical circuit 860–861 biosynthesis and structure 282 biosynthetic enzymes 281 D2 receptors, density of greater in narcolepsy 951 deficiency in Parkinson disease 862 deletion of gene encoding enzyme important for, disrupts locomotor behavior and motivation 50–51 drug-replacement therapy for Parkinson disease 865

level in basal ganglia decreased in Parkinson disease 864 released in brain increased by drugs of abuse 1010–1012 neurons releasing 979 980 and phosphorylation in the neuron 249 receptor antischizophrenic drug that blocks 1205 blocked by antipsychotic agents 1198 1199 D4, gene encoding, role in novelty-seeking human behavior 51 striatal output pathways 857 types 1199 1200 small-molecule neurotransmitter 282 synthesis and degradation 1201 transporter, site of action for cocaine and amphetamines 1011 Dopaminergic cell groups, in midbrain and forebrain 892–893 Dopaminergic fibers, sustantia nigra to striatum, effect of sectioning of feeding behavior 1003–1004 Dopaminergic innervation, prefrontal association area 361 Dopaminergic neurons in brain stem and hypothalamus 892 limbic, and novel stimuli that elicit reward 1010 in midbrain 896 in substantia nigra and corpus striatum 50 systems of 1201–1203 1203 Dopaminergic pathways, mesolimbic, recruitment by drugs of abuse 1009–1012 Dopaminergic synapses modulation of direct and indirect pathways from striatum 857 sites of action for psychoactive substances 1201 Dopaminergic synaptic transmission, abnormalities in and schizophrenic symptoms 1200–1204 Dopaminergic systems, treatment of schizophrenia with antipsychotic drugs acting on 1197–1200 Dopaminergic tracts 1203 location 283 Dormant inhibition hypothesis, temporal lobe epilepsy 931 Dorsal 321 Dorsal acoustic stria, auditory pathway 604 Dorsal anterior insular cortex, pathway of sensory information 446 Dorsal cerebellar vermis, lesions 795 Dorsal column medial lemniscal system, pathway of sensory information 446 Dorsal column nuclei pattern of excitation and inhibition in neuron of in increases spatial resolution 463 thalamus 343 Dorsal column-medial lemniscal system, pathway for perception of touch and proprioception 447–448 Dorsal columns fascicles 447–448 stimulation, relief of pain 482 transection, behavioral defects produced by 468 white matter of spinal cord 338 Dorsal commissural interneurons, development 1028 Dorsal extrastriate cortex 775 Dorsal horn, spinal cord 319 338 Dorsal lateral prefrontal cortex, motor cortex 794 Dorsal longitudinal fasciculus 987 Dorsal motor nucleus of vagus 881 Dorsal motor vagal nucleus location and function 885 noradrenergic neurons in 890 pathway of sensory information 974 Dorsal root, spinal cord 320 Dorsal root ganglion 340 cell inhibitory descending pathway, pain 486 pathway of sensory information 446 clustering of primary sensory neurons of trunk and limbs in 340 forms monosynaptic circuit with spinal motor neuron, knee-jerk stretch reflex 73 in knee jerk 26 mapping of innervation 445 neurons central axons arranged to produceN map of body surface 340–341 functions 431 innervate viscera 444 primary afferent fiber 431 sensory neurons for modalities of somatic sensory system 430–431 431–432 sensory specialization preserved in ascending pathway and central nervous system 447 topographic arrangement of skin receptors preserved in central processes of 447 rate and amount of slow axonal transport 102 Dorsolateral frontal area, damaged in transcortical motor aphasia 1180 Dorsolateral funiculus, inhibitory descending pathway, pain 486 Dorsolateral motor nucleus 668 Dorsolateral prefrontal association cortex, densely interconnected region of association cortex 362 Dorsolateral prefrontal circuit, basal ganglia, role in executive functions 866 P.1345 Dorsomedial hypothalamic nucleus 976 Dorsomedial nucleus, hypothalamus 977 Dosal motor vagal nucleus, in autonomic response control pathway 975 Dostrovsky, John 1264 Double bouquet cells 331 Double depletion hypothesis, and thirst 1006 Double-opponent cells, in striate cortex 583 Doublecortin gene, link to epilepsy 931 Drachman, Daniel 298 300 Drawings agnosia 500 Dreaming 936–947

functions of 944–945 Dreams color versus black and white 946 influence of external stimuli on content 945–946 influence of stimulation of homeostatic system on 946 organization of 946 recall after awakening from REM and non-REM sleep 945 and REM sleep 946 See also Sleep sexual content in 946 violent enactment during sleep 956 DRG cells See Dorsal root ganglion cells Drinking elicited by angiotensin II 1006 regulated by tissue osmolality and vascular volume 1006–1007 signals terminating 1007 Drive states 998–999 Drive states, purposes 999 Drosophila melanogaster circadian rhythm in 42 generation of mutations in 48–19 genes causing learning deficits in 1257 introduction of transgenes into 43 model for Huntington disease 865 neurogenesis in 1041–1047 short-term and long-term memory formation in 1258–1259 single genes affect behaviors in 42 44–56 Drug addiction, features characterizing 1011–1012 addictive See Drugs of abuse; specific drug names binding to cell-surface receptors of nerve cells 6 blocking molecules in ion channels 112 brain uptake of and lipid solubility 1291 ion channels as site of activity 105 115 Drugs of abuse dependence on in absence of dopaminergic mechanisms 1011 increase level of dopamine released in brain 1010–1012 nucleus accumbens as target of action 1011 recruitment of mesolimbic dopaminergic pathways 1009–1012 See also Self-stimulation; specific drug names withdrawal symptoms, 1011–1012 Dualism, early ideas about consciousness 1317 DuBois-Reymond, Emil 6 Duchenne muscular dystrophy 710 deletion of membrane protein distrophin in 707 inherited myopathy 701 704 705 molecular genetics of 705–706 muscle fiber distribution in 698 X-linked 705 Ductus reuniens 802 dunce, Drosophila learning mutant 1257 Dyes, tracing neural projection 98 Dying back 732 Dynamic equilibrium 817 Dynamic polarization, principle of neural organization 23 Dynamin GTPase involved in vesicle endocytosis 273 mediates endocytosis of synaptic vesicles 99 Dynorphin amino acid sequence 487 co-release with glutamate 294 interaction with opioid receptors 485–486 precursor structure 291 striatum 856 in sympathetic neurons 972 Dysarthria 700 Dysdiadochokinesia, in cerebellar disease 849 849 Dyskinesias 861 Dyslexia, developmental 1184–1185 Dysmetria 844 cerebellar abnormality 849 Dysphagia 700 Dysphoric 1210 Dysthymia 1211 Dystonia 862 Dystroglycans, muscle 708 Dystrophin 710 glycoproteins associated with 708 location on muscle plasma membrane 708 low levels in Becker muscular dystrophy 707 role in normal muscle 707–708

E E See Equilibrium potential; Potential difference E1-E5 cell groups See Histaminergic cell groups Ear functional parts 591–592 human, structure 591 inner, location of vestibular system 801 See also Cochlea; specific parts sensory transduction in, 614–624 Eardrum See Tympanum Ebbinghaus, Hermann 382 Eccles, John 176 207 212 215 1108 Echolocation, bats 609–610 Ecological constraints, effect on motivational states 1007

Ecstasy See 3, 4-Methylene-dioxymethanphetamine ECT See Electroconvulsive therapy Ectoderm 1021 development of nervous system from 1021–1022 formation of neural tube 1020 Edelman, Gerald 1318 Edema, brain, types 1299 Edges illusions of, and higher-level information processing in V2 cells 564 orientation of, detection by cortical neurons 464–465 Edinger-Westphal nucleus 881 location and function 884–885 preganglionic parasympathetic nucleus in brain stem 963 projections from pretectal area 528 role in pupillary constriction to light 904 Edrophonium, reverses symptoms of myasthenia gravis 300 EEG See Electroencephalogram Effector 229 EGF See Epidermal growth factor Egg-laying hormone neuropetide in Aplysia 288 289 precursor structure 291 Egocentric coordinate system 817 Ehrlich, Paul 6 184 Eicosanoids 236 Eighth cranial nerve cochlear component 603 fibers, excitatory synapses of with hair cells 622–623 Eisenmann, George 108 EK See Equilibrium potential, potassium Elbow, propagation of mechanical effects of muscle contraction 692 Elderly decline in memory and cognitive abilities 1151 insomnia in 955 pattern of sleep 944 REM behavior disorder in 956 senile dementias affecting 1151–1153 P.1346 Electrical activity brain, during sleep 937–939 938 cerebral cortex, desynchronized and synchronized 897 transformation of physical stimulus into 30 Electrical circuit equivalent See Electrical equivalent Electrical driving force drive ions across cell membrane 128 ions 128 Electrical equivalent circuit model calculation of end-plate current from 202–205 resting membrane potential 136–137 136 end-plate 203 equivalent circuit 134 inclusion of CI- pathway to calculate resting membrane potential 137 137 nerve cell undergoing voltage-clamp technique 155 neuron 134–138 represent functional properties of neuron 134–138 representation of functional properties of neuron as 134–138 neuronal process as 144 Electrical forces, contribution to current flow 133 Electrical parameters 1280–1282 Electrical properties, passive, of neuron 140–149 Electrical resistance, relationship to surface area of cell 687 Electrical resonance, hair cells 621 Electrical signal carry information 125 receptors transduce specific types of energy into 416 See also Action potential; Receptor potential; Synaptic potential transient, generation of in neurons 125–139 Electrical stimulation, analgesia 482 Electrical transmission, rapid and synchronous firing of interconnected cells 180 Electric potential, nerve cell membrane, factors in 27 Electrochemical driving force 131 135 determination of 111–112 and flux of ion across cell membrane 131 Electroconvulsive therapy (ECT) effect on recent memories 1244–1245 1244 treatment, depressions 1213 Electrodes, for electroencephalogram 916 Electroencephalogram (EEG) assesses electrical activity of cerebral cortex 897 as collective behavior of cortical neurons 913–917 of firing of thalamic neurons 897–899 nature of 914–915 914 915 normal in awake human subject 912 patient with epilepsy 916 patterns characterized by frequency and amplitude of electrical activity 916 during sleep 937–939 938 surface, polarity of and location of synaptic activity in cortex 915 Electroencephalography, development of 911 Electrogenic 131 Electrolyte composition, hypothalamic control 974 Electromagnetic receptors 416 Electromotive force 134

Electromyogram 676 Electromyography 695 diagnosis of muscle diseases 699 Electron diffraction studies, three-dimensional structure of gap-junction channel 179 Electron-translucent synaptic vesicles, in afferent terminals of nociceptive neurons 477 Electrotonic conduction 145 145 Electrotonic potentials 126 Electrotonic transmission 178 Elevation, eye movement 785 ELH See Egg-laying hormone Emboliform nucleus, cerebellum 833 833 Embryonic stem cells, use of to create transgenic mice 48–49 Emergency responses, hypothalamic control 975 EMG See Electromyogram Emotion 871–1013 anatomical localization 14–15 autonomic expression and cognitive experience mediated by amygdala 992–993 as bodily state 980 cognitive aspects, reciprocal connections of amygdala with neocortex allow incorporation of learning and experience into 993–994 communicative function 983 conscious perception, role of central nucleus of amygdala 992 and fight-or-flight response 984 hippocampus has indirect role 994–995 implicit memory storage 986 influenced by modulatory systems in brain 333–334 memory for, storage locations 991 neural circuit for 988 neural systems controlling 981 peripheral components 983 preparatory function 983 role of amygdala 15 323 331 872 anterior nuclei of thalamus 342 cerebral hemispheres 322 cingulate cortex 992–994 frontal lobe 992–994 parahippocampal cortex 992–994 theories of 983–986 unconscious evaluation of situation 985 Emotional events, storage of, effect of propranolol 992–993 Emotional experience 995 principal role of amygdala 988–993 Emotional expression, limbic association area 352 Emotional information, pathways for processing 990 Emotional prosody, role of right cerebral hemisphere 1182 Emotional response cognitive control through ventromedial frontal cortex 993–994 learned, processed by amygdala 990–992 and learning 995 role of amygdala, brain mapping by blood flow 989 Emotional states 980–997 components 980 conscious and unconscious 872 contribution to conscious feeling 995 peripheral expression coordinated by hypothalamus 986 memory of 995 role of second messengers 251 Empathy, role of lateral orbitofrontal circuit of basal ganglia 866 en passant synapses 85 Encephalopathy 901 metabolic presenting as coma, common causes 901 Encoding, processing of explicit knowledge 1237 1238 End-plate channels, permeability to Na+ and K+ 192 End-plate current calculation 196 from an equivalent circuit 202–205 compared with end-plate potential 192 factors determining 194–196 time course from summed contributions of ACh-gated channel 197 total, effect of membrane potential on 198 End-plate potential 190 201 analysis in terms of flow of ionic current 202–203 compared with end-plate current 192 determination of time course 204 P.1347 effect of membrane potential on 198 movement of Na+ and K+ in 193 pharmacological isolation 190 reversal potential of 194 prolonged in congenital myasthenia gravis 306 slow-channel syndrome 307 reduced amplitude in myasthenia gravis 302 End-plate 187 188 676 conductance 202 equivalent circuit 203 ion channels permeable to Na+ and K+ 191–192 Endocrine function, role of hypothalamus 8 Endocrine myopathies, acquired myopathic disease 701 Endocrine regulation, role of dopaminergic neurons 896 Endocrine system, control of by hypothalamus 978–979

Endocytic pathway, vesicular traffic from plasmalemma 103 Endocytic vesicles, neuron 69 Endocytosis bulk 98 clathrin-mediated 98 functions of 97–99 receptor-mediated 98 role of synaptotagmin 273 study of with capacitance measurements 266 types in endothelial cells 1289 Endoderm 1021 formation of neural tube 1020 Endogenous bursters, in central pattern generator 744 Endogenous depression See Melancholic depression Endolymph, 802–803 semicircular canals 805 Endolymphatic hydrops, and Meniere disease 807–808 Endolymphatic sac 802 Endolymphophatic spaces, vestibular labyrinth, edema of and Meniere disease 807–808 Endoplasmic reticulum attachment of polysomes to 90–91 element, retrograde transport to cell body 102 resident proteins 94 role in protein synthesis 91 rough 90–91 smooth, anterograde transport to axon 101 synthesis and modification of secretory and vacuolar apparatus proteins 94–96 Endosomes in endocytosis 98 neuron 68 69 retrograde transport to cell body 102 vesicles that deliver lysosomal enzymes to 97 Endothelial cells brain-derived signals induce expression of blood-brain barrier properties 1293–1294 brain microvessels specialized properties of and blood-brain barrier 1288–1289 tight junctions 1290 ultrastructural features 1289 Energy metabolism, hypothalamic control 975 Engel, Andrew 306 engrailed 1 and 2, expression in developing midbrain 1035 Enkephalins interaction with opioid receptors 485–486 precursor structure 291 Enterhinal cortex, olfactory information processing 633 Enteric division, autonomic nervous system 961 Enteric nervous system autonomous nature 964–965 effect of disruption of connections to central nervous system 965 Enteric neuron, develops from neural crest cells 1047 Enteric system, autonomic division of peripheral nervous system 335 Entorhinal area, abnormalities in Alzheimer disease 1153 Entorhinal cortex 332 1232 processing memory for explicit memory storage 1232 Environment interaction with genes 36 prediction of events in, and learning 1240–1242 shapes consequence of mutation 39 shared and nonshared components 41–42 spatial, hippocampus contains cognitive map of 1264 Enzymatic pathways calcium-dependent, activation during synaptic transmission 274 for degradation of neurotransmitter in synaptic cleft 294 Eph kinases binding of ephrins to is inhibitory signal to developing axons 1079 required for formation of retinotopic map in optic tectum 1083–1084 segmental expression in hindbrain patterning 1033 Ephaptic transmission 703 Ephrins binding to eph kinases is inhibitory signal to developing axons 1079 gradients of as guidance molecules for axonal growth cones 1082 provide inhibitory signal to axon growth cones 1081 required for formation of retinotopic map in optic tectum 1083–1084 role in axon growth cone guidance 1081 segmental expression in hindbrain patterning 1033 Epicritic sensations 431 431–32 Epidermal growth factor, binding by receptor tyrosine kinases 238 Epilepsies, classification 911–913 911 Epilepsy 910–935 913 altered cortical development as cause 931 chronic temporal lobe, ictal and interictal phenomena in 15 destructive lesions of 15 development after discrete cortical injury 931 electroencephalogram in patient with 916 factors leading to are unsolved mystery 930–933 first surgical treatment for 911 generalized GABA-ergic inhibition in 923 production by penicillin in cats 923 See also Convulsions, Benign familial neonatal hippocampal size in patients with 927 irritative lesions of 15 Jacksonian march 388 nocturnal frontal lobe, mutation of nicotinic acetylcholine receptor subunit in 931 See also Temporal lobe

surgical treatment 925–927 precursor structure 291 syndrome 913 genetic, inheritance patterns 931 temporal lobe dormant inhibition hypothesis 931 EEG rhythms at beginning of seizure 929 GABA-ergic inhibition reduced in animal models 931 hippocampal atrophy in 929 PET scan of patient with 929 surgical treatment 928–929 Epinephrine biosynthesis and structure 283 biosynthetic enzymes 281 small-molecule neurotransmitter 283 Episodic ataxia, caused by point mutation in delayed-rectifier, voltage-gated K+ channel 169 Episodic knowledge See Knowledge, episodic Epithelial cells, similarity of neurons to 69 EPSP See Excitatory postsynaptic potential Epstein, Alan 1006 P.1348 Equilibrium potential (E) calculation 128 potassium 128 ion channels, determines resting membrane potential 130 Na+ and K+, and reversal potential of membrane current 194 Equivalent circuit model See electrical equivalent circuit Erb, Wilhelm 703 erbB kinases, regulated by neuroregulin to stimulate acetylcholine receptor synthesis 1094 Error signal 656 1000 Escape responses 180 Escher, Maurits 493 493 Esterase, degradation of neurotransmitter in synaptic cleft 294 Estradiol masculinizing hormone for sexually dimorphic brain characteristics 1138–1140 prevents apoptotic cell death in sexually dimorphic nucleus of the preoptic area 1140 stimulates neurite growth 1139–1140 1139 Estrogen and brain development 1139 1140 1141–1143 exposure of developing brain to 1146 sequestered by alpha-fetoprotein in postnatal rat 1138 Estrous cycle, effect on density of synapses on dendritic spines in striatum radiatum 1142 État lacunaire, after occlusion of penetrating arteries 1309 Ethology 6 Ethosuximide, blocks absence seizures 924 Eustachian tube 591 591 Evarts, Ed 383 Evarts, Edward 764 792 Evoked otoacoustical emission, cochlea 600 Evoked potentials cortical, use in mapping neural representations of body surface 385–387 map of cortical responses to tactile stimulation 386 neural representation of specific areas of body in somatosensory cortex 385 Evolutionary conservation of molecular mechanisms of memory 1247 in voltage-gated ion channels 166 Excitability, properties of vary between regions of neuron 159–160 Excitation competitive effect with inhibition in nerve cell 226 inhibitory networks restrict spread to sharpen spatial resolution 461–163 Excitatory postsynapatic potential (EPSP) in central nervous system 226 characteristics of due to opening and closing of channels 240 compared to depolarizing receptor potential 416 current flowing during, calculation 202 determination of value 191 and end-plate current 191 effect of inhibitory synpatic input on 217 fast, principal synaptic pathways for ganglionic transmission in sympathetic and parasympathetic systems 970 fast versus slow 242 in motor neuron 209 mediated by glutamate-gated channels conducting Na+ and K+ 212–214 NMDA-type glutamate receptor-channel contribution to 215 pattern of electrical current flow 914 914 polarity in surface electroencephalogram 915 reversal potential for 210–211 slow, in postganglionic neurons 970 Excitatory synaptic current, in large-diameter and small-diameter motor neurons 686 Excitotoxicity 928 activation of AMPA receptors 930 role of apoptosis in 928 specific to certain neurons 930 underlies seizure-related brain damage 927–930 Executive functions, role of dorsolateral prefrontal circuit of basal ganglia 866 Exoendocytosis, synaptic vesicle membranes 97 Exocentric coordinate system 817 Exocrine glands, controlled by autonomic nervous system 960 Exocytosis 31 182D and formation of fusion pore 264 method by which synaptic vesicles discharge neurotransmitter 262–264 neuron 69

preparation of membrane vesicles for 270 study of with capacitance measurements 266 Exons 37 Experience choice of motor program 693 in feed-forward control 657 modifies control of saccades 795 internal representation of personal space 388–391 and unique modification of the brain 1274–1275 Experiential response 1229 Experimental allergic encephalomyelitis, demyelination in 82 Explicit memory 1231 1231 Export signals, on proteins 93 Extensor motor neuron, excitatory potentials in 208 External auditory meatus 591 External granule cell layer, neurons in cerebral cortex 326 327 External pyramidal cell layer, neurons in cerebral cortex 326 327 Externoceptors, adjust stepping 747 Exteroreceptors, skin, effect on central pattern generator for walking 749 Extinction after middle cerebral artery infarction 1307 classical conditioning 1241 Extorsion, eye movement 785 Extracellular recordings, study of central nervous system neurons 454 Extracellular space, neuron 68 Extraocular motor neurons, eye position and velocity 788 Extraocular muscles, eye complementary pairs 786–787 control by cranial nerves 787–788 insertions and origins 786 lesions 787 movements 787 Extrapersonal space 384 imagined and remembered, represented in posterior parietal association cortex 392–395 posterior parietal cortex 351 remembered, stored with body-centered frame of reference 394 Extrapyramidal tract syndrome 854 Extrastriate cortex activity during visual perception 500 cells responsive to binocular disparity 561 parvocellular and magnocellular pathways feed into two processing pathways into 549–552 Extrastriate regions multiple retinal representations in 497 visual system 496 Extrastriate visual areas, pathways 500–501 Extrastriate visual cortex, human, damage to produces deficits to motion perception 556 Eye autonomic nervous system control of pupils and lens focusing 966–967 closure branching pattern of geniculocortical fibers after 1121 effect on formation of ocular dominance columns 1118 1120 P.1349 timing of and effect on development of ocular dominance columns 1121 effect of lesions of putamen 1315 movement characteristic deficits in with brain stem lesions 792 combined with head movements in gaze 796–797 during REM sleep 938–939 evaluation of in structural coma 904–905 and level of brain dysfunction in comatose patient 907 loss of normal, and brain stem injury locations 905 midbrain connected to major pathway for control of 322 nystagmus 809 pathways for in arousal system 904 regulation by vestibulocerebellum 841 role of extraocular motor neurons 788 saccadic, control by superior colliculus 526–527 See also Saccade smooth pursuit, pathways for 796 smooth-pursuit deficits in produced by lesions in medial superior temporal area in monkey 556 deficits in produced by lesions in right occipital-parietal area in humans 556 use as monitor of working memory 357 359 muscles that control movement 785–788 two components of neural signals to 798 origins and insertions of extraocular muscles 786 position, motor neurons signaling 790 projections to visual cortex 1116 pupillary reflexes controlled by pretectum of midbrain 527–528 saccadic movements, controlled by oculomotor circuit 861 See also Cornea; Fovea; Gaze; Lens; Retina stabilized by vestibular reflexes 808–810 structure 508 synchronous activity in both organizes ocular dominance columns 1119–1122 velocity, motor neurons signaling 790 visual deprivation of one (eye closure) and effects on development of ocular dominance columns 1118 Eye-hand coordination adjustment during adaptation to prism glasses 847 area 7 of posterior parietal cortex 465 Eyeblink reflex rabbit, classical conditioning 1243 role of cerebellum in associative learning 849

F F-actin, in muscle fibers 677 708 Face identification, separate neural systems for 989 motor control and sensation mediated by brain stem 320 Face recognition 499 inferior temporal cortex 564–565 response of neuron in inferior temporal cortex 566 See also Capgras syndrome; Prosopagnosia Facial and intermediate cranial nerves (VII), origin at brain stem 876 877 Facial cranial nerve (VIII) function and dysfunction 874–875 878 and Bell's palsy 878 sensory and autonomic components 878 Facial expression, emotional, role of reticular formation of brain stem 887 Facial motor nucleus 881 location and function 884 Facial nerve 802 and homeostasis 965 in developing hindbrain 1031 innervation of taste buds 643 rate, transection and change in functional organization of primary motor cortex 762 Facial nuclei 671 Facilitating neuromuscular block 307 Facilitation activity-dependent components of 1252–1253 presynaptic, in long-term potentiation 1262 long-term, proteins synthesized during 1254–1255 long-term potentiation 1259 postspike, of muscle activity 767 Facioscapulohumeral dystrophy, inherited myopathic disease 701 Facioscapulohumeral muscular dystrophy, inherited myopathy 704 705 Falck, Bengt 292 332 False transmitters 286 Fambrough, Douglas 300 Familiar size, depth perception 558 Fanslow, Michael 985 Far cells, striate and extrastriate cortex 561 Farah, Martha 1318 Fascicles 676 Fasciculation 696 guidance cue for axon growth cone guidance 1071 in motor neuron diseases 701 Fast axonal transport 100 Fast fatigable muscle fibers 685 Fast fatigue-resistant muscle fibers 685 Fast-twitch muscle fibers 684 Fastigial nuclei, lesions 795 Fastigial nucleus cerebellum 833 833 lesions of 850 Fatigue, muscle, caused by repeated activation 683 Fatt, Paul 190 257 Fatty acid arachidonic acid, as neurotransmitter 295 Fear conditioning, classical 990 Fear amygdala 988 and hippocampus 985 memory for 990–991 response to by amygdala 990 tests for, connections between central nucleus of amygdala and hypothalamic and brain stem areas 993 Fear-potentiated startle 990 Feature abstraction, by progressive convergence in primary visual cortex 535–537 Feature maps 567 visual information 504 504 Feature-detecting neurons area 2, primary somatic sensory cortex 466 direction and orientation, in somatic sensory cortex 465 somatic sensory cortex 469 Feature-detecting properties, complex, neurons in higher cortical areas 463–468 Fechner, Gustave 411 412 421 1317 Feed-forward connections, neocortex 327 Feed-forward control in catching a ball 657 postural 819 820 in voluntary movements 656–657 656 Feed-forward inhibition activation of inhibitory interneurons 427 in knee jerk 26 Feed-forward mechanisms, spinocerebellum, regulate movement 844 Feed-forward response, anticipatory, spinocerebellum 844 Feedback circuit cortical motor program regulation, cerebrocerebellum role in 845–846 movement, in cerebellum and basal ganglia 663–665 P.1350 control postural 819 820 in voluntary movements 656–657 656 correction, corrective, spinocerebellum 844 inhibition 27

activation of inhibitory interneurons 427 loop See also Servomechanism signals, water regulation, 1006 visceral, and learning of emotional responses 995 Feeding behavior regulation 1002–1006 stimulated by neuropeptide Y 1006 Feeding center, lateral hypothalamus 1002 Feeling 980–997 as conscious sensation 980 conscious reflection of unconscious appraisal of situation 985 cortical representation 986–988 explicit memory storage 986 mediated of conscious experience 980 Feldberg, Wilhelm 299 Feminizing testis See Androgen insensitivity Fetz, Eberhard 765 767 Fever, and antipyretic area of brain 1001–1002 FGF See Fibroblast growth factor FGF8, differentiation of mesencephalon 1034 Fiber bundles, in central nervous system 323 Fibrillary structures, neuron 71 Fibrillations 696 in motor neuron diseases 701 Fibroblast growth factor binding by receptor tyrosine kinases 238 family, induction of posterior neural tissue 1030 Field potentials extracellular recording of synchronized acitivity of cells 913 spikes 913 Field receptor 434–435 Fiez, Julie 846 Fight-or-flight response and emotion 984 periaqueductal gray matter 973 Figure-ground recognition 493 493 Filaments actin and myosin, number of muscle fiber cross bridges depends on degree of overlap between 681–682 muscle fiber 677 678 Filopodia, axonal growth cone 1071 Fingerprints, mechanoreceptors in 432 Fingers coordination, disruption by inhibition of synaptic transmission in somatic sensory cortex 469 cortical neurons controlling movement distributed throughout hand-control area of primary motor cortex 771 different motor cortical areas activated during movements 773 fine control through direct corticospinal control of motor neurons 764 individual movement controlled by patterns of activity in population of cortical neurons 767–770 Fischbach, Gerald 1092 Fissures 9 cerebellar 322 Fixation, eye 797 Fixation neurons, eye movement 798 Fixation plane 560 Fixation point 524 560 560 Fixation system, eye 784 Fixation zone, superior colliculus 793 Flavors, sensation results from gustatory, olfactory, and somatosensory inputs 644 Flexion reflex, muscles involved 716 Flexion-withdrawal reflex 715 Flexor motor neuron, inhibitory potentials in 208 Flexor reflex afferents 742 Flocculonodular lobe cerebellum 833–834 833 See also Vestibulocerebellum Flocculus, lesions 795 Floor plate, neural tube 1027 Flourens, Pierre 7 Fluid-phase endocytosis, endothelial cells 1289 Fluorescent proteins, tracing neural projections 98 Fluoxetine, antidepressant, structure 1213 Fly See Drosophila FMRFamide See Phe-Met-Arg-Phe-amide fMRI See Magnetic resonance imaging, functional Focal attention 503 Focal epilepsy 759 Focal motor seizure See Seizures, partial Focal symptoms, seizures 910 Folia, cerebellar 834 Foliate papillae, on tongue 636 637 Folium, cerebellum 833 Follistatin, neural induction 1024 Food intake control by short-term and long-term cues 1004–1005 effect of cholecystokinin 1004 genes involved in 1005–1006 and hypothalamus 1002–1004 role of serotonergic neurons 896 See also Leptin; ob gene Food-aversion conditioning 1243 forager gene, Drosophila, variation in foraging behavior 42 Foramen of Luschka, cerebrospinal fluid 1295 Foramen of Magendie, cerebrospinal fluid 1295 Foramen of Monro 1294 1295 Force negative correlation of motor cortical cells activity with 770

trajectories of responses, parallel processing in movement 664 Forebrain 8 basal cholinergic system vulnerable in Alzheimer disease 1153 control of sleep 941 bilateral damage, causes and effects 900 cholinergic cell groups in 894 894 division into six prosomeres during development 1035–1036 domains of during development 1036 dopaminergic cell groups in 892–893 function in primitive vertebrates 873 motor circuits 663 regions of that control sleep 941 See also Amygdala; Basal ganglia; Cerebral cortex; Hippocampal formation; Hypothalamus; Olfactory bulb; Optic nerves; Prosencephalon; Thalamus; Retina Form cells in inferior temporal cortex respond to 565 cells in V4 respond to 563–564 complex, inferior temporal cortex 564–565 perception 548–571 processing in cerebral cortex 497–500 Fornix 367 369 987 Fovea 419 508 508 524 783 control of position 797 density of ganglion cells in 528 directed to object by coordinated head and eye movements 797 eye 508 neuronal control systems 783–785 representation in rostral portion of superior colliculus 793 Foveal region, included in receptive field of every cell in inferior temporal cortex 564 Foveola 508 508 FRA See Flexor reflex afferents Fractured somatotopy 842 Fragile X mental retardation, trinucleotide repeats in 55 Frames of reference, visual perception 498 FRAXE mental retardation, trinucleotide repeats in 55 Free energy of binding, of ions 109 Freeze-fracture technique 263 study of exocytosis 265 P.1351 study of vesicles and active zone plasma membrane 277 Frequency code 603 Frequency-modulated emission, echolocation 610 Freud, Sigmund 498 945 999 1210 Friedrich's ataxia, type of trinculeotide repeats involved in 56 Fritsch, Gustav 10 669 Frontal cortex effects of removal 993 left hemisphere, initiation and maintenance of speech 1182 lesions 795 olfactory information processing 633 responses of neurons enhanced by selective attention 401 See also Frontal lobe ventromedial, cognitive control of emotional responses 993–994 Frontal eye field lesions 795 movement signal to superior colliculus 794–795 types of neurons in 794 Frontal granular cortex, association area in prefrontal cortex 356 Frontal lobes 8 324 325 332 367 368 abnormal cortical connection in schizophrenia 1196 association areas, long-term storage of episodic knowledge 1237 of cerebral cortex 325 basal ganglia-thalamocortical circuit targets in 857 damage, dissociation between autonomic responses to emotive stimuli and cognitive evaluation of stimuli 994 disturbance in schizophrenia 1195 and emotion 992–994 function 9 lesion, Broca aphasia 1175–1177 mediation of feelings 980 tests of function 358 ventral, lesion, disinhibition effects 994 ventromedial, effects of damage of 994 Frontal operculum 332 Frontal region, inferior, and category-specific knowledge 1236 Fronterotemporal system, impairment of integrated activity during verbal tests in patients with schizophrenia 1204 Fruit fly See Drosophila Fulton, John 993 Functional imaging, use of to determine cognitive function 366–379 Functional magnetic resonance imaging, imaging of somatopic functioning of cortex 458–459 Functional set 715 Fungiform papillae, on tongue 636 637 Fused tetanus 681 Fusiform cell, cochlear nucleus 605 606 Fusiform system, activity levels in different types of behavior, cat walking example 727 Fusimotor system, and gamma motor neurons 725 Fusion pore 277 formation of during exocytosis 264 leakage of neurotransmitter through 267 neurotransmitter release from synaptic vesicles through 267 release of neurotransmitters through 268 Fuster, Joachim 357 Future actions, prefrontal association area 356

G g See Conductance G-protein-coupled mechanism, in olfactory transduction 629 G protein-coupled receptor 229 activation 251 binding of sweet tastants to 638 639 C. elegans 636 include opiate receptors 484 See also Odorant receptors structure 232 transduction of bitter tastes 640 G protein-linked prostaglandin receptors 237 G proteins direct modulation of ion channels 244–248 during phototransduction 512 514 in olfactory signal transduction 629 629 open ion channels directly 247 in phototransduction 521 role in sensitization 1250–1251 stimulatory 231–232 structure 234 GABA See Gamma-aminobutyric acid GABA-ergic inhibition in generalized epilepsy 923 reduced in animal models of temporalb lobe epilepsy 931 GABA-ergic inhibitory interneurons, mediate sleeping action of hypothalamus 939 GABA-ergic neurons, connections with pyramidal and spiny nonpyramidal cells in neocortex 331 GABA-ergic transmission, and loss of surround inhibition in seizure focus 919 Gage, Phineas 994 frontal lobe accident, study of behavior 352 Gain 795 in feedback systems 656–657 Gait, modulation by medial and lateral reticulospinal pathways 896 Galanin effect on feeding responses 1004 neuroactive peptide 289 in sympathetic neurons 972 Galen 6 Gall, Franz Joseph 6 1166 Galli, Lucia 1123 Galton, Francis 40 Galvani, Luigi 6 Gambling experiment, test of ventrolmedial frontal lobe damage 994 Gamma motor neurons activation during active muscle contraction 726 adjust sensitivity of muscle spindles 734–725 coactivation with alpha motor neurons in voluntary movements 729 dynamic and static 718 719 rate of firing in voluntary movements 728–729 Gamma-aminobutyric acid (GABA) -B receptors, role in absence seizures 924 biosynthesis and structure 285 biosynthetic enzyme 281 central nervous system transmitter 227 comparison of single-channel current activated by with glutamate-activated current 218 inhibitory transmitter in central nervous system 214 mediates inhibition in cerebral cortex 923 neurotransmitter 285 in local interneurons 329 in nonpyramidal cells of cerebral cortex 922 in nuclei of basal ganglia 855 in smooth stellate cells of primary visual cortex 533 receptors -channel, structure 220 clustering at synaptic sites on central neurons 1102–1103 role in generalized anxiety disorder 1222 structure 219 transmitter in reticular nucleus of thalamus 344 Gamma-globulin, in cerebrospinal fluid 1297–1298 Gandular reflexes, mechanism 968 Ganglion, firing rate is measure of light intensity differences illuminating center and surround 519 P.1352 Ganglion cell 508 bipolar cells convey cone signals to 520–521 cochlea 601 conveys output of retina 517 density of in fovea 528 detection of contrasts and rapid changes 519–520 from hemiretinas, make divergent choices at optic chiasm 1066 in phototransduction 521 process different aspects of visual image 520 receive signals from photoreceptors through interneurons 520–521 retinal concentrically organized receptive fields 529 582 parallel pathways for processing visual information 517 response to contrast in their receptive fields 516 See also Amacrine cells; Bipolar cells; Horizontal cells structure 515 structure of receptive field 517–518 Ganglionic transmission, fast and flow synaptic potentials in 970 Gap junction channels, mechanism of gating in 113 GAP-43 See Growth-associated protein of 43kDa

Gap-junctions 176 Gap-junction channels 176 conditions for closing 180 connect communicating cells at electrical synapse 178–179 flow of inorganic cations and anions through 180 hemichannels 178 role in glial function and disease 180–182 structure 118–119 118 three-dimensional model 179 Gastrin, neuroactive peptide 289 290 Gastrocnemius muscle, histochemical analysis for muscle diseases 698 See also Stretch reflex Gastrointestinal reflexes, mechanism 968 Gate-control theory, pain 482–483 486 Gated ion channels 125 See also Gating; Ion channels Gating 112 charge 162 controlled by redistribution of charges within voltage-gated Na+ channels 162 current 162 currents, measure changes in charge distribution associated with Na+ channel activation 163 glutamate receptors 213 ion channels, molecular mechanisms 112–113 modification when phosphorylation state is changed by a protein kinase 159 modulation by calcium 159 Na+ channel 155 springs, hair cells 617 through ionotropic versus metabotropic receptors 240 voltage-sensitive ion channels, influence of cytoplasmic factors 159 Gaze combined head and eye movements 796–797 control of 782–800 movements, controlled by many of same centers that control saccades 797 paralysis, ocular reflexes characteristic 907 system, components 783 Gazzaniga, Michael 16 364 365 GDNF See Glial-derived neurotrophic factor Gelineau, Jean-Baptiste 949 Gene expression 37–38 alteration of in mental disorders 1276 1277 altered by second messenger mediation of phosphorylation of transcriptional proteins 249–250 changes in induced by psychotherapy 1275 1277 in consolidation of long-term implicit memory 1256–1257 Gene knockout methods of restricting 1268–1270 1269–1270 techniques 51 Gene transcription, changes in as longest-lasting form of synaptic transmission 251 General anosmia 635 Generalized anxiety disorder alterations in synaptic function 1224 role of GABA-A receptor system 1224 symptoms 1222 Generalized seizures See Seizures, generalized Genes and behavior 36–62 expression 37–38 housekeeping functions 59 interaction with environment 36 See also specific names segregation pattern 38 single affect behaviors in flies 42 44–6 defects in can affect complex behaviors in mice 47 50 in human behavioral traits 51–55 specialized functions 59 Genetic anticipation 54 Genetic component, mental disorders, alteration of gene expression 1276 Genetic diversity, origins of 40 Genetic factors, in homosexuality 1145–1146 Genetic linkage analysis detection of coinheritance of mutated disease gene and genetic marker 53 study of schizophrenia and bipolar affective disorder 59 Genetic markers, and genetic polymorphisms 52–53 Genetic polymorphism 38 and genetic markers 52–53 Genetic predisposition panic attacks 1221 schizophrenia 1193–1195 Genetic risk factors, Alzheimer disease 1156–1157 Geniculate ganglion innervation of taste buds 643 taste information pathway 642 Geniculocortical fibers, branching patterns after eye closure and in normal development 1121 Genital ducts, sexual differentiation 1133 Genitalia, external, sexual differentiation depends on hormones produced by testes 1132–1134 Genome analysis, behavioral traits 59 60 Caenorhabditis elegans, sequencing of genome, identification of genes for channels 120 instability, and aging 1150 Genotype 38 as determinant of human behavior 40–42 relationship with phenotype 38–40 Genu of seventh nerve, control of sleep 941 Geocentric coordinate system 817

Georgopoulos, Apostolos 765 Gephyrin, and clustering of neurotransmitter receptors at central neuron synapses 1103 1004 Germ cells 38 Geschwind, Norman 500 Gestalt psychology 412 493–44 GGF See Glial growth factor Gibbs, F.A. 922 Gibson, James J. 553 Gill-withdrawal reflex, Aplysia 243 cellular mechanisms of habituation 1248 1249 1249 classical conditioning 1252–1253 1253 long-term sensitization 1254–1255 sensitization in 1250–1251 Gilman, A1 231 P.1353 GIRK See Ion channels, G protein-regulated inward-rectifying K+ g1 See Leakage conductance Glabrous 432 Glaucoma, disturbance of color vision 585 gli gene, effections of mutation in 1029 Glial cell cell fate controlled by local signaling 1047–1049 classes of 1049 differentiation in central nervous system 1049 ensheathment, after axotomy 1109 function within seizure foci 919 generation of from neural crest 1047–1048 growth factor control diversification 1048 network 180 produce myelin sheath around signal-conducting axons 85 radial 20 resting channel selective for K+ 128 resting ion channels selective for K+ 128–129 role of gap junctions in 180–182 secreted factor direct differentiation of neural crest cells into 1048–1049 See also Astrocytes; Oligodendrocytes as support cells in nervous system, 20–21 types 20–21 21 Glial growth factor and development of neuronal identity 1049 neural crest cell fate 1047 Glial-derived neurotrophic factor, neurotrophic receptor 1057 Global aphasia after middle cerebral artery infarction 1308 brain areas damaged in 1181 characteristics 1176 no ability to comprehend language, formulate speech, and repeat sentences 1181 spontaneous speech, auditory comprehension, and repetition in 1178 Global motion, object, computation by brain 556 Globose nucleus, cerebellum 833 833 Globus pallidus 325 332 347 761 basal ganglia 331 855 855 left, reduction in blood flow in schizophrenia 1195 surgical intervention at in Parkinson disease 863 863 Glomerulius olfactory bulb neurons 630 631 structure 631 Glossopharyngeal cranial nerve (IX) in developing hindbrain 1031 functions 879–880 and dysfunction 874–875 and homeostasis 965 innervation of taste buds 637 643 origin at brain stem 876 877 taste information pathway 642 Glove and stocking pattern, paresthesias 702 Glucagon, neuroactive peptide 289 Glucose concentration in cerebrospinal fluid 1297–1298 pattern of consumption in brain measured with PET 376–377 transporter isotype-1, hexose transporter of blood-brain barrier 1290 Glut1 See Glucose transporter isotype-1 Glutamate biosynthesis and structure 284–285 biosynthetic enzymes 281 channel gated by and conducting Na+ and K+ mediate EPSP 212–214 comparison of single-channel current activated by with GABA- and glycine-activated 218 co-release with dynorphin 294 enhanced release of during long-term potentiation 1262 excitatory transmitter in central nervous system 226 excitotoxicity 214 866 late response of NMDA-type channel to 213 in mossy fiber pathway 1260 neuronal cell death induced by in Huntington disease 865–866 neurotransmitter 284–285 in cone cells 518 in hair cells 622 in nociceptive afferent fibers 477 in pyramidal and spiny stellate cells of primary visual cortex 533 in pyramidal cells of cerebral cortex 922 released by cochlear hair cells 601 receptors 226–227 agonists, initiation of locomotor activity 751–752 AMPA-type, determinants of Ca2+ permeability in 221

classes that regulate excitatory synaptic actions in CNS neurons 213 clustering at synaptic sites on central neurons 1102–1103 ionotropic gating 213 effect of drugs on 212 types 212 metabotropic effect of drugs on 212 types 212 gating 213 transduction of umami taste 642 NMDA-type, and wind-up phenomenon of C fibers 479 overactivation, in amnestic shellfish poisoning 930 structure 219–221 220 types 212 in withdrawal reflex pathway in Aplylsia 1252–1253 receptor-channel, NMDA-type contribution to excitatory postsynaptic current 215 current flow through 214 postsynaptic clustering 221 in Schaffer collateral pathway 1260 toxicity to neurons 213–214 transmitter in nuclei of thalamus, except reticular nucleus 344 versus metabolic in neurons 285 uptake 287 Glutamic-oxaloacetic transaminase, diagnosis of myopathic disease 699 Glutamine receptors, mechanism of clustering at central neuron synapses 1104 Glutaminergic cells, in subthalamic nucleus of basal ganglia 855 Glutaminergic pathways, descending, initiation of locomotor activity 752 Glycine biosynthesis and structure 285 biosynthetic enzymes 281 central nervous system transmitter 227 comparison of single-channel current activated by with glutamate-activated current 218 inhibitory transmitter in central nervous system 214 aneurotransmitter 285 receptor mechanisms of clustering at central neuron synapses 1104 structure 219 receptor-channel, structure 220 Glycogen histochemical analysis for in neurogenic diseases 699 storage diseases, inherited myopathy 705 Glycoprotein dystrophin-associated 708 ion channel component 116 Glycosylation of proteins in Golgi complex 96 protein modification in endoplasmic reticulum 95 P.1354 Glycosylphosphatidyl inositol, conjugation to membrane-anchored protein in endoplasmic reticulum 96 Goal, grasping, and activity of neurons in ventral premotor area 776 Goal-directed action, multimodal association areas of cerebral cortex as anatomical substrate for 350 Gold, Philip 1220 Goldberg, Michael 400 565 Goldman equation, quantification of contributions of different ions to resting membrane potential 132–134 Goldman-Rakic, Patricia 357 Goldstein, Kurt 11 Golgi cell cerebellar cortex 836 cerebellum, effects of firing of 839 Golgi complex delivery of proteins to 96 enzymatic reactions within 96 neuron 68 69 70 processing of secretory proteins 96–97 role in protein synthesis 91 93 Golgi stain, layers of neurons in cerebral cortex 326 Golgi tendon organs 432 443 720 discharge rate and force in muscle 723 function 722–724 and initiation of swing phase of stepping 749 input to Ib inhibitory interneurons 722–724 and reflex action of Ib afferent fibers 724 regulation of step cycle 748 structure 723 Golgi, Camillo 6 Gonadal hormones See Hormones, gonadal Gonadotropin-releasing hormone neuroactive peptide 289 neurons releasing 979 980 Gonads, development 1132–1134 Gorski, Roger 1134 Gottesman, Irving 1194 Gouras, Peter 579 GPI See Glycosylphosphatidyl inositol Gracile fascicle 342 dorsal column 447–448 pathway of sensory information 446 spinal cord 338 Gracile nucleus 342 448 pathway of sensory information 446 Gramicidin A

channel, proposed structure 110 use in study of ion channels 109 Grammar 1170 components of 1170–1171 See also Language understanding subtleties 1172 Grand mal seizure See Seizure, secondarily generalized tonic-clonic Granit, Ragnar 728 Granule cell cerebellar cortex 835 836 interneurons, olfactory bulb, negative feedback circuits 632 layer, terminaton of mediodorsal thalamic nucleus in 356 olfactory bulb 631 GABA as major transmitter 285 Graphesthesia 468 Grasping activity of neurons in ventral premotor area depends on goal 776 mediated by parieto-premotor channel 777–778 movement, pathways for 775 parameters for movement 778 Gray communicating ramus 962 Gray matter, spinal cord 319 functional regions 447 laminae 447 structure 338 Gray type I synapatic connections in brain 209 210 212 Gray type II synaptic connections in brain 209 210 212 Gray unmyelinated rami 963 Gray, Charles 567 Gray, E.G. 209 Great anterior medullary artery of Adamkiewicz 1314 Greater saccular nerve 802 Greater superficial petrosal branch, cranial nerve VII, innervation of taste buds 643 Greengard, Paul 248 Gregory, Richard L. 490 587 Group atrophy, in neurogenic diseases 699 Growth cones, axonal 6 1070–1074 Growth factor receptors, delivered to cell body by retrograde transport 102 released by glial cells 20 Growth hormone, neuroactive peptide 289 Growth hormone release-inhibiting hormone, hypothalamic 980 Growth hormone-releasing hormone neuroactive peptide 289 neurons releasing 979 980 Growth-associated protein of 43kDa, decreased expression in central neurons as development proceeds 1111 Growth-promoting molecules, guidance cues for axon growth cone guidance 1071 Grusser, Otto-Joachim 813 GTP-binding proteins, low-molecular-weight, control of synaptic vesicle mobilization, docking, and fusion 272 Guanidine, treatment botulism 307 Lambert-Eaton syndrome 307 Guanine nucleotides, during phototransduction 514 Guanylyl cyclase, activation 239 Guarente, Leonard 1150 Guillain-Barré syndrome 82 neurogenic disease of peripheral nerve 701 symptoms 702 Gurfinkel, Viktor 830 Gustatory area projections to thalamus 643 taste information pathway 642 Gustatory cortex, taste information pathway 642 Gustatory fibers, response to types of taste stimuli 644 Gustducin in bitter taste transduction 640 in sweet taste transduction 639 Gut feelings 995 Gut smooth muscle function, enteric system of peripheral nervous system 335 Gyri 9 324

H H-reflex 731 H-wave, Hoffmann reflex 731 H.M. patient learning of skilled tasks 1229 MRI image of brain 353 patient with temporal lobes removed, study of short-term and long-term memory 352 study of 1229–1230 temporal lobe lesions in 1228 types of memory in after surgery 1229–1230 Habituation activity-dependent presynaptic depression of synaptic transmission 1248–1250 cellular mechanisms in gill-withdrawal reflex of Aplysia 1248 1249 1249 long-term and pruning of synaptic connections 1257 structural changes in presynpatic terminals of sensory neurons 1256 nonassociative learning 1240 of vestibular apparatus 809–810 Hagbarth, Karl-Erik 729 Hair bundles mechanical deflection transduced into receptor potential 598–599 semicircular canals 805 806

stereocilia 614–615 vestibular system 801 P.1355 Hair cells adaptation to sustained stimuli 619–620 afferent synapses 622 623 cochlea 592 functional distinction between inner and outer 601 innervated by ganglion cells 601 loss of and deafness 610 sensitivity 600 efferent inputs from brain stem 803 efferent synaptic inputs from brain stem 623 electrical resonance 621 excitatory synapses with eighth-nerve fibers 622–623 functions 623–624 glutamate neurotransmitter in 622 inner ear sense of equilibrium 614 structure 614 mechanically active 600 601 mechanical sensitivity 616 mechanoelectrical transduction 616–617 olfactory 417 model for mechanoelectrical transduction 616 of adaptation 621 organ of Corti 597 602 receptors in organ of Corti 597–599 of internal ear 590 saccule 804 speed of response 619 stimulation 598 structure 615 tuning curve represents frequency sensitivity 599 599 tonotopic mapping 620 tonotopic organization 597 toxic effect of aminoglycoside antibiotics 617 transduce mechanical stimulation into receptor potentials 600 601 tuned to specific stimulus frequencies 620–622 turtle, electrical resonance 622 types 597–598 utricle 804 804 vestibular labyrinth 802–808 803 output to vestibular nuclei 803 vestibular system 814 Hair follicle receptor 434 Hair-tylotrich 432 Half-center hypothesis, neurons in spinal cord 742 Hallucinations auditory-verbal, PET results in schizophrenia 1191 in schizophrenia 1193 visual, during sleep onset paralysis 949 Haloperidol, structure 1198 Hamburger, Viktor 1054 1056 Hamer, Dean 1145 Hamstring muscle, single muscle that affects motion of many joints 692 Hand cortical representation can be modified 389–390 with fused and nonfused digits 391 increased use of fingers enlarges cortical representation of 390 large number of cortical columns receive input from 459–460 movements disturbed by lesions of dorsal columns of spinal cord 468 role of cerebrocerebellum in planning and programming 846 muscles, activation by stimulation of motor cortex 758 See also Syndactyly Haploid 37 Haplotype 707 Harlow, Harry 1128 Harlow, Margaret 1128 Harris, Geoffrey 1134 Harrison, Ross 6 Harvey, A. McGhee 299 Hauptmann, A. 911 Haw Rive syndrome, type of trinucleotide repeats involved in 56 Hayflick, Leonard 1149 Head and eye movements, coordinated by cerebellum 322 Head ganglion See Hypothalamus Head motion, velocity, 813, 814 Head movement combined with eye movements in gaze 796–797 system, gaze system 783 Head, Henry 11 Head motor control and sensation mediated by brain stem 320 position See Vestibular system Head-centered frame of reference 498 Hearing information, pathway 590–591 Hearing 590–613 brain stem is site of entry for information from 320 capture of sound energy 593

loss conductive 593 otosclerosis 593 sensorineural 610–612 treatment 610–612 role of temporal lobe 9 sensory neurons for organized according to sensitivity 419 Heart effects of norepinephrine and acetylcholine 967 muscle, controlled by autonomic nervous system 960 Heat, conservation and dissipation, hypothalamus regions concerned with 1000–1002 1000 Hebb, Donald 659 1122 1260 Hebbian mechanism, in long-term potentiation 1262 Hebephrenia 1193 Hedonic factors, effect on motivational states 1007 1009 Helicotrema 595 802 cochlea 592 Helmholtz, Hermann 411 421 594 783 Hemiballism after infarction of posterior cerebral artery 1308 basal ganglia-thalamocortical circuit in 860–861 reduced output from internal pallidus in 864 Hemiballismus, and basal ganglia 853 Hemiparesis pure, after occlusion of penetrating arteries 1309 See also Todd paralysis Hemisensory loss, pure, after occlusion of penetrating arteries 1309 Hemispheres See Left hemisphere; Right hemisphere Hemorrhage, brain 1306 Henneman, Elwood 721 Hereditary neuropathy with liability to pressure palsies 709 Hering, Ewald 578 Hering-Breuer reflex, proprioceptive signals in 726–727 Herpes simplex virus, to trace cortical pathways 99 Heschl's gyri 326 Hess, Walter 871 986 Heston, Leonary 1193 Heteronymous connections 717 Heterosynaptic process 1250 Heterozygous 38 Hetherington, Albert W. 1002 Heuser, John 264 Hexose transporter, blood-brain barrier 1290–1292 Higher-order motor cortex, cerebral cortex, lobes and location 351 Higher-order unimodal sensory areas, cerebral cortex, lobes and location 351 Hillarp, Nils 292 332 Hille, Bertil 108 248 276 Hindbrain 8 mutations of Hox genes changes motor neuron identity 1034 organization of motor neurons during development 1031 rhombomeres 1031 See also Pons; Cerebellum; Medulla; Rhombencephalon segmental expression of genes patterning 1033 P.1356 segmental organization by Hox genes 1030–1034 Hinge joints 687 Hip extension, control of transition from stance to swing 748 Hip-balancing strategy, vestibular response 823–824 Hippocampal circuits, vulnerable in Alzheimer disease 1153 Hippocampal formation 369 anatomical organization 1232 of cerebral hemispheres 322 input and output pathways 1232 in limbic lobe 986 987 nuclei in 331 Hippocampal neurons, distribution of ribosomal RNA 90 Hippocampus 332 987 abnormalities in Alzheimer disease 1153 anterior portion smaller in schizophrenia 1195 1196 in ascending arousal system 900 atrophy in temporal lobe seizure patient, MRI 929 contains cognitive map of spatial environment 1264 1266 damage to specific subregions impairs explicit memory storage 1233 dentate gyrus as gatekeeper of excitabiltiy in 931–933 932 entorhinal cortex as major output of 1232 function 8 in hallucinations in schizophrenia 1190 indirect role in emotions 994–995 kindling experimental model of hyperexcitability 931–932 lack of NMDA receptor and defect in long-term potentiation and spatial memory 1270–1271 1272 lesion effect on explicit memory 1231 effect on remembering cognitive features of fear 985 long-term memory and long-term potentiation 1259–1272 maintenance of early phase of long-term potentiation 1262 major afferent pathways 1257 major pathways in 1259 memory storage 323 mesial portions, atrophy and cell loss in patients with complex partial seizures 925 mossy fiber pathway, long-term potentiation of 1258 olfactory information processing 633 pattern of brain injury by prolonged seizures 928 phosphorylation cascade in 249 place cells 1264–1267

projections to posterior parietal association cortex 392–395 pyramidal cells in 78 and rabies virus 987 right, lesions of affect spatial representation 1233 role in memory 1234 sensitive to damage by domoic acid 930 size in patients with epilepsy 927 storage of long-term memories 331 stratum pyramidale 85 susceptibility to epilepsy 931 Hippocrates 910 1165 1209 Histamine activation of nociceptors 480 as autocoid 283 as chemical intermediary for pain 442 biosynthesis and structure 284 biosynthetic enzyme 281 neurotransmitter in invertebrates 284 and nociceptor sensitization 477–478 Histaminergic cell groups, hypothalamus 894–895 895 Histaminergic neurons posterior hypothalamus, destruction of produces sleep 939 in tuberomammillary nucleus 896 Histofluorescence technique detection of chemical messengers within neurons 292 staining monoamine neurotransmitters 332 Hitzig, Eduard 10 669 Hodgkin, A.L. 23 Hodgkin, Alan 133 151 155 Hodgkin, Jonathan 42 Hoffmann reflex 730 components 731 electrical stimulation 731 Holmes, Gordon 351 496 556 846 849 Homeobox 1032 Homeobox genes, evolutionary conservation 1032 1032 Homeodomain proteins, specify regional identity along anteroposterior axis of Drosophila and vertebrates 1032 Homeostasis coordinated by hypothalamus 960 negative feedback regulation 962 parasympathetic system of peripheral nervous system 335 processes in nervous system 871 role of hypothalamus 871 sensory inputs to autonomic nervous system 965–969 Homeostatic functions, circadian rhythm for 1007 Homeostatic processes analysis in terms of control systems 999 and drive states 998–999 Homo erectus, possible language 1174 Homo habilis, possible language 1174 Homo sapiens, language in 1174 Homogenetic induction 1030 Homologous recombination 48 Homonymous connections 717 Homonymous hemianopsia 1306 545 after infarction of posterior cerebral artery 1308 after middle cerebral artery infarction 1307 Homonymous muscle 77 Homosexuality concordance for in twins 1145–1146 1145 genetic factors 1145–1146 neural correlates 1145–1146 possible genetic and anatomical basis 1143–1146 Homosynaptic process 1250 Homozygous 38 Homunculus cortical 459 motor cortex 757 sensory and motor 344 387 Horak, Fay 821 Hore, Jonathan 844 Horizontal cells mediation of signals from cones 519 passive transmission of signals 520–521 retina, structure 515 520 synapses on 518 Horizontal connections, primary visual cortex, links with columns 542 Horizontal plane 321 Horizontal vestibulo-ocular reflex, excitatory and inhibitory connections, head rotation 811 Hormones 281 dynamic influence on central nervous system 1146 effect on neuron morphology 1137 gonadal effects of manipulation 1136 effects on neurons 1136 induction of apoptotic cell death in anteroventral periventricular nucleus 1140–1141 permanent effects on developing central nervous system 1136 structural changes in adult brains 1141

transient effects on adult brain 1136 structures of precursors 291 Horseradish peroxidase detection of horizontal connections in primary visual cortex 540 tracing neural projects 98 98 Horsley, Victor 911 Horynekiewicz, Oleh 862 Hospitalism 1128 Hot spot, receptive field 436 Hox genes control of rhombomere identity 1031 mutations, change motor neuron identity in hindbrain 1034 P.1357 organization 1032 overlapping domains in developing hindbrain and spinal cord 1033 segmental expression in hindbrain patterning 1033 segmental organization of hindbrain 1030–1034 HPETE See Hydroperoxyeicosatetraenoic acid Hubel, David 529 533 537 550 579 1116 Huganir, Richard 248 Human speech, vowel, response of basilar membrane 594 597 Hume, David 411 Humoral signals, effect on hypothalamus 1004 Humors, and moods 1210 Hunger See Drive states Huntingtin gene for Huntington disease 52–55 864–865 protein, accumulation in brain cell nuclei of Huntington disease patients 865 Huntington disease 864–866 and basal ganglia 853 caused by mutations in huntingtin gene 52–55 cellular model 865 characteristics 52–53 Drosophila model 865 genetic linkage analysis 53 glutamate-induced neuronal cell death 865–866 glutamate toxicity in 214 identification of gene for 864–865 nature of mutation causing 54 trinucleotide repeats in 55 56 704 Huntington protein 53–54 Hurvich, Leo 579 Huxley, A.F. 23 678 Huxley, Andrew 152 155 Hydra head activator, neuroactive peptide 289 Hydrencephalus 873 Hydrocephalus causes 1299–1300 types 1299 Hydroperoxyeicosatetraenoic acid, modulation of ion channels 238 Hydrophobicity plot, identification of membrane-spanning region of ion channel 117 6-Hydroxydopamine, injection into cortex surrounding principal sulcus disrupts performance of delayed-response tasks 361–362 5-Hydroxytryptamine see Serotonin Hyperalgesia 475 and histamine release from mast cells 478 hyperexcitability of dorsal horn neurons 479 peripheral and central origins 477–479 Hypercolumns 539 545 Hyperekplexia See Startle disease Hyperexcitability, hippocampus and amygdala, experimental model of 931–932 Hyperkalemia periodic paralysis results from ion channel defects 123 caused by point mutation in alpha-subunit of gene for voltage-gated Na+ channel in skeletal muscle 167 169 Hyperkinetic disorders 861 See also Hemiballismus; Huntington disease underactivity in indirect pathway of basal ganglia 864 Hyperphagia 1002 Hyperpolarization 28 126 127 127 127 after-potential 157 cochlear hair cells 601 decreases steady-state Ca2+ influx 274 loss of accompanies onset of partial seizure 924 membrane of cone photoreceptors after light absorption 574 photoreceptor 513 514–515 responding to light 416 Hyperpolarizing currents, transmitted by electrical synapses 178 Hyperreflexia 700 following spinal cord transection 730–735 Hypertonus 730 Hypoglassal cranial nerve (XII) in developing hindbrain 1031 function and dysfunction 874–875 800 origin at brain stem 876 877 Hypoglossal nuclei 671 881 location 883 Hypokalemic periodic paralysis, caused by mutation in Ca2+ channels 169 Hypokinetic disorders 861 See also Parkinson disease Hypopnea methods for documenting 949 obstructive sleep apnea syndrome 952

Hypoperfusion, diffuse, and ischemia or infarction 1313–1314 Hyposmia 635 Hypotension, cause of spinal cord infarction 1314 Hypothalamic nucleus INAH-3, larger in heterosexual than in homosexual men 1145 Hypothalamus 332 367 980 abalation experiments and temperature regulation 1001 anterior, sexual dimorphism of four interstitial nuclei 1144 1142 ascending projections from monoaminergic cell groups increase wakefulness and vigilance 896–897 and autonomic nervous system 960–981 in autonomic response control pathway 975 connections with central nucleus of amgydala and tests for fear and anxiety 993 control of endocrine responses to temperature 1001 endocrine system 978–979 coordinates peripheral expression of emotional states 986 descending pathway from regulates pupillary dilation 905 dopaminergic neurons in 892 893 effect of humoral signals 1004 leptin on 47 satiety signals on 1004 and endocrine system 960 and food intake 1002–1004 function 8 871 960 histaminergic cell groups in 894–895 895 896 integration of autonomic and endocrine functions with behavior 974–977 lateral and medial, effect of lesions on feeding 1002 1002 lesions, effect on emotion 986 mediation of emotions 980 and motivation 960 olfactory information processing 633 paraventricular nucleus, structure and pathways 978 pathway of control of pituitary gland 977 visceral sensory information 974 peptides that regulate anterior pituitary 980 peripheral component of emotion 985 physiological regulation by 974–975 posterior control of sleep 941 destruction of histaminergic neurons produces sleep 939 stimulation produces arousal 939 in pupillary dilation 905 regions 977–978 of concerned with heat conservation and heat dissipation 1000–10002 1000 regulation of water balance 1006–1007 release of neuropeptide Y and feeding behavior 1006 role in emotion 872 mediating emotion 984 unipolar depression 1220 sleeping action of mediated by non-REM-on cells 939 specialized groups of neurons in nuclei 977–978 P.1358 structures, frontal and medial 976 subdivision of diencephalon 322 summation of peripheral and central information on temperature 1001 suprachiasmatic nucleus, internal clock site 937 in vomeronasal system 634 Hypotonia 861 cerebellar abnormality 849 Hypotonus 730 Hypoxia 900

I I See Current Ia afferent fibers distribution of action potentials distributed among spinal motor neurons 721 motor cortex reflex circuit 765 presynaptic inhibition and modulation of spinal reflexes 724 Ia axons, excitatory inputs to motor neurons innervating synergist muscles 721 Ia fibers, direct connections on motor neurons in stretch reflex 717 Ia inhibitory interneurons 717 motor cortex reflex circuit 765 pathways of reflex action 722 spinal cord, complex excitatory and inhibitory inputs 765 stretch reflex, coordinate muscle contraction during voluntary XSmovements 717 720 Ia sensory fiber, response to selective activation of motor neurons 719 Ib inhibitory interneurons, input from Golgi tendon organs 722–724 Ic See Capacitive current ICMS See Intracortical microstimulation, 759 Ictal phenomena 15 II See Leakage current Illusion apparent motion 551 552 and visual perception 495 495 496 496 Image, saliency map 567 Imagined space 384 Imaging techniques See Magnetic resonance imaging; Positron emission tomography; Magnetoencephalography functional, use of to determine cognitive function 366–379 Imipramine, antidepressant, structure 1213

Immobilized preparations, study of stepping 738–739 Immunocytochemistry, detection of chemical messengers within neurons 292 Immunoglobulin superfamily cell adhesion molecules, promote neurite outgrowth 1076 1077 Immunogold, detection of chemical messengers within neurons 292–293 Immunohistochemistry, detection of chemical messengers within neurons 292–293 Implementation system, language 1174 1175 Implicit memory 1231 1231 See Memory, implicit Imprinting 1128 In situ hybridization, detection of chemical messengers within neurons 292 Inactivation gate, Na+ channels 155 inhibitors, effect on noradrenergic neurons 1218–1219 voltage-gated channels entering refractory state after activation 114 Incus 591 591 595 Indirect immunofluorescence, detection of chemical messengers within neurons 292–293 Individuality biological basis 1247–1279 biological expression of and somatotopic map produced by learning 1274–1275 unique modification of brain by experience as biological basis of 1275 Inducing factor 1022 Inertia, overcome by muscle force 688–689 690 Infants, pattern of sleep 943 Infarction anterior cerebral artery 1305 1308 brain stem, characteristic syndrome produced 1311–1312 caused by diffuse hypoperfusion 1313–1314 cerebellar 1313 middle cerebral artery 1305 types and symptoms 1306–1308 pons, PET scan 1311 posterior cerebral artery 1306 1308 spinal cord 1313 Inferior cerebellar peduncle 833 Inferior cervical ganglion 964 Inferior colliculus 788 877 auditory pathway 604 608 cranial nerve nuclei at level of 884 formation of tonotopic maps on neurons in 1127 tonotopic map and layers 608 sound localization 608 Inferior mesenteric ganglion 964 Inferior olive, lesions, effect on motor learning 848–849 Inferior parietal lobe, damage to in conduction aphasia 1180 Inferior parietal lobule effect of damage to 355 in visual attention 354 Inferior salivatory nucleus, location and function 885 Inferior temporal cortex 501 cells in respond to both form and color 565 cells responding to similar features are organized into columns 565 effect of lesions in on visual system 498 effects of visual attention of cells of 565–566 face recognition 564–565 form and color 502 inputs to 564 response of one neuron to complex visual stimuli 566 Inferior temporal gyrus 333 Inferior temporal lobe, ventral pathway to and object vision 562–565 Inferior temporal pathway cross talk with posterior parietal pathway 567–568 visual 500–501 Inferior 321 Inferotemporal cortex and basal ganglia, hallucinations in schizophrenia 1190 1190 explicit learning of facial identity 989 Inflammation neurogenic 479 symptoms reproduced by substance P 478–479 Information amount reaching cortex limited by selective attention 504–505 carried by electrical and chemical signals 125 295 cognitive, parallel and distributed processing of 349 conveyed by action potentials 22 diversity transferred in single synaptic action 295 features of conducting signal that carry 31 flow in primary visual cortex 533 from sensory neurons to motor neurons is divergent and convergent 79 through relay nuclei controlled by inhibitory mechanisms 427 genetic, stored in chromosomes 37–38 integration in higher cortical areas 463–468 nociceptive, ascending pathways 480–482 processing 383 functional systems for in central nervous system 323 highest level in cerebral cortex 344–346 P.1359 nature of in neocortex 330 rapid, ion channels tuned for 105 sensory, principles of 352–362 sequence in motor system reversed from that in sensory system 355–356 specific areas for in cerebral cortex 325–326

in thalamus 344 recursive comparison by different brain regions 1318 sensory conveyed by populations of sensory neurons 416 parallel processing 319 processed in serial pathways 426–427 somatosensory, carried by parallel and hierarchical pathways to spinal cord and brain 341 steps for processing in memory 1231–1232 stored, recall is not exact copy of original information 1239 tactile, object, fragmented by peripheral sensors and integrated by brain 452 theory, focus on cognition 313 time-sensitive, carried rapidly and over long distances by transient electrical signals 125 transmitted from receptors by modulation of frequency of electrical impulses 430 types of storage of in memory 1228–1233 visual, processing in multiple cortical areas 496–497 Ingram, Vernon 867 Inhibition competitive effect with excitation in nerve cell 226 feed-forward and feedback 26–27 27 lateral, and two-point discrimination 461 reduction of EPSP 216 sculpturing role 209 209 461 and reduced output of projection neurons 461 Inhibitory current, impact in postsynaptic neuron 225 Inhibitory inhibition, interneurons, and central pattern generators 744 Inhibitory interneurons See Interneurons, inhibitory Inhibitory molecules, guidance cue for axon growth cone guidance 1071 Inhibitory neurons, eye movement 798 Inhibitory postsynaptic potential recorded from hippocampal pyramidal cell 923 polarity in surface electroencephalogram 915 in postganglionic neurons 970 spinal motor neurons, mechanism of 215 217 Inhibitory surround cortical neuron 461 seizure focus 921 Inhibitory synaptic action, mediated by GAB A- and gly cine-gated channels that conduct chloride 214–219 Inhibitory synpatic potential, reversal 216 Ink gland, Aplysia, inking response mediated by electrically coupled high-threshold motor cells 180 181 Inner ear bony and membranous labryrinths 802 structure 592 vestibular and cochlear divisions 802 Inner hair cells cochlea 596 organ of Corti 596 Innervation, dorsal root ganglia, mapping 445 Inositol polyphosphates, second messenger in synaptic transmission 230 Input component, nerve cell signaling 28–29 Input signal 27 30 Insertional plaque, hair cells 619 Insomnia 948 954–955 advanced sleep phase syndrome 954 delayed sleep phase syndrome 954 disturbed circadian rhythm in 954–955 Inspiratory cramps, in coma 903 Instructed-delay task 772 Insula affected in conduction aphasia 1180 damaged in global aphasia 1181 left, and category-specific knowledge 1236 planning and coordinating articulatory movements for speech 1182 1183 Insular cortex 332 of cerebral cortex 325 language 1175 lesions 482 role in processing pain 481–82 somatosensory cortical area 452 Insulation, membrane, effect on conducting properties 144–145 Insulin euroactive peptide 289 290 precursor structure 291 Integral membrane protein 94 Integrator 1000 Integrins, on axon growth cone interact with laminins in extracellular matrix 1074 Intelligence, general, dissociation from language 1172 Intensity, stimulus attribute conveyed by sensory systems 412 413 414 Intention tremor 849 Interblobs primary visual cortex 549–550 visual cortex 501 Interdental cells, organ of Corti 598 Interhemispheric fissue 368 369 Interictal phenomena 15 Interictal spikes, in vitro brain slice 917 Interleukin-1 hypnogenic properties 943 increases temperature set point 1001 Intermediolateral cell column, in autonomic response control pathway 975 Intermediolateral gray matter 962 Internal acoustic meatus 807

Internal auditory artery 1303 1304 Internal capsule 346 369 482 and basal ganglia 855 855 ventral corticospinal tract 670 Internal carotid artery 1303 cerebral hemispheres 1302 Internal clock, circadian rhythm 937 Internal granule cell layer, neurons in cerebral cortex 326 327 Internal medullary lamina 343 Internal pallidus, reduced output in hemiballism 864 Internal pyramidal cell layer, neurons in cerebral cortex 326 327 Interneurons 25 323 329 330 693 convergence of inputs on and flexibility of reflex responses 721–724 decision to initiate action potential 222 diseases attacking 33 excitatory 329 GABA as major transmitter 285 GABA-ergic 329 generate flexor bursts 742–743 Ia inhibitory 717 inhibitory responses in somatic sensory cortex 461 in reflex pathways 735 inhibitory action potentials not generated 33 coordination of reflex actions 722 and hierarchical organization of somatosensory system 416 in knee jerk 26 pathways of activation 427 production of feed-forward and feedback inhibition 26–27 27 Renshaw cells 720–721 sharpen contrast between stimuli within each relay nucleus 427–428 local 25 local-circuit, dorsal horn of spinal cord, integrate descending and nociceptor afferent pathways 488 local inhibitory, striatum 856 P.1360 motor circuits 663 neocortex, affected in Alzheimer disease 1153 periglomerular, olfactory bulb 630 631 projection 25 relay 25 relay signals from photoreceptors to ganglion cells 520–521 retinal, function 517 See also Bipolar cell serotonergic, in sensitization 1252 site of modification of reflex pathway 724 725 synpatic contact of spinal motor neuron with 77 types in retina 517 Internodal regions, axon capacitative and ionic membrane current densities in 148 Internuclear ophthalmoplegia in multiple sclerosis 792 ocular reflexes characteristic 907 Interpeduncular cistern 367 Interposed nuclei, cerebellum, lesion of 850 Interposed nucleus cerebellum 833 effect of damage to 844 inactivation of 844 inactivation of and disruption of agonist/antagonist activation following perturbation 843 Interventricular foramen 368 Intonation, language, role of right cerebral hemisphere 1182 Intorsion, eye movement 785 Intracellular recording, inferring number of synapses in reflex pathways 721 Intracerebral steal 1316 Intracortical excitatory circuits 457 Intracortical microstimulation 759 Intracranial fluid compartments, and blood-brain and blood-CSF barriers 1296 Intracranial pressure, techniques for measuring 1298 Intrafusal muscle fibers 718 719 Intralaminar nuclei 343 Intramolecular disulfide linkages, protein modification in endoplasmic reticulum 94 Intraparietal sulcus 457 Introns 37 Introspection, early method for understanding the mind 382–383 Inversion, chromosomal 40 Involuntary motor system See Autonomic nervous system Inward rectifying channels 248 Inward rectifying K+ channels, structure 119 Ion channels 27 105–124 A-type K+ channel 159 acetylcholine-activated, localized to end-plate 200–201 acetylcholine-gated all-or-none opening 195 197 as resistors 193 196 effect of membrane potential on 198 genes encoding 198–199 mechanism of gating in 113 molecular properties of at nerve-muscle synapse 196–201 opened by ligand 194 production of synaptic potential at end-plate 190 relation between current and voltage is linear 109–110 reversal potential 193 structure of channel pore 198–200

all-or-none characteristic 110 anion-selective 110–111 conductors or resistors in electrical equivalent circuit 134 behavior as rectifier 111–112 binding of drugs or toxins and functional state 115 calcium closely related to Na+ channels 164–166 concentration at presynaptic terminal of neuromuscular junction 259 molecular bases for diversity 257 -sensitive K+ channels 621 622 types 256–257 and voltage-dependent K+, and afterhyperpolarization in paroxysmal depolarizing shift 919 calcium-activated K+ channel 158 cation-selective 110 cGMP-gated during phototransduction 512 in photoreceptors 511 during darkness 513 chimeric 117 chloride effect of opening on EPSP 217 mechanism for inhibition of postsynaptic cell 29 217 cloning and sequencing of genes for 116 combinations of and response to excitatory input 160 common ancestor for genes of Na+, K+, and Ca2+ channels 164–166 comparison of synaptic excitation produced by opening and closing 240 conductance and ion permeation 111–112 contribute to determination of ionic permeability properties of cell membrane 106–107 control rapid changes in membrane potential 123 current linearly related to voltage 110 current flow as nonlinear function of driving force 111–112 delayed rectifier 158 different combinations expressed 33 differing selectivities 123 direct gating 230 mediated by ionotropic receptors 184 direct modulation by G proteins 244–248 dissociation constant 112 each acting as conductor and battery in parallel 134 effect of drugs and toxins on gating 114 end-plate motor neuron opens to excite muscle 190 permeability to Na+ and K+ 192 evolutionary conservation of structure and function 117 factors contributing to selectivity of 163–164 families of 118 flux of ions through is passive 110–112 functional methods of study 109–110 functional properties can change over course of development 120 120 functional states 114 G protein-regulated inward-rectifying K+ 248 G-protein-coupled inward rectifying, activation by ACh 247 GABA, role in disease 219 GABA-A chloride, structural model 1223 GABA-gated, recording of current 217 GABA-gated Clactivation of and presynaptic inhibition 275 mediate inhibitory synaptic action 214–219 opening can cause excitation in brain cells 219 gap-junction, structure 118–119 118 gated 107 125 directly or indirectly by postsynaptic receptors 185 gating 112 in hair cells 617 physical models for 113 types of stimuli controlling 113 glutamate-gated and conducting Na+ and K+, mediates EPSP 212–214 glycine, role in disease 219 glycine-gated CL-, mediate inhibitory synaptic action 214–219 recording of current 217 gramicidin A 109 P.1361 hydrophilic 70 gramicidin, current varies with membrane potential in linear manner 109 hydrophobicity plot to identify membrane-spanning regions of 117 grouping into gene families 118–120 h-type 158 hair cells, opened by mechanical force 617–619 indirect gating 230 230 mediated by metabotropic receptors 184 individual acetylcholine-gated, conduct unitary current 193–194 influx of Ca2+ alters metabolic processes in cell 123 initiation of signal 65 inward rectifying K+, structure 119 inward rectifying 248 ions conducted across by receptors 108 length of time open 194 ligand-gated 107 185 acetylcholine receptor, structure 118 118 ATP-activated channels, gene family 119 differences from voltage-gated channel 196 See also Ion channels, acetylcholine-gated

structure 118 118 220 ligand-gates, as on-off switches 240 linear nature of current flow through 112 M-type K+ channel 159 241 control excitability 243 M-type, outward K+ current and accommodation to prolonged depolarizing stimuli 243 malfunctioning 105 measurement of current flow with patch clamp 192–193 mechanically gated 107 mechanoelectrical transduction, cation-passing pores 616–617 mediate electrolyte movement across blood-brain barrier 1292–1293 mediation of changes in membrane potential 105 methods of testing proposed structure 117–118 model for selectivity for Na+ or K+ ions 106–107 modification of activity 123 monovalent cation-permeable 158 nicotinic acetylcholine activation, proteins forming 201 gated, and receptor, formed by single macromolecule 197–201 nonlinear relation between current and membrane potential 112 number of types 119–120 occlusion of 112 ohmic 112 open and close as result of conformational changes 112–116 P region as selectivity filter 119 passive potassium, as equivalent electrical circuit 134 patch-clamp recording of current flow 111 permeability for specific ions 138 potassium blockade of in sour taste transduction 641 in bitter taste transduction 640 closed by cAMP-dependent protein kinase 243 increased opening following action potential 157 possible common ancestral channel 164–166 responses during long-term depolarization 156 -selective, structure solved by X-ray crystallography 120–123 122 substances that block 154 study with voltage clamp technique 151–154 properties 105 107 proposed structure of gramicidin A channel 110 proteins 108 and rapid informaton processing 105 and resting potential 149 rectifying 112 regulate flow of ions across cell membrane 123 regulation of 107 regulatory mechanisms for amount of time channel is open and active 114 relationship between structure and function 169 relative proportion of types determines resting membrane potential 130 resting 65 107 125 determination of resting membrane potential 126 128 determine resting membrane potential 126–132 Na+, K+, and C-, representation by single equivalent conductance and battery 137 selective for K+ only in glial cells 128–129 selective for several ion species in nerve cells 129–131 S-type K+ activated by FMRFamide 243 activity recorded by patch-clamp technique 245–246 closed by serotonin 243 slow synaptic action mediated by FMRF amide opens those that are closed by sertonin 246 selective for Na+, K+, or Cl-, represented by a battery in series with a conductor 134 selective for Na+, K+, or Cl, represented by battery in series with conductor in electrical equivalent circuit 134–135 134 selectivity 107 108 selectivity filters in 108–109 selectivity for types of ions 110–112 serotonin ligand-gated, in central nervous system 221–222 shared characteristics 110–116 short-term and long-term effects of chemical transmitter 250 signaling in the nervous system 105–107 site of action of drugs, poisons, and toxins 105 sodium activation gate 155 closely related to Ca2+ channels 164–166 different conformations of in response to depolarization 154–155 distinct entities 160 during action potential 156–157 gating currents directly measure changes in charge distribution 163 gating relies on redistribution of net charge in S4 region 167 inactivation after end of depolarization 156 inactivation gate 155 mechanism of inactivation 163 rapid rate of turning on and off over range of membrane potentials 156 residual inactivation following action potential 157 response during long-term depolarization 156 in salty taste transduction 640 structure 164 study with voltage clamp technique 151–154 substances that block 154 and velocity of action potential 160 structure 116–123 116 study of function 123

T channel, in thalamic relay neurons 924 targets of disease 123 transmitter-gated ATP receptor 222 gene families 227 two classes 65 types 125 P.1362 voltage-gated 65 107 all-or-none nature of opening 161–162 162 Ca2+ 158 antibodies against in presynaptic terminals and Lambert-Eaton syndrome 307 density at active zone of neuromuscular junction 189 molecular structure of pore 163 along presynaptic density 264 role in transmitter release 256 selection for Na+ on basis of size, charge, energy, and hydration 163–164 in thalamic relay nuclei 898 types 159 Cl- 158 common molecular design 168 in dendrites 159–160 differences from ligand-gated channel 196 different types of and repetitive firing properties of neurons 161 diversity of types due to genetic mechanisms 167 flow of ions through generates action potential 150–158 inactivation 166 K+ gene family encoding 119 expression of variants in different regions of brain 121 four major types 158–159 mechanisms for entering the refractory state 115 membrane-spanning domains 165 mutations cause neurological diseases 167–169 Na+ 188 activation at end-plate 201 contribution to transmitter release 254 gating controlled by redistribution of charges within 162 at neuromuscular junction 189 open when membrane potential reaches depolarization threshold for action potential 132 Na+ and Ca2+, insertion of into membranes of denervated muscle fibers cause fibrillations 701 Na+, K+, and Ca2+, in taste cells 637 sequential activation of two types of 153 signaling functions related to molecular structure 160–164 smaller subunits contribute to properties 166 structure 119 118 two conductance states of 162 variations in properties increase signaling capabilities 158–160 voltage-sensitive Ca2+, hair cells 621 622 gating of influenced by cytoplasmic factors 159 Na+ and K+, blockage in presynaptic terminals 255 Ion flux calculation 131 131 See also Current Ion permeation and ion channel conductance 111–112 saturation effect 112 Ion transporters, mediate electrolyte movement across blood-brain barrier 1292–1293 Ionic conductance, and action potential 151 Ionic gradients, dissipation prevented by Na+ -K+ pump 131 Ionic membrane current 142 Ionic permeability, determination of in cell membrane 106–107 Ionotropic receptor 229 Ionotropic receptors 185 212 229 250 physiological actions differ from those of metabotropic receptors 240–250 Ions active pumping balances passive flux of Na+ and K+ ions 131 balance of fluxes for resting membrane potential is abolished by action potential 132 concentration and current in ion channels 112 concentration gradients 126 as batteries in electrical equivalent circuit 134 conductance across cell membranes by transporters 108 conducted across channels by receptors 108 conduction through ion channels enhanced during gating 114 contributions to resting membrane potential quantified by Goldman equation 132–134 distribution across cell membrane 128 neuronal cell membrane at rest 128 distribution on either side of cell membrane 126 flow through voltage-gated ion channels generates action potential 150–158 forces driving across cell membrane 128 flux through ion channels is passive 110–112 forces driving them across cell membrane 128 free energy of binding 109 interactions with water contribute to determination of ionic permeability properties of cell membrane 106–107 localization of charge and strength of electric field 108 membrane lipid bilayer impermeable to 108 permeability and conductance 135 of membrane to 135

rate of flow through channels 105 108 transfer across membranes 108 See also specific types; Channels, ion selectivity of ion channels for types of 110–112 size and mobility 108 transport across blood-brain barrier 1292 water shell surrounding 108 IP3, in sweet taste transduction 638–639 Ipsilateral propriospinal projection, motor cortex reflex circuit 765 Ipsilateral vestibulospinal projection, motor cortex reflex circuit 765 IPSP See Inhibitory postsynaptic potential Ischemia 900 1306 caused by diffuse hypoperfusion 1313–1314 Ishihara test, color blindness 584 584 Isocarboxazide, antidepressant, structure 1213 Isoforms 120 Isoniazide, effect on depression 1217 Isoprenylation post-translational chemical modification of protein 90 post-translational protein modification 92 Isthmus, organizing center for midbrain development 1034 1035 Ito, Maso 825 826–827 840 848 1243 Ivry, Richard 846

J Jackson, John Hughlings 7 349 363 388 397 666 759 910 Jacksonian march 759 911 920 epileptic attack 388 Jacobsen, Carlyle 356 993 Jahn, Reinhard 270 Jahnsen, Henrik 924 James, William 400 504 983–984 995 James-Lange theory, emotion 983–984 Jameson, Dorothea 579 Jasper, Herbert 344 911 Jet lag cause of delayed sleep phase syndrome 954 sleep-wake cycle with eastward versus westward 955 treatment with melatonin 943 P.1363 Joint capsule receptors 432 443 Joint torque, sequential activation of agonist and antagonist muscles 688 Joints degree of freedom 688 muscle force creates stiffness at 689–690 skeletal, actions of muscles at 687–688 types 687–688 Jones, Edward 1196 Jugular foramen 877 Julesz, Bela 502 561 566 Junctional fold 187 188 1089 Just noticeable difference 421

K K complexes, EEG activity during sleep 938 K+ See Potassium ions Kaas, Jon 496 Kainate, activates ionotropic glutamate receptors 212 Kainic acid, electrical stimulation of afferents to hippocampus 928 Kallman, Franz 1193 Kanizsa triangle 495 495 Kant, Immanuel 412 1317 Kappa receptors, opiates 484 Karlin, Arthur 197 199 Katz, Bernard 108 133 151 190 253 255 257 259 260 262 280 846 1193 1212 Keele, Steven 846 Kety, Seymour 1193 1212 KIFs, kinesin-related proteins, molecular motor in anterograde transport to axon 101–102 Kindling experimental model of hyperexcitability 931–932 synaptic plasticity associated with 932–933 Kinesin model for movement along microtubules 101 motor molecule for anterograde transport in axon 101 structure 101–102 Kinesthesia 443 Kinocilium 615 615 hair cells in vestibular labyrinth 803 Kinship, analysis of in genetic studies of behavior 40 Kiss-and-run release, neurotransmitter 270 Kleitman, Nathaniel 936 945 Klippel-Feil syndrome, M2 responses in 727 Klonopin See Benzodiazepines Kluver, Heinrich 988 Kluver-Bucy syndrome, pathophysiology 988 Knee jerk anatomical components 25 feed-forward inhibition in 26 monosynaptic reflex system 25 production of receptor potential in 28–29

stretch reflex circuit for 208 synaptic potential in 29 Knowledge category-specific, neural correlates 1236–1237 1236 division into categories and separate storage in the brain 16 episodic, and prefrontal cortex 1237–1239 explicit, encoding and recall, requires working memory 1238–1239 explicit, four types of processing 1237–1238 See also Memory semantic acquisition 1234–1235 storage in neocortex 1233–1237 Koch, Christof 401 1318 Koffka, Kurt 493 Kohler, Wolfgang 493 Konorski, Jerzy 34 Kordorka, Ron 42 Kraepelin, Emil 1189 Krebs, Edward 234 Kunkel, Louis 706 Kuypers, Hans 668

L L cones 576 577 L-Dihydroxyphenylalanine blood-brain barrier to 1293 and half-center hypothesis 742 reversal of Parkinsonian symptoms 862 L-dopa See L-Dihydroxyphenylalanine L-glutamate cause of neuronal damage during seizure 928 neurotransmitter in pyramidal cells of cerebral cortex 85 Labeled line code 414 encodes stimulus modality 414–416 Laborit, Henri 1197 Lactate dehydrogenase, diagnosis of myopathic disease 699 Lambert-Eaton syndrome, disorder of neuromuscular transmission 307–308 Lamellipodia, axonal growth cone 1071 Laminae dorsal horn of spinal cord 475–477 gray matter of spinal cord 447 Laminin-11, as retrograde synaptic organizer 1100 Laminins in extracellular matrix, interaction with integrins on axon growth cone 1074 1075 major component of basal lamina 1098 organizer of presynaptic specialization 1100 Land, Edwin 587 Landott, Edwin 783 Lange, Carl 984 Langley, J.N. 1063 Langley, John 6 184 966 Langston, William 862 Language 1169–1170 activity in cerebrocerebellum 846 affective aspects localized in right hemisphere of cerebral cortex 14–15 aphasias 1169–1187 articulatory loop for in working memory 1239 dissociation from general intelligence 1172 disturbance after middle cerebral artery infarction 1307–1308 after occlusion of recurrent artery of Heubner or branches of anterior cerebral artery 1309 emotional prosody, role of right cerebral hemisphere 1182 evolution by Darwinian selection 1173–1174 experimental confirmation of areas of in cerebral cortex 12–13 human, homologs of not in other animals 1173–1174 identification of brain areas through study of aphasias 1174–1181 in split-brain patients 1182 independence from vision 364–365 innate capacity for learning 1172–1173 neural basis of brain localization studies 13 history 10–13 other brain areas important beyond classical language areas 1181–1182 PET identification of regions of cerebral cortex involved in processing 14 imaging to study 379 pragmatics, role of right cerebral hemisphere 1182 processed, by large network of interacting brain areas 1175 processing parallel and serial nature of 13 in primary auditory cortex 609 role of cerebellum 322 See also Communication systems; Grammar; Reading; Words spontaneous development in children 1171–1172 tests, brain areas of significant change in activity during 1184 theory of innate neural circuitry for acquisition 1172 in relation to brain functon 11 P.1364 universal design 1170–1174 versus reading and writing 1170 Wernicke-Geschwind model 1175 Lashley, Karl 11–12

Latency 178 Lateral 321 Lateral brain stem pathway, major tracts 668 Lateral column 346 Lateral columns spinal cord 338 white matter of spinal cord 338 Lateral corticospinal tract 346 347 pathway 670 Lateral descending systems, role in goal-directed movements 663 Lateral dorsal premotor area 760 learning to associate sensory event with specific movement 777 Lateral geniculate nucleus 324 333 circular receptive fields of cells of 545 concentric cells, receptive fields 535 effect of lesions in parvocellular and magnocellular layers 531 effects of lesions in 530 530 inputs to in visual processing 529 optic radiation to 543 543 organizational complexity 334 P cells groups according to color 583 pathways to cortex 523 projection of optic nerve to 517 retina to 523 retinal projections to 527 retinotopic map in 545 segregation of afferent fibers after birth 1119 segregation of retinal axon terminals in 1124 structure 529 termination of retinal axons 528–529 thalamus 343 343 visual system 496 Lateral inferior pontine syndrome, brain stem vascular lesion 1310 Lateral inhibition 463 Lateral intermediate zone 346 Lateral lemniscus, auditory pathway 607–608 Lateral medullary syndrome, brain stem areas affected 886 vascular lesion 1310 Lateral motor nuclei 346 Lateral nuclear group, thalamus, relay nociceptive information to cerebral cortex 480–81 Lateral nucleus, vestibular 812 Lateral olfactory tract, olfactory information processing 633 Lateral orbitofrontal circuit, basal ganglia, role in mediating empathetic and socially appropriate responses 866 Lateral premotor areas movements triggered by external sensory events 770 selection of action 774–777 sensorimotor transformations 774–777 Lateral preoptic nucleus 976 Lateral reticular formation 885 Lateral skin temperature test 485 Lateral sulcus 324 368 369 of cerebral cortex 325 Lateral superior olive auditory pathway 606 localization of sound sources 607 Lateral superior pontine syndrome, brain stem vascular lesion 1310 Lateral tubular nucleus 976 Lateral ventral premotor area 760 Lateral ventrical 368 Lateral-dorsal tegmental nucleus, control of sleep 941 Lateral superior olive, tonotopic organization 607 Laterodorsal tegmental nucleus, cholinergic cell groups in 894 Laws of correlation 400 Lazarus syndrome 900 LDH See Lactate dehydrogenase Le Douarin, Nicole 1048 Lead intoxication, chronic neuropathy 702 Leakage conductance 153 Leakage current 153 Learning 1227–1246 1227 adaptive, vestibulo-ocular reflex, memory of in brain stem 828 appropriate anticipatory responses to postural disturbances 820 820 associative, and biology of organsim 1242–1243 cellular mechanisms 1247–1279 and changes in synaptic strength 1250 classical conditioning 1240–1242 consolidation of long-term implicit memory, processes of 1256–1257 effect of strychnine on 1245 emotional response 995 explicit and implicit memory involved 1243–1244 implicit 672 nonassociative and associative 1240 improves accuracy of reaching 666 innate capacity regarding language 1172–1173 molecular alphabet for 1272–1274 motor long-term effect of climbing fiber on mossy fiber transmission of signals 841 role of cerebellum 848–849 850 premotor-cerebello-rubrocerebellar loop 846

in vestibulo-ocular control 824–828 neuronal changes associated with, insight into psychiatric disorders 1275–1277 and prediction of events in environment 1240–1242 procedural, role of anterior cingulate circuit of basal ganglia 866 refines motor programs 672 role of NMDA receptor 213 sequences of movements, supplementary and presupplementary motor areas 771–774 somatotopic map produced by as biological expression of individuality 1274–1275 steps of storing knowledge 1231–1232 LeDoux, Joseph 985 Lee, C.-Y. 300 Left hemisphere category-specific knowledge 1236 convexity damage, after middle cerebral artery infarction 1308 language depends principally on 1174–1175 removal, effect on language in infant versus adult 1182 Left inferotemporal cortex, language 1174 Left midtemporal sector, damage causes difficulty recalling unique and common names 1182 Left posterior inferotemporal sector, damage affects recall of words for items 1182 Left prefrontal cortex language 1174 reduced blood flow in schizophrenia 1196 Left superior oblique muscle, eye, symptoms of deficit 789 Left superior temporal gyrus, damage to in conduction aphasia 1180 Left temporal cortices, damage causes naming defects 1182 Left temporal lobe damage in Wernicke aphasia 1179–1180 damages causes difficulty in recalling unique names 1182 language 1174 Leg movements, periodic, methods for documenting 949 Lemon, Roger 769 Length constant, passive membrane property of neuron 222–223 Lens chromatic aberration 580–581 eye 508 Lenticulostriate arteries effects of occlusion 1309 white matter and diencephalic structures 1304 Leptin control of body fat 1005–1006 effect on food intake 1004 gene, mutations in affect feeding behavior in mice 47 protein encoded by obese gene 47 P.1365 Lesions brain, and increased intracranial pressure 1298 somatic sensory cortex, produce sensory deficits 468–469 spinal cord, sensory and motor signs 732–734 Lethargic 901 Letter memory test, brain areas of significant change in activity during 1184 Letters, embossed, detailed representations by cortical neurons 464 465 See also Braille dots Leucine-enkephalin amino acid sequence 487 neuroactive peptide 289 Leukemia inhibitory factor (LIF) induction of switch from noradrenergic to cholinergic neurotransmitter phenotype 1051–1052 neurotrophic receptor 1057 Leukotrienes and nociceptor sensitizaton 477–478 sensitization of nociceptors 480 Levi-Montalcini, Rita 1054 1055 1056 1057 Lewis, Ed 1032 Lexical processing 13 LHRH See Luteinizing hormone release hormone Lichtman, Jeff 1101 LIF See Leukemia inhibitory factor Ligand-gated channel See Ion channels, ligand-gated Light absorption by visual pigments in photoreceptors 510 adaptation to and calcium role 514 effect on cone photopigments 573–574 membrane potential in rods and cones 509 See also Pupillary reflexes; Vision slow adaptation of photoreceptors to changes in intensity 515–517 source, visual perception 496 497 wavelengths and color 572 Limb amputation, and use of anesthesia 479 Limb kinetic apraxia 355 Limb muscles, M2 response 727 Limb-girdle muscle dystrophies classification of 709 inherited myopathic disease 701 704 705 mutations of sarcoglycan genes in 707–708 Limb-position sense 443 Limbic association area cerebral cortex 350 function 352 Limbic circuit, basal ganglia, links thalamus and cerebral cortex 858 Limbic dopaminergic neurons, and behavioral activation 1009–1010 Limbic lobe 325 cortical representation of feeling 986–988

Limbic system beta-adrenergic mechanisms and storage of emotional events in mice 992–993 components 987 developing forebrain 1036 interconnections of deep-lying structures 987 See also Amygdala Limbic thalamo-cortical system, vulnerable in Alzheimer disease 1153 Limbs motor control and sensation mediated by spinal cord 320 somatosensory information conveyed from by dorsal root ganglion neurons 431 from carried to spinal cord 338–340 Lindstrom, Jon 300 Linear perspective depth perception 558 monocular depth cue 559 Linguistics, focus on cognition 313 Linkage analysis genetic mapping strategy 56 See Genetic linkage analysis sensitivity to model of transmission, 57–58 Lipid bilayers artificial characterization of current in gramicidin A channel 110 study of ion channels 109 planar, use in patch-clamp recording 111 Lipid solubility, and brain uptake of drugs 1291 Lipid-soluble substances, and blood-brain barrier 1289–1290 Lisberger, Stephen 826–827 Lithium salts mechanism of action 1220 1220 treatment, bipolar mood disorder 1216 Livingstone, David 489 Livingstone, Margaret 550 Llinas, Rodolfo 255 840 924 Lobes, cerebellar 322 Lobotomy 993 Local interneurons 329 335 afferent connections within spinal cord 667 functional regions 28 organization in spinal cord 667 Local sign 654 Location, stimulus attribute conveyed by sensory systems 412 413 413 Locke, John 6 411 493 1240 1317 Locked-in syndrome bilateral lesions of corticospinal tract 1313 result of injury to lower brain stem 900 Locomotion 737–755 adaptive postural control learned during 821 descending signals initiating transmitted via reticulospinal pathway 751–752 initiation via descending glutaminergic pathways 752 pattern generator, hypothetical 746 and posture, adaptability 822 See also Stepping stereotyped action 737 Locomotor pattern, fine-tuning by cerebellum 753 Locomotor responses, electrical stimulation of mesencephalic locomotor region 751 Locus ceruleus abnormalities in Alzheimer disease 1153 in ascending arousal system 900 brain stem nucleus, functions 871 control of sleep 941 inhibitory descending pathway, pain 486 location and function 891 891 895–896 noradrenergic neurons in 891 891 895–896 noradrenergic pathways originating in 1215 1216 ventral, lesions of in cats and dream enactment 956 Locus coeruleus See Locus ceruleus Lod score 56 Loewi, Otto 175 280 966 967 Lomo, Terje 1259 Long-loop reflexes 727–728 728 Long-loop responses 767 Long-term depression (LTD) induction by climbing fibers 840 synpatic transmission, cGMP cascade role in 240 Long-term potentiation (LTP) 275 associative in Schaffer collateral and perforant pathways 1260 and spatial memory 1267 1272 defect in and lack of NMDA receptor in hipppocampus 1270–1271 1272 enhanced release of glutamate 1262 fine-tunes properties of place cells 1267 genetic interference with 1264 hippocampal, and explicit memory 1259–1272 increase of neurotransmitter vesicles and receptors in 1264 model for early and late phases 1265 induction 1260–1261 P.1366 mossy fiber pathway of hippocampus 1258 new protein synthesis during late phase 1262–1264 nonassociative in mossy fiber pathway 1260 phases of 1262–1264 1263 reversal of deficit of in hippocampus 1273 See also Calcium influx Longevity, human, trends from ancient times to present 1150 Longitudinal fasciculus, left medial, vestibulo-ocular reflex 811 Lorazepam See Benzodiazepines

treatment, prolonged repetitive seizures 919 Lorente de No, Raphael 329 Lorenz, Konrad 1128 Lou Gehrig disease See Amyotrophic lateral sclerosis Lower motor neurons 696 symptoms of disorders of 696 LTD See Long-term depression LTP See Long-term potentiation Luciani, Luigi 849 Lumbar puncture, measurement of cerebrospinal fluid pressure 1298 Lumbar region, spinal cord 338–340 339 Luminance contrast 531 response of P and M cells 530 Luria, A.R. 402 Luria, Aleksander 351 Luteinizing hormone, neuroactive peptide 289 Luteinizing hormone release hormone, sex difference in control of release 1135 Luxury perfusion 1316 Lysosomes, role in protein synthesis 91 93

M M cells attributes 581 chromatic properties 579 and image movement 580 retinal ganglion cells 501 520 projections 545 sensitivity to stimuli, compared with P cells 530 M cones 576 577 M current anti-accommodation effect of inhibition 242 effect of muscarine on 242 M ganglion cells, projection to magnocellular layers of lateral geniculate nucleus 529 M pathway function 545 projections 567–568 visual system 501 505 functions mediated by 502 M-type K+ channel See Ion channels, M-type K+ M-wave, Hoffmann reflex 731 M1 response, reflex 727 M2 response, reflex 727 Machado-Joseph disease, type of trinucleotide repeats involved in 56 MacKinnon, Rod 12 MacLean, Paul 987 988 Macroglia, types 20 Macrophage infiltration, after axotomy 1109 Macula, utricle and saccule 804 Maffei, Lamberto 1123 MAG See Myelin-associated glycoprotein Magnesium ions, as blocking molecules in ion channels 112 Magnesium, blocks current flow in NMDA-activated channels 212 Magnetic resonance 371 Magnetic resonance imaging 13 336 anatomical mapping of seizure foci 925 different time constants used for contrast 372 functional, physical bases 374–375 functional imaging of brain 366 functional study of visual cortex 374 image of major regions of central nervous system 367 physical basis of technique 366 scan of horizontal section of cerebral hemisphere and diencephalon 368 scan through coronal section of cerebral hemisphere and diencephalon 369 See also Functional magnetic resonance imaging signal produced 370–371 technique 370 three-dimensional coding of signal 373 Magnetoencephalography imaging of somatotopic functioning of cortex 458–459 use of to construct functional maps 389 390 Magnification factor 529 Magnocellular layers, lateral geniculate nucleus 529 Magnocellular neurons, hypothalamus, secrete oxytocin and vasopressin 979 Magnocellular pathway 548 continues in dorsal (parietal) pathway 549 550 projections 549–552 selective inactivation in lateral geniculate nucleus 551 to visual cortex 529–532 visual system, slower conduction in people with dyslexia 1185 Magnus, Rudolf 817 Magoun, Horace 936 939 Major affective disorder, genetic component 58 Major histocompatibility complex, class II antigen, association with narcolepsy 950 role in myasthenia gravis 304 Malleus 591 591 595 Maloney, Lawrence 577 Mammals, phylogenetic variations in sleep 944 Mammillary body 788 987 Mammillothalamic tract 987 Mandibular division, trigenimal nerve 878 Mangold, Hilde 1023

Mania 1209–1226 Manic-depressive disorder as multigenic disease 55 See also Bipolar mood disorder Manic-depressive psychosis 1192 MAP See Microtubule-associated proteins MAP-1C, motor molecule for retrograde fast transfer 103 MAPK See Mitogen-activated kinase Maps See Cognitive map; Master map; Neural maps; Somatotopic map; Tonotopic map Marr, David 505 827 848 Marshall, Wade 12 385 496 Mash-1 protein, and development of neuronal identity 1048–1049 Mass action theory, brain function 12 Master map image 567 visual information 504 Materialism, view of consciousness 1318 Mathematical reasoning, sex differences 1142 Mauthner's cell, depolarized by electrical synapses in goldfish tail-flip response 180 Maxillary division, trigeminal nerve 878 Maximal tetanic contraction 681 Mayford, Mark 1266 McCarthy, Rosaleen 1237 McCormick, David 924 McGaugh, James 992 McGinn, Colin 397 1318 McHugh, Thomas 1267 McLeod syndrome 706 Mechanical nociceptors 416 443 473–44 Mechanoelectrical transduction adaptation in hair cells 619–620 620 hair cells 617–619 Mechanoreceptors depolarization 415 glabrous skin, size and structure of receptive fields 434 hairy skin 434–435 muscle and skeletal, types 432 pseudo-unipolar neurons in 24 P.1367 rapidly adapting, stimulus response over time 424 skeletal muscle and joint capsules, mediate proprioception 443 skin density of and spatial resolution of stimuli 436 different adaptation properties 438 different receptive fields 436–437 different sensory thresholds 438 firing patterns encode texture of objects 440 mediate touch 432–1 populations of signal spatial characteristics of objects 438–1 structure and location 432–435 433 types 432 vibration sense coded by spike trains in 437 slowly adapting, stimulus response over time 424 threshold sensitivity to vibration 437 Mechanosensory receptors, in viscera 443–444 Medial brain stem pathway, major tracts 668 Medial corticospinal tract 347 Medial descending systems, control of posture 663 Medial dorsal nucleus of thalamus 987 Medial forebrain bundle 987 hypothalamus 977 Medial geniculate body multimodal nature 608 thalamic relay of auditory system 608 Medial geniculate nucleus auditory pathway 604 thalamus 343 343 Medial inferior pontine syndrome, brain stem vascular lesion 1310 Medial lemniscus 342 ascending somatosensory pathway 448 major afferent pathway for somatosensory information 342 pathway of sensory information 446 Medial longitudinal fasciculus 788 lesion, ocular reflexes characteristic 907 lesions 792 motor circuit for horizontal saccades 791 Medial medullary syndrome, brain stem vascular lesion 1310 Medial motor area, blood flow in during finger movements 773 Medial nuclear group, thalamus, relay nociceptive information to cerebral cortex 480–481 Medial nuclei 343 Medial premotor area, blood flow in during finger movements 773 Medial preoptic nucleus 976 Medial rectus motor neurons, motor circuit for horizontal saccades 791 Medial reticular formation 669 751 885 Medial skin temperature test 485 Medial superior olive auditory pathway 606 temporal discrimination of sound 607 Medial superior pontine syndrome, brain stem vascular lesion 1310 Medial superior temporal area lesions produce deficits in smooth-pursuit eye movement in monkey 556 monkey, lesions in produce deficits in pursuing a target moving to the right 556 processing of optic flow 553 Medial temporal lobe, abnormalities in Alzheimer disease 1152

in cortex of in schizophrenia 1195 Medial vestibular nucleus convergence of visual and vestibularm signals on neuron in 813 motor circuit for horizontal saccades 791 neural integration of velocity signal in saccade 790 Medial 321 Median eminence 976 Mediational system, language 1174 1175 Medium spiny projection neurons, striatum, GABA-ergic 856 Medulla 9 320 324 367 anatomy 1310 blood supply to 1310 brain stem, blood supply to 886 distinct terminal patterns in by afferents carrying somatic sensory information 447–449 inhibits midbrain reticular formation 939 noradrenergic cell groups in 890–891 890 part of brain stem 320 regulation of blood pressure and respiration 320–321 respiratory center, and obstructive sleep apnea syndrome 953 vascular lesion syndromes of 1310 Medullar oblongata cranial nerve nuclei at level of 884 function 7 8 8 Medullary pyramid 671 Medullary pyramidal tracts, sectioning of produces contralateral weakness 763 MEG See Magnetoencephalography Meiosis 38 pupillary 788 Meissner's corpuscle 432 433 433 434 436 input to each region of somatic sensory cortex 459 resolution 440 sensitivity 438 surface of object 452 threshold sensitivity to vibration 437 Meissner's plexus See Submucous plexus Meister, Marcus 1123 Melancholic depression 1210 Melanin, in pigment epithelium of eye 508 Melanin concentrating hormone, in ascending arousal system 900 Melanocyte, develops from neural crest cells 1047 Melanocyte-stimulating hormone release-inhibiting factor 980 Melanocyte-stimulating hormone-releasing factor, hypothalamic 980 Melatonin, hypnogenic effects 943 Membrane capacitance 142–143 conductance 135 insulation, effect on conducting properties 144–145 resistance 141 See also Cell membrane total amount is constant in cell 269 Membrane anchor, on proteins for outer leaflet of plasmalemma 96 Membrane capacitance, as passive electrical property of neuron 140 Membrane conductance calculation from voltage-clamp data 155 and flux of ion across cell membrane 131 Membrane depolarization See Depolarization Membrane glycoprotein, forms nicotinic ACh receptor 197 Membrane potential (Vm) 125–139 126 analysis of changes in by Goldman equation 133 change in capacitive and resistive elements 143 during action potential 105 mediated by ion channels 105 produced by sensory stimulus transformed into digital pulse code 421 and refractory state of voltage-gated ion channels 115 rods and cones 510–511 as signaling mechanism in excitable cells 28 at synaptic terminal affects intracellular calcium 274 controlling with voltage clamp technique 152 depolarization 131 during light adaptation in cones 515 effect of membrane capacitance on 143 effect on end-plate potential, total end-plate current, and ACh-gated single-channel current 198 ion channel gating 114 P.1368 equal to voltage 143 generation of changes in response to stimuli 105 graded changes in rods and cones responding to light 509 magnitude of passive changes determined by input resistance 140–142 method of recoding 127 127 nature of 29 photoreceptor during darkness 513 positive feedback cycle 151 rate of change slowed by membrane capacitance 143 relationship to current injected into nerve cell 141 resting, calculation using equivalent circuit model 136–137 136 resting See Resting membrane potential separation of charges across cell membrane 126 Membrane proteins integral, ion channel component 116 See also Bacteriorhodopsin; Membrane-spanning proteins; Transporter Membrane recovery See Synaptic vesicles, recycling

Membrane resistance 144 decrease in after opening of M-type channels 243 Membrane time constant 143 Membrane-soluble molecules, as neurotransmitters 295 Membrane-spanning proteins as transporter molecules 295 odorant receptors 628 pheromone receptors 634 secondary structure 117 See also Rhodopsin Membranes artificial, study of ion channels 109 pre- and postsynaptic, study with freeze-fracture technique 263 synaptic, exocytosis 264 Membranous labyrinth 802 Memory 1227–1246 1227 adaptive learning in vestibulo-ocular reflex 828 animals studies used 1231–1232 cellular, residual calcium 275 and changes in strength at synaptic connections 1254 disturbed, diffuse hypoperfusion 1313 effect of lesions to right posterior parietal cortex 398–399 emotional state 995 episodic, encoding and retrieval, brain areas involved 1238 explicit 1228–1233 1245 as constructive process 1239 episodic or semantic nature 1231 lesions affecting 1231 and long-term potentiation in the hippocampus 1259–1272 storage of impaired by damage to specific subregions of hippocampus 1233 stored in association cortices 1233–1239 transformation 1239 explicit and implicit distinction between 1230–1231 1231 involved in some learned behaviors 1243–1244 stages in storage 1244–1245 for fear 990–991 fields, in neurons of principal sulcus 359 formation, limbic association area 352 impairment in Alzheimer disease 1154 implicit 1228–1233 1245 construction of 1239 long-term storage for sensitization and classical conditioning involves cAMP-PKA-CREB pathway 1254–1259 role of cerebellum and amygdala in 1243 short-term storage, changes in effectiveness of synaptic transmission 1248–1254 storage for classical conditioning, cAMP-PKA-CREB pathway 1257–1259 stored in perceptual and reflex pathways 1239–1243 influenced by modulatory systems in brain 333–334 long-term information from working memory systems 1239 new protein synthesis in Aplysia, Drosophila 1250–1259 role of synaptically induced activation of gene expression in storage of 251 storage in hippocampus 331 molecular mechanisms of storage conserved throughout evolution 1247 parallel processing in 1245 processing, and cocaine craving 1008 recent, easily disrupted 1245 role of anterior nuclei of thalamus 342 cerebral hemispheres 322 hippocampus 1234 medial nuclei of thalamus 342 NMDA receptor 213 See also Hippocampus: Knowledge; Long-term potentiation; Working Memory semantic 1233 short-term role of protein kinase A in Drosophila 1258 working memory 1238–1239 working, prefrontal association area 356 357 spatial and associative long-term potentiation 1267 1272 defect in and lack of NMDA receptor in hippocampus 1270–1271 and NMDA-mediated synaptic plasticity in Schaffer collateral pathway 1272 stages of 1245 storage associative, similar molecular mechanisms in implicit and explicit learning 1272 1274 explicit and implicit 986 role of hippocampus 323 verbal and nonverbal, controlled through central executive function 360 working component systems 1239 encoding and recall of explicit knowledge 1238–1239 See also Working memory Mendel, Gregor 38–40 Mendell, Lorne 721 Meniere disease, receptor cells of vestibular labyrinth 807–808 Mental activity, interconnected networks of neurons involved 313 Mental acts, study of neural representations 382–383 Mental disease definition 1189 diagnosis using classical medical criteria 1188–1189 Mental disorders functional 1275 genetic component of, alteration in gene expression 1276 1277 heritability 1277

organic 1275 See Mental illness Mental health, effects of sleep 944 Mental illness classification in psychiatry 1189 See Mental disease Mental operations, role of cerebellum 850 Mental processes division into subfunctions 16 elementary processing operations in the brain 16 Mental retardation See also specific types X-linked, and impulsive behavior 50 Mergner, Thomas 829 Merkel cell receptor, input to each region of somatic sensory cortex 459 P.1369 Merkel disc receptors 432 433 433 434 436 encode size and shape of objects 439 resolution 440 sensitivity 438 shape of object 452 threshold sensitivity to vibration 437 Merritt, Houston 911 Merzenich, Michael 388 Mesaxon 85 Mesencepahlon, development 1021 1022 Mesencephalic locomotor region, locomotor responses to electrical stimulation of 751 Mesencephalic nucleus sound source location 608 trigeminal nerve, control of sleep 941 Mesencephalic reticular formation 788 generation of vertical saccades 792 Mesencephalic trigeminal nucleus 881 location and function 882 Mesencephalon 1021 1022 1022 Mesenteric ganglia 963 Mesocortical system, dopaminergic pathway 1202–1203 1203 Mesocortical tracts 283 Mesoderm 1021 formation of neural tube 1020 Mesolimbic dopaminergic pathways, recruitment by drugs of abuse 1009–1012 Mesolimbic system, dopaminergic pathway 1201–1203 1203 Mesolimbic tracts 283 Mesopontine tegmentum, cholinergic cell groups in 894 894 Messenger RNA generated from precursor RNA 89 translation 90–91 transport along dendrites of motor neuron 77 Metabolic encephalopathy, ocular reflexes characteristic 907 Metabolic energy, conservation during sleep 944 Metabolic mapping, study of seizures with 927 Metabolic signals, transmission between cells by electrical synapses 180 Metabolism, use of PET for imaging 375 Metabotropic glutamate receptor, transduction of umami taste 642 Metabotropic receptors 185 212 229 activation of and presynaptic inhibition 275 second-messenger pathways 230–240 physiological actions differ from those of metabotropic receptors 240–250 synaptic actions can increase and decrease channel opening 240 Metarhodopsin II, during phototransduction 512 Metencephalon, development 1021 1022 Methionine-enkephalin, amino acid sequence 487 neuroactive peptide 289 Methylphenidate, treatment, narcolepsy 951 1-Methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine, causes Parkinsonian state 862 3, 4-Methylene-dioxymethamphetamine, depletes vesicles of amine transmitter 286 Methylprednisolone, treatment, spinal cord trauma 1111 Meyer's loop 543 543 Mice See Mouse Microaneurysms, rupture of and intraparenchymal stroke 1315 Microelectrodes, extracellular 454 Microfilaments, in neuron cytoskeleton 74 Microga infiltration, after axotomy 1109 phagocytic nature 20 Microneurography, recording technique 729 Microtubule neuron 71 sliding, mechanism in slow axonal transport 103 Microtubule-associated proteins, polymerization and assembly of microtubules 72 Microtubules model for kinesin movement along 101 in neuron cytoskeleton 72 role in anterograde transport to axon 101 retrograde fast transport 103 tracks for molecular motors in, cell 75 Micturition, spinal reflex control 968 Midbrain 8 9 320 347 367 bilateral lesion, ocular reflexes characteristic 907 cholinergic neurons in 896 dopaminergic cell groups in 892–893

function 7 8 8 322 gaze centers, lesions 792 and infarction of posterior cerebral artery 1308 junction with pons, location of nuclei that regulate REM sleep 940–943 location 671 organizes vergence 796 part of brain stem 320 patterning by signals from neural organizing center 1034–1035 retinal projections to 527 See also Mesencephalon; Pretectum; Superior colliculus Middle cerebellar peduncle 833 Middle cerebral artery 1303 cortex and white matter 1304 infarction, types and symptoms 1306–1308 PET scan of infarction 1305 role of anastomses in retrograde refilling after occlusion 1307 Middle cervical ganglion 964 neuropeptides in 972 Middle ear cavity 591 functional parts 591–592 Middle temporal area aperture problem 553–556 lesions of selectively impair motion 556–558 monkey alteration of perceived direction of motion by stimulation of neurons 558 lesions in produce deficits in motion perception 556 motion processing 553 sensitivity of neurons to motion of entire object 555 response of cells to moving plaid pattern 554 Middle temporal gyrus, damage in Wernicke aphasia 1179 Middleton, Frank 1190 Midline raphe nuclei, brain stem, location of serotonergic neurons 283 MIH See Mullerian duct inhibiting hormone Miledi, Ricardo 108 253 255 259 300 Miles, Frederick 826–827 Miller, Christopher 111 Miller, George 382 Milner, Brenda 1229 1230 Milner, Peter 1009 Mind dualistic view 396 early studies of 382–383 See also Brain understanding 3 Miniature end-plate potentials 257 abnormally low amplitude in slow-channel syndrome 307 amount of ACh needed for 259 prolonged in congenital myasthenia gravis 306 Miniature synaptic potentials 277 Mirror neurons, discharge during grasping movements and during observing grasping movements 778 Mishkin, Mortimer 500 1231 Mitochondria 188 anterograde transport to axon 101 contain circular DNA for transfer and ribosomal RNAs for synthesis of mitochondrial proteins 89 importation of proteins synthesized in cytosol 93–94 modification of proteins after import 93 muscle fiber 677 neuron 70 P.1370 retrograde transport to cell body 102 role in protein synthesis 91 Mitogen-activated kinase in long-term facilitation 1254–1255 in long-term sensitization 1256 Mitosis 38 Mitral cells, olfactory bulb 630 631 MK801, inhibits NMDA receptor-channel 213 MLR See Mesencephalic locomotor region Modalities, and columns in cerebral cortex 456–457 Modality, stimulus attribute conveyed by sensory systems 412 413 413 Modality, stimulus See Stimulus modality Modiolus cochlea 592 inner ear 592 Modulation antagonistic 248 in cell body 241 postsynaptic 241 presynaptic 241 sites of 241 Modulatory synaptic actions 240 types 240–241 Modulatory systems, brain 333–334 Modules, in neocortex 325 Molecular disease concept 867 Molecular layer, neurons in cerebral cortex 326 327 Molecular mimicry 303 Molecular motors in axon growth cone filopodia 1071 1073 drive organelles within cytoplasm 103 in neuron 75

role in anterograde transport to axon 101–102 Molecular sieving, and ion channel selectivity 108 109 Molecule motors See also MAP-1C Moment arm, joint 688 Moniz, Egas 993 Monoamine oxidase inhibitors antidepressant, structure 1213 1214 block degradation of amine transmitters in synaptic cleft 294 effect on serotonergic and noradrenergic neurons 1218–1219 treatment cataplexy 951 panic attacks 1221 Monoamine system, vulnerable in Alzheimer disease 1153 Monoaminergic cell groups, ascending projections from brain stem and hypothalamus, increase wakefulness and vigilance 896–897 Monoaminergic nuclei, brain stem, abnormalities in Alzheimer disease 1153 Monoaminergic pathways, raphe magnus nucleus to spinal cord, inhibit transmission of nociceptive information 896 Monoaminergic projections, descending, modulation of pain 896 Monocular cues for far-field depth perception 558 559 information on relative distance of objects 559 Monocular zone 525 visual field 524 Monofilament, neuron 71 Monosodium glutamate, umami taste stimulus 642 Monosynaptic circuits 26 Monosynaptic pathway 717 Montage, electrode 916 Mood 1209 disorders 1209–1226 abnormality in biogenic amine transmission in 1216–1220 genetic component 1211–1212 unipolar or bipolar 1209–1211 states, role of serotonin 50 role of basal ganglia 866 Morgan, Thomas Hunt 38 Morphemes 1177 Morphine activation of opioid receptors to control pain 486–489 analgesia 483 minimization of side effects 487 spinal administration 487–498 Morphogen 1027 Morphology, grammar 1170 Morris maze See Water maze Morris, Richard 1272 Moruzzi, Guiseppi 936 939 Mossy fiber pathway direct and indirect, bring somatosensory information to spinocerebellum 841–842 hippocampus 1257 1259 long-term potentiation of 1258 long-term potentiation in is nonassociative 1260 Mossy fiber system, compared with climbing and parallel fiber systems 838 Mossy fibers cerebellar afferent input 835–839 836 837 encoding of peripheral and descending information 839–840 reorganization in epileptic temporal lobe 933 Motilin, neuroactive peptide 289 Motion actual versus apparent 551 agnosia 499 analyzed in dorsal pathway leading to parietal cortex 522–558 areas of brain activated by 552 direction of, alteration of perception by stimulation of neurons of monkey middle temporal area 558 direction of, detection by cortical neurons 464–65 illusion of 551 illusory 829 parallax, depth perception 558 perception 548–571 altered by lesions and microstimulation of middle temporal area 556–558 deficits produced by damage to human extrastriate visual cortex 556 monkey middle temporal area 556 of in visual field 551 processing in cerebral cortex 497–500 at junction of temporal, parietal, and occipital cortices in humans 553 in monkey middle temporal area 553 sensitivity of cells to in middle temporal area of monkey 555 Motivation disrupted by deletion of gene that encodes enzyme important for dopamine 50–51 influenced by modulatory systems in brain 333–334 response to internal stimuli 998 Motivational states 998–1013 factors regulating 1007–1009 modeled as servo-control systems 1000 and neuronal responses in S-II 468 types 998–999 Motor act, neural representation 383 Motor action, anticipatory learning of to postural disturbances 820 postural control 830

precedes postural readjustment 817–818 818 819 Motor areas cerebral cortex, somatotopic organization 757 functional organization 778 Motor axon controls aspects of postsynaptic differentiation 1098 pathway to skeletal muscles 1069 1070 Motor cells, survival control by change in size or activity of muscle target 1054 1055 Motor circuit horizontal saccades 791 See also Basal ganglia-thalamocortical motor circuit; Oculomotor circuit; Skeletomotor circuit P.1371 Motor commands hierarchical organization 672 parallel processing 662 Motor control, role of ventral nuclei of thalamus 342 Motor cortex 345 347 cell activity according to nature of sequence of movements 774 columnar arrays of neurons in 778 control of precise stepping movements in visually guided movement 752–753 cortical and subcortical inputs 671 different areas activated during finger movements 773 encodes direction of movement 769 inputs from cerebellum via the thalamus 761 language 1174 monkey concentric organization 759 major inputs 760 mosaic arrangement of muscle and joint representations in 778 neuron activity and stepping movements, visual system inputs 752 pathway of descending signals from and stepping 750 plasticity of somatotopic organization 761 projections from cerebellar hemisphere 842 reciprocal nature of connections 761 reflex circuit 765 See also Premotor cortex; Primary motor cortex; Supplementary motor area stimulation in awake humans 758 Motor cortical cells code force needed to maintain a reaching trajectory 770 firing rate, direct relationship to muscle force generation 768 Motor disturbances, in diseases affecting basal ganglia 853 Motor equivalence 657 659 Motor function basal ganglia 853 integration with sensory function 349–380 role of cerebral hemispheres 322 midbrain 8 Motor hierarchy, features of 672 Motor information, integration by thalamus 322 Motor learning 672 role of cerebellum 848–849 850 in vestibulo-ocular control 824–828 Motor maps 758 Motor molecule See Kinesin Motor nerve organizes differentiation of postsynaptic muscle membrane 1091–1098 terminals differentiation organized by muscle fiber 1098–1100 use electrical and chemical signals to influence postsynaptic apparatus of muscle fiber 1112 Motor neurons 693 activation by central pattern generators 744 afferent connections with, in spinal cord 667 agonist and antagonist, in motor cortex reflex circuit 765 alpha, direct connections of Ia fibers on in stretch reflex 717 autonomic nervous system 962–963 brain stem and spinal cord, action modulated by cerebral cortex 669–671 connections to Renshaw cells form negative feedback system 721 with sensory neurons in spinal cord 74 conveys central motor commands to muscle fiber 77–78 676 decision to initiate action potential 222 dendritic trees 77 determination of conduction velocity 703 direct corticospinal control and fine control of fingers 764 diseases 696 acute or chronic 700–701 attacking 33 fasciculation and fibrillation in 701 end-plate connection with muscle fiber 676 excitation of muscle by opening end-plate ion channels 190 excitatory postsynaptic potential in 209 enteric 964 extensor, excitatory pathways of information to from extensor sensory fibers 748 functional regions 28 Ia sensory fiber response to selective activation of 719 inhibition pathways 722 integration of many EPSPs to initiate action potential 209 inputs from axons descending from higher centers 663 interactions with skeletal muscles organizes development of neuromuscular junction 1089–1091 1089 lower versus upper 696 non-NMDA and NMDA receptors 212 and nuclei, in gray matter of ventral horn of spinal cord 338 number of presynaptic endings on 222

recurrent excitatory and inhibitory inputs 78 in reflex 32 resting membrane potential of different sizes of 686 sensory neurons synpase selectively on 1106 signaling of eye position and velocity 790 spinal, synaptic contact with interneurons 77 spinal cord, multipolar neuron 24 spinal neurons, dendritic trees of compared with those of pyramidal neurons of cerebral cortex 85 structure 73 synapses with muscle cells 78–79 81 85 stimulate synthesis of acetylcholine receptors 1094–1096 tonic and phasic 1107 Motor nuclei 667 medial-lateral arrangement of in spinal cord 668 proximal-distal rule of spatial organization 667 Motor pathways descending pathways, diseases affecting 666 lesions of produce positive and negative signs 666 modulated by descending pathways from brain stem to spinal cord 896 Motor patterns complex, generated by rhythm-generating system in spinal cord 743 746–747 generated in absence of sensory signals input to spinal cord 746 repetitive rhythmic 656 Motor performance, perturbations 693 Motor planning contributions of premotor area 770–777 disrupted by lesions of cerebrocerebellum 846 pathways involved in 355–356 Motor pool, spinal cord 1069 1070 Motor programs adjustments 692–693 control voluntary movements 659–661 cortical, cerebrocerebellum role in feedback circuit regulating 845–846 and experience 693 refined by learning 672 Motor representation, hierarchical arrangement 654 Motor responses evaluation of in structural coma 903–904 stereotyped, brain stem 873 Motor set 861 Motor signals, role in reflex 32 P.1372 Motor signs, spinal cord lesions 732–734 734 Motor skills, role of cerebellum 322 Motor systems abilities to plan, coordinate, and execute 653 cortical and brain stem, influenced by cerebellum and basal ganglia 663–665 dependence on neurotrophic factors 1059 descending in brain stem and cerebral cortex, modulated by spinocerebellum 843–844 generation of reflexive, rhythmic, and voluntary movements 654–658 hierarchical organization 663–666 influence of cerebellum on 832 levels of control 667 motor map in primary motor cortex 323 relationship of basal ganglia to 854 sequence of information processing is reversed from that in sensory system 355–356 Motor tasks, hierarchical organization 778–779 Motor tone role of serotonergic neurons 896 influence of locus ceruleus 896 Motor unit 81 675 676 695 contractile force 685 differential diagnosis of neurogenic and myopathic diseases 700 diseases of 695–712 effects of neurogenic and myopathic diseases on 697 electrical properties determine responses to synaptic input 686–687 electromyographic analysis of action potentials 699 gastrocnemius muscle of cat, distinctive actions of slow-twitch and fast-twitch motor units 685 and muscle action 674–694 ocular versus skeletal 788 progressive recruitment 685 motor tasks 687 recruitment in fixed order 686–687 types and qualities 684 types 683–686 variations in twitch, tetanic force and fatiguability 684 Mountcastle, Vernon 383 454 813 Mouse animal model for Alzheimer disease 1158 generation of mutations in 48–49 introduction of transgenes into 43 See also specific mutations single gene defects can affect complex behaviors in 47 Movement 648–867 accuracy in proportion to speed of 665 activty of set-related neuron in dorsal premotor area 775 actual versus intended, cerebellar comparison 753 adaptation to new conditions, role of primary motor cortex 764–770 agnosia 500 central commands for reinforced by stretch reflexes 728–730 complex, composed of discrete segments 661 decomposition of 846

direction encoded by populations of cortical neurons 765–766 encoded in motor cortex 769 disorders basal ganglia, types of motor disturbances 853 imbalances in direct and indirect basal ganglia pathways 861–864 dynamics 658 elicits complex patterns of vestibular stimulation 806–807 executed by spinal motor neurons 667–668 execution of controlled by primary motor cortex 764–770 extent and direction of processed in parallel 665 eye convergence and divergence 785 types of 783–785 factors for guidance of 648 feed-forward circuits 655 feedback control 655 in catching a ball 657 in motor system for control of 657 field, neurons in superior colliculus 793 fine, role of basal ganglia 323 functional differentiation of cerebral hemispheres in 364 functional organization 337–348 goal-directed role of lateral descending systems 663 sensorimotor transformation 778 guidance, role of posterior parietal cortex 453 hand acceleration and velocity 658 role of cerebrocerebellum in planning and programming 846 vestibulo-ocular reflexes compensate for 808–809 image, role of M cells 580 information about, role of pons 8 integration basal ganglia-thalamocortical circuits 859 role of putamen 859 integrative responses in areas 5 and 7 of posterior parietal cortex 465 internally initiated, role of supplementary motor area 770 kinematics 658 learning sequences of, supplementary and presupplementary motor areas 771–774 learned, shift of neural control from supplementary motor area to primary motor cortex 773 lesions of middle temporal area impair 556 limb and body, regulation by spinocerebellum 841–844 direction of and neuronal function in skeletomotor circuit 859–861 linear, otolith reflexes compensate forn relative to gravity 809 mental rehearsal role of premotor-cerebello-rubrocerebellar loop 846 same patterns of activity in premotor and posterior parietal cortical areas 771 modulaton by brain stem 889–909 organization of 653–673 parallel processing in 664 parietal cortex 567 and posture 817–821 preparation, and neuronal function in skeletomotor circuit 859–861 primitives 661 purposeful, representation in brain 658 reaching, planned by brain 658 reflex, compared with voluntary 756 reflexive, production by stereotyped patterns of muscle contraction 654–656 regulated by feed-forward mechanisms in spinocerebellum 844 -related neurons, in frontal eye field 794 requires coordinated work of many muscles acting on skeletal joints 687–693 rhythmic, production by stererotyped patterns of muscle contraction 654–656 role of cerebrocerebellum in planning 845–848 frontal lobe 9 proprioceptive reflexes 726–730 sensory information in regulation 713 rotational, convergence of vestibular and optokinetic signals during 828–829 saccadic eye, controlled by oculomotor circuit 861 P.1373 schemas 661 See also Grasping; Reaching; Stepping sensory information related to processed in parallel 663 spatiotemporal elements 661 triggered by external sensory events 770 voluntary 756–781 adaptability of 779 coactivation of alpha and gamma motor neurons 729 compared with reflex 756 components of motor system involved 347 control by motor programs 659–661 effect of inactivation of dentate and interposed nuclei 843 feedback and feed-forward mechanisms 656–657 goal-directed nature 656–657 improve with practice 656–657 762 organization of in primary motor cortex 758–759 psychophysical principles 658–663 rate of firing of alpha and gamma motor neurons 728–729

reaction time variables 662 reactive time and amount of information processed 661–662 role of stretch reflex pathways 721 sensorimotor transformations 779 speed versus accuracy 662–663 Movshon, Tony 554 558 MPTP See 1-Methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine MPZ See Myelin zero protein MRI See Magnetic resonance imaging MT See Middle temporal area Mu receptors, opiates 484–485 Mucosal plexus 965 Mucus, detection of odor 626 Mueller, Paul 109 Muir, R.B. 769 Muller, Johannes 6 414 430 Muller-Lyer illusion 495 495 Mullerian duct inhibiting hormone 1133 Mullerian ducts, sexual differentiation 1133 1133 Multifactorial model, for multigenic traits 59 Multiform layer, neurons in cerebral cortex 326 327 Multigenic diseases 55–56 Multigenic traits 55 analysis of 57 multifactorial model for 59 Multimodal association areas 350 cerebral cortex 345 Multimodal association cortex, processing of sensory information in cerebral cortex 345 Multimodal motor association areas 350 Multimodal sensory association cortex, function 354 Multiple drug resistance transporter, in blood-brain barrier 1292 Multiple latency sleep test, and narcolepsy 950 Multiple sclerosis demyelinating disease 82 experimental allergic encephalomyelitis as model for 82 internuclear ophthalmoplegia in 792 role of microglia 20 Multiple sleep latency test, apnea and narcolepsy 952 Muramyl peptides, hypnogenic properties 943 Muscarine, effect on M current 242 Muscarinic acetylecholine receptor 189 Muscimol, inhibition of neural activity in cortex 468 469 Muscle action, and motor unit 674–694 Muscle and limb position, somatic division of peripheral nervous system 335 Muscle cells cardiac, hyperpolarization by ACh 247 motor neurons synapses with 78–79 81 85 passive membrane properties and determination of time course of end-plate potential 204 postsynaptic, acetylcholine binding in 199 See also Muscle spindles specialized for signaling over long distances 110 Muscle contraction information about state of conveyed by sensory neurons 76–77 involuntary 654 produced by cyclical attachment and detachment of myosin heads on thin filaments 679 tendons and aponeuroses store mechanical energy during 678 Muscle fibers 676 active force produced depends on velocity at which it changes length 682 682 all-or-none response 676 aponeuroses transmit force to connective tissue 682 central motor commands to conveyed by motor neuron 77–78 contractile force depends on level, length, and velocity of activation 680–683 overlap of thick and thin filaments 681 cross bridges formation depends of calcium 680–681 produce contractile force 678 end-plate connection with motor neuron 676 force of contraction depends on number of recruited motor neurons and firing rates 687 produced by cross bridges depends on velocity of sarcomere 683 motor neurons convey commands to 676 myofibrils in 677 neuromuscular junctions 81 noncontractile components 678 680 number of cross bridges depends on overlap between actin and myosin filaments 681–682 organization into sarcomeres and cross bridges 676–683 organizes differentiation of motor nerve terminals 1098–1100 total force produced, length, velocity 683 Muscle force amount held in reserve for transient use 687 creates stiffness at joints 689–690 to overcome inertia 688–689 690 Muscle movements, fine-tuning by cerebellum 322 Muscle nerve, afferent fiber groups in 444 Muscle signals, role in reflex 32 Muscle spindles agonist and antagonist, in motor cortex reflex circuit 765 and initiation of swing phase of stepping 749 extensor muscles, regulation of step cycle 748 fibers 719 fine-tuning by fusimotor system 725 in knee jerk 26

innervation 718 in reflex 32 sensitivity of adjusted by gamma motor neurons 734–735 structure 719 structure and functional behavior 718 types 718 Muscle tone characteristic alterations in caused by damage to central nervous system 730–735 loss of during REM sleep 943 mechanism for loss during REM sleep 942 modulation by medial and lateral reticulospinal pathways 896 Muscle unit 676 Muscles act on more than one joint 690–693 692 active tension and rate of stimulation of nerve 680 activity, postspike facilitation of 767 antagonist 715 arm and hand, activation by stimulation of motor cortex 758 P.1374 classification of sensory fibers 720 contraction, activation of gamma motor neurons during 726 Golgi tendon organs provide information about 723 produces reflexive and rhythmic movements 654–656 spatial extent and force depend on stimulus intensity 715 co-contraction 720 complex sequence of contractions in stepping 740 741 coordinated patterns of contraction in spinal reflexes 715–717 coordination of contractions and divergence of reflex pathways 721 denervated, and density of acetylcholine receptors 1096 different actions of at individual joints 687–688 effects of cerebellar lesions 849–850 direction and amplitude of force, correlates with activity of corticospinal axon 766 ending of sensory nerve in 74 excitation by motor neuron, opening of end-plate ion channels 190 force generation, direct relationship to firing rate of motor cortical cells 768 force in and discharge rate of Golgi tendon organs 723 fused tetanus 680 histochemistry to distinguish neurogenic and myopathic diseases 698 intrinsic mechanical properties and force 691 individual, distribution of sites controlling in primary motor cortex 759 limb, M2 response 727 lengthening resisted in stretch reflex 717 multiarticular 690–693 692 postsynaptic membrane clustering of acetylcholine receptors on 1092 differentiation of organized by motor nerve 1091–1098 programming and adjustment of motor programs 692–693 propagation of contraction effects 692 proteins of cytoskeleton on surface membrane 708 rapid exertion of force 689 red 684 in reflex 32 repeated activation causes fatigue 683 retrograde signals to nerve in formation of neuromuscular junction 1099 role in synapse elimination 1101 See also Stretch reflex selective activation of sensory fibers 720 sequential activation of agonist and antagonist and changes in joint torque 688 skeletal, during obstructive sleep apnea syndrome 953 spatial and temporal control of combinations of 687 spontaneously active at rest in neurogenic disease 699 stretch depolarizes mechanoreceptors 415 structure 675 successive isometric twitches 680 summation of successive isometric twithces 680 surrounding joint, coordinated by inhibitory interneurons 717 720–721 synergist 721 tonic and phasic 1107 torque as product of contractile force and moment arm 688 types 674 transduction of electrical and chemical energy to mechanical energy 693 type I and type II fibers, in 698 699 unfused tetanus 680 white 684–685 Muscular dystrophies as myopathies 696 See also Becker muscular dystrophy; Duchenne muscular dystrophy; Facioscapulohumeral muscular dystrophy; Limb-girdle muscular dystrophy; Myotonic muscular dystrophy Muscular dystrophy deletion in distrophin gene and severity of 707 distrophin-normal, mutations of sarcoglycan genes in 707–708 major forms 705 Musculoskeletal system 693 MuSK, role in clustering of acetylcholine receptors at synaptic sites in muscle fiber 1093 1094 Mutation consequence of shaped by environment 39 dominant 39 dominant negative 39 loss of function 40 frameshift 40 gain of function 39 generating in flies and mice 48–49 method for testing proposed ion channel structure 118 missense 40 nonsense 40

point 40 recessive 40 types 38–40 Mutism 1182 Mutual inhibition, interneurons, and central pattern generators 744 Myalgia 696 Myasthenia gravis antibodies to ACh receptor produced in 201 antibody binds to alpha-subunit of ACh receptor in 303–304 autoimmune disease 300 reaction against ACh receptor 305 therapy for 306 caused by disruption in transmission at synapse 174 chemical synapses as target 867 congenital forms 306–307 disease of chemical transmission at nerve-muscle synapse 298–309 experimental autoimmune 300–301 failure of transmission at neuromuscular junction 302 immunological changes cause physiological abnormality 302–303 major forms 298 neonatal 306 rate of destruction of ACh receptors 304 results from antibody interference with ion channel function 123 Mydriasis 788 Myelencephalon, development 1021 1022 Myelin 188 inhibitor of axon outgrowth 1111 inhibits regeneration of central axons 1110 production by glial cells 20 protein components of 83 proteolipid component of 83 Myelin basic proteins, role in myelin compaction 82 Myelin debris, after axotomy 1109 Myelin genes, regulation of expression in Schwann cells and oligodendrocytes 85 Myelin protein zero, major protein in mature peripheral myelin 83 Myelin proteins affected in hereditary peripheral neuropathies 709 defects in disrupt conduction of nerve signals 82–83 Myelin sheath 22 on axons of central and peripheral neurons 81 degeneration of in axons of corticospinal tracts in spinal muscular atrophy 700–701 Schwann cells, gap junctions enhance communication 182 P.1375 sensory neurons 76–77 signal-conducting axons, produced by glial cells 85 Myelin-associated glycoprotein in myelin 82–83 inhibits axonal elongation 1111 Myelination, axonal, effect on increasing conduction velocity 147–148 148 Myenteric plexus 964–965 965 Myocardial infarction, referred pain in 475 477 Myoclonus 767 Myofibril muscle fiber 677 skeletal muscle fiber 676 Myofilaments 677 Myogenic diseases, clinical and laboratory criteria for 696–699 Myoglobinuria 696 acquired myopathic disease 701 Myomodulins, neuroactive peptide 289 Myopathic diseases differential diagnosis from neurogenic diseases 700 effect of motor unit 697 histochemical diagnosis 698 laboratory criteria for diagnosis 697–699 molecular genetics of 705–709 Myopathies causes of weakness in 705 inherited See Glycogen storage diseases; Muscular dystrophy Myosin in axon growth cone filopodia 1071 1073 form of in fast-twitch white muscles 684 in hair cells 600 in muscle fibers 677 muscle contraction 679 Myosin heads actin-binding sites 680 as actin motors 75 cyclical attachment and detachment on thin filaments produces muscle contraction 679 muscle fiber, ATPase converts ATP into mechanical energy 678 Myosin I-beta, near stereociliary tips in hair cells 620 Myotonia 696 704 Myotonia congenita, caused by mutation in Cr channel 169 Myotonic dystrophy inherited myopathic disease 701 trinucleotide repeats in 55 56 Myotonic muscular dystrophy, inherited myopathy 704 705 Myotube 1089 Mypathic diseases, symptoms 696

N N-acylation, cotranslational protein modification 92 N-cadherin candidate for organization of presynaptic differentiation 1100 N-CAM See Neural cell adhesion molecule N-ethylmaleimide-sensitive fusion protein 271 N-methyl-D-aspartate activates ionotropic glutamate receptors 212 NMDA-type glutamate receptor 197 N-methyl-D-aspartate receptor-channels-channel, properties of 212–213 opening, and plateau potentials 745 N-methyl-D-aspartate glutamate receptors (NMDA) activation in long-term potentiation 1260 and stabilization of synapses 1121–1122 lack of in hippocampus and defect in long-term potentiation and spatial memory 1270–1271 1272 role in correlated firing of pyramidal cells in hippocampus 1267 and segregation of afferent input in frog optic tectum 1123 N-myristoylaton, protein modification 92 Na+ See Sodium ions Na+ -K+ pump 27 balances passive Na+ and K+ currents by active Na+ and K+ fluxes under steady state conditions 135 drives active fluxes of Na+ and K+ 135 138 electrogenic nature 131 prevents dissipation of ionic gradients 131 structure 131 as transporter 108 Nagel, Thomas 396 397 398 1318 Naloxone opiate antagonist 483–484 opioid withdrawal 489 Narcolepsy in dogs 951 familial incidence 950 immunological basis of 950–951 multiple sleep latency test 952 neural system that normally produces arousal instead triggers atonia 950 polysomnogram of sleep-onset REM period 950 sleep disorder 949–951 treatment 951 Narcoleptic syndrome, symptoms 949 Nasal hemiretina 524 Nashner, Lew 820 Nathans, Jeremy 584 Natural history 1189 Nausea, cerebellar infarction 1313 Near cells, striate and extrastriate cortex 561 Neck contributions to postural control 821–824 motor control and sensation mediated by brain stem 320 volitional control 822–823 Necrotic cell death, compared with apoptotic cell death 1058 Negative feedback system, motor neuron connections to Renshaw cells 721 Negative signs, lesions of motor pathways 666 Negative symptoms, schizophrenia 1192 1196 Neglect syndrome See Personal neglect syndrome Neher, Erwin 111 193 Neisser, Ulric 383 Neocortex abnormalities in Alzheimer disease 1153 columns as computational modules of 331 developing forebrain 1036 distribution of neurons in columns 329–331 excitatory interneurons in 329 and hypothalamus, information about conscious and peripheral aspects of emotion 987 nature of information processing in 330 organization of inputs and outputs by layers 327 329 projections of neurons to different parts of brain 329 reciprocal connections with amygdala, incorporation of learning and experience into congnitive aspects of emotion 993–994 storage of semantic knowledge in 1233–1237 structure 324–325 transfer of odorant information to from olfactory bulb 633 Neonatal rat preparation, study of stepping 738–739 739 Neospinothalamic tract 481 Neostigmine myasthenic mouse before and after treatment with 301 reverses symptoms of myasthenia gravis 299 300 300 Nernst equation, calculation of equilibrium potential 128 Nernst potential 129 Nernst, Walter 128 Nerve block 703 Nerve cells Alzheimer disease affected versus normal 1154 anatomical circuits formed by 19 and behavior 19–35 cell plan of 65 connections altered by activity and learning 382 P.1376 correlation of patterns of firing with higher cognitive processes, cognitive neural science approach 383 development of precise connections between types 1019

each makes specific connections 23 competitive effect of excitatory and inhibitory currents 226 electrical signals flow only in one direction 23 formation of specific signaling networks mediating specific behaviors 25–27 generation of 1041–1062 main signaling unit in nervous system 21–25 membrane capacitance 138 molecular differences among 33 numb inhibits notch signaling and controls cell fate 1043 organization of signaling 27–33 resting ion channels selective form several ion species 129–131 same basic architecture 19 See also Neurons selective vulnerability 701 signaling conductile component 31 input component 28–29 output component 31 trigger component 29–30 specialized for signaling over long distances 110 specific networks convey information 33–34 specification of identity controlled by Notch signaling 1042 spontaneously active, controlled by synaptic inhibition 209 survival of 1041–1062 Nerve endings, free 720 Nerve fibers, demyelinated, impaired conduction in 702 Nerve growth factor binding by receptor tyrosine kinases 238 discovery of 1056 effect on formation of ocular dominance columns 1125 neurotrophin 1055 1056 Nerve injury, reformation of nerve connections following 1108–1112 Nerve roots, segmental, damage to and sensory deficits 733 Nerve signals, defects in myelin proteins disrupt conduction of 82–83 Nerve terminal elimination by local postsynaptic inactivity 1099 organized by components of basal lamina at synaptic site 1097 Nerve-muscle synapse diseases of chemical transmission at 298–309 molecular properties of ACh-gated channel at 196–201 See also Ion channels, acetylcholine-gated; Neuromuscular junction signaling at 187–206 Nervous system classes of cells in 20–25 development 1017–1162 ectodermal 1021–1022 functional subdivisions 315 homeostatic functon 871 induction of patterning 1019–1040 integrative action of 29–30 and hierarchies of motor control 648 ion channels as site of signaling in 105–107 localization of function 33 parallel distributed processing organizational principle 9 pharmacology of 6 physiological investigtion of 6 predominance of multipolar neurons 24 sexual differentiation 1131–1148 structure 335 Nervous tissue as network of discrete cells 6 and neuron doctrine history 6 Netrin 1, attractant and repellent for axon growth cones 1082 Netrin genes, structural similarity to C. elegans unc-6 gene 1081 Netrins chemoattractant factors promoting axon growth 1078–1081 mediate chemotropic responses of neurons to targets 1077 Network properties, functional circuits in brain 384 Networks, neural, convey information in brain 33–34 Neural activity regulates expression of acetylcholine receptors in nonsynaptic areas 1096 1096–1098 relationship to specific subjective experience 397 398 Neural cell adhesion molecule (N-CAM) candidate for organization of presynaptic differentiation 1100 promotes neurite outgrowth 1078 Neural circuit enhancement of computing power 160 organization 314 Neural crest classes of neurons that develop from 1047 growth factors involved in cell fate 1047 pathways of cell migration in chick embryo 1046 target-dependent differentiation of neurons in 1053 Neural crest cells differentiation 1047–1048 neural tube 1027 secreted factors direct differentiation 1048–1049 Neural gain 825 Neural groove 1020 Neural induction inhibition of bone morphogenetic protein signals 1024 pathways of, Xenopus 1024 Neural map 323 body surface 385 in brain create representation of outside world 33–34

somatotopic representation in somatosensory cortex is according to degree of innervation of portions of body 344–345 Neural maturation, effects of sleep 944 Neural organization, principles 23 Neural plate 1019 1022 dorsoventral axis patterning 1027–1030 induction by signals from adjacent mesoderm 1023–1024 Neural projections, tracing with use of labels 98 Neural representation maps based on patterns of evoked potetials 385 uses of term 384–385 Neural science convergence with congitive psychology 1227 emergence 3 fundamental questions of 5 modern 4 unification with study of behavior 5 Neural tube development 880 883 dorsal, patterning by bone morphogenetic protein 1029–1030 dorsoventral patterning maintained through rostrocaudal length 1030 formation 1020 inductive signaling in both halves 1030 patterning, signaling of sonic hedgehog and bone morphogenetic protein 1025 roof plate, BMP signaling induction of dorsal commissural interneurons 1028 rostrocaudal axis patterning 1030–1036 sonic hedgehog signaling 1026 stages in development of 1021 ventral, patterning by sonic hedgehog 1027–1029 Neuregulin gene, and development of neuronal identity 1049 P.1377 Neurexin 271 in central neuron synaptic clefts 1104 1105 Neurite inhibitor of 35kDa, inhibits axonal elongation 1111 outgrowth promoted by extracellular matrix molecules 1075 1076 promoted by molecules that mediate cell-cell adhesion 1074 1075 Neuroactive peptides as chemical substances for signaling 281 as neurotransmitters 286–290 biosynthesis 286 288 brain, tissue localization 289 co-release with small-molecule transmitters 290 294 compared with small-molecule transmitters 290 families of 290 proteins precursor synthesis 295 structures of precursors 291 Neuroblasts, subcellular localization of numb during mitosis 1043 Neurodegenerative diseases, role of microglia 20 Neuroendocrine cells, functional regions 28 Neuroendocrine function, disturbances of in unipolar depression 1220 Neuroepithelium, local cues in guide formation of optic tract 1069 Neurofilaments, in neuron cytoskeleton 73–74 Neurofilbrillary tangle cerebral cortex topography of in Alzheimer disease 1153 characteristic of Alzheimer disease 74 1154 1154 Neurofilament, neuron 71 Neurogenesis 1041–1062 Neurogenic diseases clinical and laboratory criteria for 696–699 conduction velocities of peripheral motor axons in 699 differential diagnosis from myopathic diseases 700 effect on motor unit 697 histochemical diagnosis 698 laboratory criteria for diagnosis 697–699 molecular genetics of 705–709 muscle fiber type grouping in 699 muscle spontaneously active at rest 699 symptoms 696 Neurogenic inflammation 479 Neurogenic, expression in proneural stripes 1047 Neurogliaform cells 331 in cerebral cortex 922 Neurohypophyseal hormones, family of neuroactive peptides 290 Neurokinin A See Substance K Neuroligins, in central neuron synaptic clefts 1104 1105 Neurological diseases caused by mutations in voltage-gated ion channels 167–169 types of trinucleotide repeats involved in 56 Neuromuscular junction concentration of ACh receptors on postsynaptic membrane 259 concentration of Ca2+ channels at presynaptic nerve terminal 259 development of 1088 1089–1091 development of acetylcholine receptors 1091–1092 directly gated synaptic transmission 187 elimination of some after birth 1099 1100–1101 failure of transmission at in myasthenia gravis 302 mechanisms underlying synapse formation 1090–1091 motor axon controls aspects of postsynaptic differentiation 1098 normal versus myasthenic 303 number of active zones 261

postsynaptic differentiation 1091–1098 presynaptic differentiation 1100 See also Nerve-muscle synapse structure 187 188 189 for study of synapse formation 1087 synaptic cleft compared with that at central neurons 1103–1104 synaptic connections compared with those in central nervous system 207 synaptic contacts of motor neurons with muscle fibers 81 types of cells in 1089 Neuromuscular transmission botulism as disorder of 307–308 Lambert-Eaton syndrome as disorder of 307–308 Neuronal divergence 26 Neuronal integration 222–223 Neuronal network, rhythmic locomotor pattern for swimming in the lamprey 745 Neuronal process, representation as electrical equivalent circuit 144 Neuronal protein, synthesis and trafficking 88–104 Neurons afferent 25 arrangement into functional pathways 335 as individual cells 6 bipolar 24 24 cell and molecular biology of 65–170 cell body, synthesis of proteins 8 cell death program activated by removal of neurotrophic factors 1058–1061 cell fate controlled by local signaling 1047–1049 in cortex controlled by timing of cell differentiation 1049–1051 central nervous system, study with extracellular recordings 454 classification according to shape 23 24 common features 67–68 current flow in 1280–1287 cytoplasm 69 cytoskeleton 72–75 cytology 67–87 death of as normal occurrence during embryonic development 1054 diversity of anatomy 68 doctrine 6 effect of diameter of process on axial and membrane resistance 145 geometry on signaling 145 hormones on morphology 1137 steroids on 1136 electrical properties of cell membrane and signaling types 27 epithelial blueprint 68 69 establishment of neurotransmitter phenotype by signals from neuronal target 1051–1052 excitability properties vary between regions of 159–160 features that maximize computing power 148–149 functional groups 25 28 fibrillary structures in 71 functional properties represented as electrical equivalent circuit 134–138 generation of action potential 29–30 transient electrical signals 125–139 increase in firing rate related specifically to attention 401 individual, as signaling units of the brain 7 input component produces graded local signals 28–29 mature, chromosomes function only in gene expression 89 membranous organelles 69–71 model populations with computers, cognitive neural science approach 384 molecular basis evolutionarily conserved 1041–1047 morphology 21 motor 25 multipolar 24 24 P.1378 nature of membrane potential 29 number of synaptic connections 173 175 passive current flow in modeled with electrical equivalent circuit 135 passive electrical properties 140–149 passive membrane properties of 222–223 pseudo-unipolar 24 24 patterns of connection 26 polarization and electrical excitability 67 processes 70 produce electricity 6 production of inhibitory signals 26 proteins that promote survival 1056 repetitive firing properties of different types and types of voltage-gated ion channels 161 secreted factors direct differentiation of neural crest cells into 1048–1049 See also Nerve cells sensory 25 staining of to reveal structure 6 structure 22 survival regulated by signals from neuronal target 1052–1058 study of functional properties with brain slice preparation 918 with imaging techniques, cognitive neural science approach 384 substrates for PKA in 235–236 and understanding the mind 3–4 types of signals produced by 27 unipolar 24 24 Neuropathic pain 473 Neuropathies

axon 702 demyelinating 702 hereditary peripheral, myelin proteins affected in 709 positive and negative signs and symptoms in 703 Neuropeptide Y, neuroactive peptide 289 in autonomic neurons 970 and food intake 47 50 receptor gene, conservation in mammals and C. elegans 42 stimulation of feeding behavior 1006 Neuropeptides in autonomic neurons 970 972 coexistence with norepinephrine and acetylcholine in sympathetic ganglia 972 histochemical detection within neurons 292–293 modulatory functions 973 neurotransmitter in nociceptive afferent fibers 477 nonpyramidal cells of cerebral cortex 922 Neurophypophysis See Pituitary gland, posterior Neurophysin, in neurons that release vasopressin and oxytocin 979 Neuropilins, binding of semaphorins to repulses growing axons 1080 Neuropilins, receptors for semaphorins 1081 Neuropsychology, founding of 10 Neuroregulin, stimulates synthesis of acetylcholine receptors 1094–1096 1095 Neurotensin, neuroactive peptide 289 Neurotransmitters 182 280 act directly or indirectly on ion channels 184 all-or-none release from active zones of presynaptic terminal 261 amount released modulated by intracellular calcium concentration 274–276 274 calculation of probability of release 261 in cerebral cortex cells 922 chemical in autonomic neurons 969–970 criteria for 280–281 isolation of acetylcholine 966 histochemical detection within neurons 292–293 concentrations 295 definition of brain stem cell groups with long projections 889–898 discharged from synaptic vesicles by exocytosis 262–264 effects depend on type of receptor 32 establishment of phenotype by signals from neuronal target 1051–1052 false 286 increase of vesicles and receptors in long-term potentiation 1264 leakage through fusion pore 267 kiss-and-run release 270 membrane-soluble molecules as 295 modulation of amount released 277 neuroactive peptides as 286–290 in nociceptive afferent fibers 477 packaged in vesicles 277 proteins involved in vesicular release 270–273 quantal release 257–267 in fixed increments 260 receptors, clustering at synapses on central neurons 1103 release 253–279 contribution of K+ efflux 254–255 contribution of voltage-gated Na+ channels 254 depends on presynaptic depolarizaton 253 inhibited or facilitated by axo-axonic synapses on postsynaptic cell 276 mechanism of intracellular calcium effect on 260–261 by output component of signaling 31–32 regulated by depolarization of presynaptic terminal 253–255 from synaptic vesicles through opening of fusion pore 267 through fusion pore 268 triggered by calcium influx 255–258 into presynpatic terminal 256 removal from synaptic cleft terminates synaptic transmission 294–295 reuptake mechanisms 294–295 See also Serotonin small-molecule 281 actively taken up into vesicles 285–286 as chemical substances for signaling 281 co-release with neuroactive peptides 290 294 compared with neuroactive peptides 290 transport from cytosol into vesicles 287 synaptic cleft into cytosol 287 storage and release by synaptic vesicles 261–267 substances identified as 282–286 Neurotrophic factor hypothesis 1055 1055 Neurotrophic factors 1056 deprivation of triggers caspase activation 1060 receptor interaction 1056 1057 release from target neurons enhanced by synchronous presynaptic activity 1123–1125 secretion by target cells 1055–1056 1056 Neurotrophin 3 1055 1056 Neurotrophin 4/5 1055 1056 Neurotrophins mechanism of action 1058 modulation of formation of ocular dominance columns 1125 and survival of neurons in central nervous system 1057–1058 Neurturin, neurotrophin receptor 1057

Newsome, William 558 Newson-Davis, John 306 Newton's laws of mechanics, and muscle force 689 690 NGF See Nerve growth factor NI-35, inhibits axonal elongation 1111 Nicotinamide adenine dinucleotide phosphate diaphorase (NADPD), staining of cortical neurons for in schizophrenia 1196 Nicotine effect on rate of electrical self-stimulation of brain 1010 mechanism of action in brain 1011 positive reinforcement action 1010 Nicotinic acetylcholine receptor 189 secondary structure of subunit 117 P.1379 Nicotinic acetylcholine receptor-channel functional model 201 three-dimensional model 200 transmembrane subunits 200 Night blindness, vitamin A deficiency 512 Night vision, role of rods 509–510 Nigrostriatal pathway, dopaminergic neurons in 892–893 Nigrostriatal system, dopaminergic pathway 1201 1203 Nissl stain, layers of neurons in cerebral cortex 326 Nissl substance motor neuron 73 stained ribosomal RNA 91 Nitric oxide action at synapses 262 as neurotransmitter 295 as transcellular messenger 239 receptors, in autonomic nervous system 971 retrograde messenger in long-term potentiation 1262 second messenger in synaptic transmission 230 stimulates cGMP synthesis 239–240 295 NMD A See N-methyl-D-aspartate NO See Nitric oxide Nociception 430 neural mechanisms of, versus pain 472–473 Nociceptive afferent fibers neurotransmitters 477 terminate on neurons in dorsal horn of spinal cord 475–77 Nociceptive information transmission inhibited by monoaminergic pathways from raphe magnus nucleus to spinal cord 896 Nociceptive neurons primary, chemical mediators 478 synapses with neurons of substantia gelatinosa of spinal cord 476 Nociceptive pain 473 Nociceptive projection neurons, inhibitory descending pathway 486 Nociceptive-specific neurons, in dorsal horn of spinal cord 475 Nociceptors 472 activation by noxious insults 473–475 and sensitization by chemical mediators 481 agents that activate or sensitize 480 as chemoreceptors 442 classes 473–475 mediate pain 442–443 pain 430 sensitization by thermal injury 479 types 432 442–443 viscera, and pain elsewhere in body 475 Node of Ranvier 22 75 85 action potential repolarization 160 boost amplitude of action potential 148 148 regeneration of action potentials 22 sensory neurons 77 structure 21 Nodose ganglion, taste information pathway 642 Nodulus, cerebellum 833 Noebels, Jeff 925 Noggin, neural induction 1024 Non-REM-cells, patterns of activity during REM sleep 940 Non-REM-on cell, mediation of sleep 939 Nonspiny neurons, in cerebral cortex 923 Nondeclarative memory See Memory, implicit Nonpyramidal cells, in primary visual cortex 533 Nonspindle endings 720 Noradrenergic cell groups, in medulla and pons 890–891 890 Noradrenergic neurons effects of antidepressant drugs on 1218–1219 in locus ceruleus 895 in pons 891 Noradrenergic pathways drugs effect in treatment of depression act on 1216 originating in locus ceruleus 1215 1216 Noradrenergic receptors, linked to second-messenger systems 1216 Norepinephrine abnormal function in narcoleptic dogs 951 as small-molecule neurotransmitter 282–283 biosynthesis and structure 282–283 biosynthetic enzymes 281 contribution to primary generalized seizures 925 effect on

feeding responses 1004 heart 967 high levels in patients with post-traumatic stress disorder 1222 neurotransmitter in autonomic nervous system 970 production varies with neuronal activity 284 receptors for in autonomic nervous system 971 uptake blocked by cocaine 295 Nose, olfactory sensory neurons in 626 Notch protein, role in determining neuronal cell fate 1043 1046 Notch signaling regulates neuronal cell fate in central nervous system 1045 specifies specification of nerve cell identity 1042 Notch, in cortical progenitor cells 1051 Notochord 1020 inductive signals 1027 Novelty-seeking behavior, human, and gene that encodes D4 dopamine receptor 51 NPY See Neuropeptide Y NSF See N-ethylmaleimide-sensitive fusion protein NT-4, blocks formation of ocular dominance columns 1124 1125 NT3, effect on formation of ocular dominance columns 1125 Nuclear bag fibers, muscle spindles 718 719 Nuclear chain fibers, muscle spindles 718 719 Nuclear envelope, neuron 70 Nuclear localization signal 90 on proteins 93 Nuclear pore neuron 70 role in protein synthesis 93 site of mRNA and ribosome export to cytosol 89 size limitation of proteins that can pass through 94 Nuclear prepositus hyperglossi, neural integration of velocity signal in saccade 790 Nuclei 337 brain, regularity of position and components 332 333 diffusely projecting 343 location of in thalamus 343 organizational complexity 334 relay 343 in right hemisphere, macaque monkey 333 in subcortical regions of brain 331–333 in thalamus 341 relay nociceptive information to cerebral cortex 480–481 Nucleoli, site of ribosomal RNA transcription 89 Nucleus importation of proteins synthesized in cytosol 93–94 role in protein synthesis 91 Nucleus accumbens projections of mesolimbic system to 1201 target for action of addictive drugs 1011 Nucleus ambiguus 881 in autonomic response control pathway 975 location and function 884 885 noradrenergic neurons associated with, projections and functions 890–891 pathway of sensory information 974 preganglionic parasympathetic, in brain stem, projections 963 P.1380 Nucleus basalis, abnormalities in Alzheimer disease 1153 Nucleus basalis of Meynert, cholinergic neurons in 896 Nucleus of Clarke's column 448 Nucleus of dorsal raphe, motor circuit for horizontal saccades 791 Nucleus of lateral lemniscus, auditory pathway 604 Nucleus of preoptic area, sexually dimorphic 1137 Nucleus of sixth nerve, control of sleep 941 Nucleus of solitary tract, taste information pathway 642 Nucleus of the solitary tract in autonomic response control pathway 975 C2 adrenergic neurons in 8892 and homeostasis 965–966 location and function 882–883 modulation of autonomic function 972–973 noradrenergic neurons in 890 pathway of visceral sensory information 974 Nucleus prepositus hypoglossi, motor circuit for horizontal saccades 791 Nucleus proprius 448 Nucleus raphe magnus, inhibitory descending pathway, pain 486 Nucleus reticularis, GABA-ergic inhibitory neurons and rhythmic firing of thalamic relay neurons during non-REM sleep 940 Nucleus reticularis pontis oralis PGO-on cells in 942 REM-on cells, activity during REM sleep 943 REM-waking-on cells, fire during REM sleep and non-REM sleep 942–943 Nucleus reticularis pontis oralis/caudalis, control of sleep 941 941 Numa, Shosaku 198 numb, in cortical progenitor cells 1051 Numb protein inhibits notch signaling and controls nerve cell fate 1043 role in determining neuronal cell fate 1045 subcellular localization in neuroblasts during mitosis 1043 Nusslein-Volhard, Christiane 1032 Nystagmus 809 812 814 cerebellar infarction 1313 defective optokinetic 813

O O'Keefe, John 1264 ob gene, role in food intake 1005–1006 Obese gene, mice, mutation in causes obesity 47 Obesity genetic mechanisms of 47 and obstructive sleep apnea syndrome 952 953 Object category-specific knowledge of and brain areas associated 1236–1237 computation by brain of global motion 556 contrast rather than intensity of light source important 517 detection by preattentive process 502–503 edges, and recognition 537 and illusions 495 illusory and actual contours, V2 cells respond to both 562–563 lifting of, role of feedback and feed-forward controls 660 light reflected from surface of 573 575 search for unique 503 See also Color vision; Brightness vision selection and highlighting of features, attentive process 503 spatial characterizations signaled by populations of mechanoreceptors 438–441 surface reflectance curves 577 function and light 575 visual analysis of contours 537 Object agnosia 500 Object location, activity of parietal cortex during 498 Object recognition 494 activity of occipital temporal cortex during 498 disrupted by lesions in temporal cortex 498 role of hippocampus 1233 Object vision depends on ventral pathway to inferior temporal lobe 562–565 separate from stereopsis 561–562 Obsessions 1223 Obsessive-compulsive disorder hyperactivity in the head of the caudate nucleus 1224 symptoms 1223–1224 Obstructive sleep apnea syndrome and breathing 951–953 multiple sleep latency test 952 pathophysiology 952–953 polysomnogram of episode 952 treatment 953 Obtunded 901 Occipital lobe 8 324 367 368 of cerebral cortex 325 function 9 Occlusion, depth perception 558 OCD See Obsessive-compulsive disorder Octopus cell, cochlear nucleus 606 Ocular counter-rolling response 809 Ocular dominance columns 1116 539 540 541 545 effects if visual deprivation of one eye during development 1118 experiments with three-eyed frog 1121–1122 1122 formation blocked by brain-derived neurotrophic factor and NT-4 1124 1125 formation modulated by neurotrophins 1125 inputs to 540 organization after birth 1118–1119 1119 organized by synchronous activity in pathways from each eye 1119–1122 Ocular motor nerves, function 877 Ocular motor neuron, pulse-step nature of saccade signal 788 Ocular motor nuclei, brain stem 788 Ocular reflexes, mechanism of 966 Oculomotor circuit basal ganglia, links thalamus and cerebral cortex 858 control of saccadic eye movements 861 Oculomotor cranial nerve (III) function and dysfunction 874–875 877 origin at brain stem 876 877 Oculomotor nerve in developing hindbrain 1031 innervation of extraocular muscle 787 lesion 788 motor circuit for horizontal saccades 791 vestibulo-ocular reflex 811 Oculomotor nucleus 881 location 883 motor circuit for horizontal saccades 791 vestibulo-ocular reflex 811 Oculomotor responses See Eye movements Oculomotor system 797 gaze system 783 vestibular nuclei projections to 814 Odor detection, cilia of olfactory neuron 626 Odorant information spatial encoding in olfactory bulb 630–632 transfer from olfactory bulb to neocortex via the thalamus 633 Odorant receptors adaptation 629 desensitization 629 diverse amino acid sequences 628

localization of types in olfactory epithelium 630 permit discrimination of wide variety of odorants 627–629 Odorants 625 adaptation to 629 identification 644–645 P.1381 identity encoded by combination of receptors 62 interaction with receptor activates second messenger system 629 stimulate different olfactory sensory neurons 627 Odors, detection by nasal olfactory sensory neurons 626–630 Off-center cells, retinal ganglion cells 582 Off-center ganglion cells 517 Ohm's law applied to synaptic current 193 calculation of magnitude of depolarization 141 use to obtain amplitude of single-channel current 109 Ojemann, George 12 Olds, James 1009 Olfaction, abnormalities 634–635 Olfaction, acuity in humans 634–635 Olfactory bulb 626 inputs from olfactory cortex 632 layers of 631 lesions, degeneration of neurons in olfactory epithelium 631 negative feedback circuits in granule cell interneurons 632 olfactory information processing 633 receives signals of olfactory sensory neurons 631 See also Accessory olfactory bulb spatial encoding of odorant information in 630–632 spatial mapping of sensory information 632 632 transfer of odorant information to thalamus and then neocortex 633 Olfactory cortex, main areas 633 Olfactory cranial nerve (I), function and dysfunction 874–875 Olfactory epithelium 626 626 631 bipolar neurons in 24 localization of odorant receptor types in 630 olfactory information processing 633 structure 627 Olfactory hair cell 417 Olfactory information processing in several areas of cerebral cortex 633 spatial mapping in olfactory bulb 632 632 Olfactory marker protein, in olfactory sensory neurons 630 Olfactory odorant neurons, highly distributed nature of information coding in 630 Olfactory receptors, segregation 644 Olfactory sensory neuron 627 depolarization 629 nasal cavity 626 signals from received by olfactory bulb 631 Olfactory system dopaminergic neurons in 893 pathways 644 sensory cells 625 Olfactory tubercle, olfactory information processing 633 Oligodendrocytes glial cells that elaborates central myelin 85 differentiation controlled by platelet-derived growth factor 1049 myelin production by 20 perineural 21 regulation of expression of myelin genes by 85 type of glial cell 20 in white matter 21 Oligogenic trait 55 Oligosaccharides, O-linked, addition to proteins in Golgi complex 96 Olive 877 Olney, John 928 Omega-agatoxin blocks P/Q-type Ca2+ channel 257 blocks N-type Ca2+ channel 257 Omega-conotoxin, use in identification of Ca+ channel subtype affected in Lambert-Eaton syndrome 307 Omnipause neurons, firing during eye saccades 790 798 On-center ganglion cells 517 582 One and a half syndrome, ocular reflexes characteristic 907 Open loop, in feed-forward control 657 Operant conditioning associating specific behavior with reinforcing event 1242–1243 associative learning 1240 Operculum 325 Ophthalmic artery, cerebral hemispheres 1302 Ophthalmic division, trigeminal nerve 878 Opiates analgesia 490 effect on feeding responses 1004 pathways of analgesia induction 483 positive reinforcement action 1010 family of neuroactive peptides 290 Opioid peptide family, biosynthesis 288 Opioid peptides endogenous, amino acid sequences 487 endogenous, families 487 interaction of opioid receptors 485–486

receptors for 483–489 tolerance versus addiction 489 Opioid receptors, activation by morphine to control pain 486–489 Opponent mechanisms, color vision 578 Opsin 573 in cone pigments 576 common precursor gene 576 structure 511 511–512 Opsin genes, mutations in influence color perception 51–52 Optic chiasm 525 876 lesion, loss of vision in temporal halves of both visual fields 544 545 Optic cranial nerve (II) function and dysfunction 874–875 origin at brain stem 876 877 Optic disc 508 508 Optic disc 525 Optic flow 553 processing in medial superior temporal area 553 representation in brain 553 Optic nerve 507 508 524 bilateral 526 projection to lateral geniculate nucleus, superior colliculus, and pretectum 517 visual system 496 Optic radiation 543 fibers, lesion, loss of vison in upper quadrant of opposite half of visual field of both eyes 544 545 Optic tectum formation of refined map in 1125 1127 frog, effect of EMDA receptors on segregation of afferent input in 1123 Optic tract 525 876 lesion, loss of vision in opposite half of visual field 544 545 local cues in neuroepithelium guide formation of 1069 nuclei, preferential response to stimuli moving across retina 813 Optican, Lance 567 Optokinetic eye movements 783 797 Optokinetic reflex, contributions to subcortical and cortical structures 812–813 Optokinetic signals convergence with vestibular signals during rotational movement 828–829 provides visual information to central vestibular system to stabilize eyes 810 supplement to vestibulo-ocular reflexes 809–810 Orbitofrontal cortex in hallucinations in schizophrenia 1190 olfactory information processing 633 Orexin system, in ascending arousal system 900 Organ of Corti cellular architecture 596 cochlea 592 innervation 602 mechanoelectrical transduction 597–599 scanning electron micrographs 597 P.1382 Organelles membranous carried by fast axonal transport 100–103 in neurons 69–71 transport along axon 99–103 Organizer graft experiment, amphibian embryos 1023 Organizer region differentiation of neural plate 1023 inductive signals 1027 proteins expressed by 1026 neural, signals from pattern the midbrain 1034–1035 Orientation columns 537 540 541 development directed by intracortical connections 1125 Orientation-sensitive neurons area 2, primary somatic sensory cortex 466 in somatic sensory cortex 464 Orientation-specific columns 545 Orlovsky, Grigori 750 Orphan receptor, novel opioid-like 486 Orthologs 60 Oscillator, in circadian clock 44 Osmolality, tissue, regulation of drinking 1006–1007 Osmosis 108 Ossicles, ear 591–592 591 Otic ganglion 964 Otoacoustical emission, evoked and spontaneous 600 Otoconia, utricle 804 804 Otolith organs, in vestibulo-ocular reflexes 809 Otolith reflexes 809 compensate for linear motion and head deviations relative to gravity 809 Otolithic membrane, utricle 804 804 Otolithic organs 804 Otolithic organs, detect accelerations by inertia of internal contents 804 Otosclerosis, hearing loss 593 Outer hair cell cochlea 596 organ of Corti 596 Output component, nerve cell signaling 31 Output signal 27 30 Oval window 595 cochlea 592 Ovulated, related to absence of testes at neonatal stages 1134–1135

Oxytocin magnocellular endocrine neurons 978 posterior pituitary gland 979 secretion by hypothalamic magnocellular neurons 979

P P cells attributes 581 carry signals for color to cortex 588 chromatic properties 579 convey brightness and color information in complex signal 580 inputs from L and M cones 581 retinal 501 ganglion cells 520 projections 545 sensitivity to stimuli, compared with M cells 530 subtypes 579 P element 43 48 P ganglion cells, projection to parvocellular layers of lateral geniculate nucleus 529 P pathway function 545 projections 567–568 visual system 501 502 505 P See Permeability P-region loop, K+ ions bind to in inward rectifying K+ channel 121 P-region 119 p75-NTR, neurotrophic receptor 1056 1057 Pacing, neuronal 923 Pacinian corpuscle 432 433 433 434 436 sensitivity 438 resolution 440 response and adaptation 425 threshold sensitivity to vibration 437 Pain abnormal states 475 as complex perception 489–490 asymbolia for 482 central 481 chemical intermediaries for 442 control by central mechanisms 482–483 control by morphine activation of opioid receptors 486–489 gate-control hypothesis 486 gate-control theory 482–483 importance of purinergic transmission in 285 individual and subjective nature 473 mechanical thresholds for 479 mediated by nociceptors 442–443 modulation by descending monoaminergic projections 896 neuropathic 473 nociceptive 473 nociceptors 430 perception 472–491 role of serotonergic neurons 896 processing in cerebral cortex 481–482 propagation of action potentials in sensory fibers 473 referred 475 relief of 482 sensations of mediated by anterolateral system 448–449 sensory illusion of in cerebral cortex 484 484 spontaneous 479 transmission 490 versus neural mechanisms of nociception 472–473 Painful sensations, mediated by dorsal root ganglion neurons with bare nerve endings 431 Paleocortex, developing forebrain 1036 Paleospinothalamic tract 481 Pallidotomy, surgical procedure hemiballism 864 Parkinson disease 863 Pallidum developing forebrain 1036 dopaminergic synapses 857 Palmitoylation, post-translational chemical modification of protein 90 Panic attacks substances that induce 1221 symptoms 1221–1222 Panic disorder 1221 abnormality in biogenic amine pathways 1224 alterations in synaptic function 1224 Papez, James 986 987 988 Papillary ridges, deformation in sensed by mechanoreceptors 433 Papio papio, animal model for seizures 930 Parabrachial nucleus 892 in ascending arousal system 900 in autonomic response control pathway 975 behavioral responses to taste and visceral sensations 973 pathway of sensory information 974 Paradoxical sleep 938 Parahippocampal cortex 1232 and emotion 992–994 storage of emotional memory 991 Parahippocampal gyrus 369

in limbic lobe 986 987 perception of feeling and emotion 988 Paralimbic region, in hallucinations in schizophrenia 1190 Parallel distributed processing, organizational principle of nervous system 9 Parallel fiber system, compared with mossy and climbing fiber systems 838 Parallel fiber-Purkinje cell synapses, selection of specific Purkinje cells to program or correct eye or limb movements 848 Parallel fibers, effect of climbing fiber activity on 840–841 Parallel pathways and construction of visual images 502–504 dorsal visual pathways for visuomotor transformations 775 processing of acoustical information 606 P.1383 projection from higher motor centers to spinal cord 648 visual information 500–501 in visual system 504–505 521 567–568 on-center and off-center ganglion cells 519–520 Parallel processing in brain 34 distinct areas of somatic sensory cortex for stimulus features 465–468 information for stereognosis in somatic sensory cortex 467 motor commands 662 preattentive visual system 503 sensory information 319 352 354 somatic sensation 469 in vision 416 505 517 545 Paralysis diffuse hypoperfusion 1313 sleep, symptom of narcoleptic syndrome 949 Paramedian pontine reticular formation 788 motor circuit for horizontal saccades 791 Paramedian pontine, right, lesion, ocular reflexes characteristic 907 Paramedian reticular formation, location and function 887 Paranoid schizophrenia 1193 Paraphasia 11 1179 Parasomnias 955–958 familial nature 956 Parasympathetic division, autonomic nervous system 961 neurons and projections 964 Parasympathetic neuron, develops from neural crest cells 1047 Parasympathetic pathways 963–964 Parasympathetic system, autonomic division of peripheral nervous system 335 Parataenial nucleus, thalamus 343 Paraventricular nucleus 976 hypothalamus 977 thalamus 343 Paravertebral chain ganglion 962 Paresthesias 701 symptoms 701–702 Parietal areas 775 Parietal association cortex common output targets of 363 densely interconnected region of association cortex 362 inputs to premotor cortex 355 prominence of particular cell layers 328 Parietal cortex controls visual attention 794 lesions 794 795 disrupt visual orientation 498 produce deficits in smooth-pursuit eye movements 556 medial superior temporal area, analysis of optic flow 553 motion analyzed in dorsal pathway leading to 522–558 and movement 567 sensory homunculus 387 topographic maps constructed from sensory-evoked potentials 458 Parietal lobe 8 324 325 367 of cerebral cortex 325 decreased blood flow in Alzheimer disease 1152 function 9 human aspects of cortical organization 402 Parietal occipital sulcus 324 Parieto-occipital extrastriate area 775 Parieto-premotor channels, separate, mediate reaching and grasping 777–778 Parinaud syndrome, midbrain infarction 1312 Parkinson disease 767 and basal ganglia 853 basal ganglia-thalamocortical circuit in 860–861 chemical synapses as target 867 damage of dopaminergic neurons in substantia nigra 322 degeneration of dopaminergic neurons in 50 dopamine level in basal ganglia decreased in 864 therapy 865 effect of L-dopa 862 as molecular disease 854 neurons of basal ganglia 649 neurotransmitter deficiency in 862 nigrostriatal pathway 283 overactivity in direct pathway of basal ganglia 862–864 PET imaging of fetal dopaminergic cells implanted in brain of patient with 378 role of microglia 20

surgical intervention 863 863 symptoms 862 and interneurons 33 Parkinson, James 862 Parkinsonian signs, excessive activity in indirect pathway at subthalamic nucleus 862–863 Paroxysmal depolarizing shift conductances underlying in seizure focus 920 in seizure focus neurons 917–918 Pars compacta, basal ganglia 855 Pars reticulata, basal ganglia 855 Partial seizure See Seizure, partial Parvocellular layers, lateral geniculate nucleus 529 Parvocellular neurons, hypothalamus, secrete peptides that regulate release of anterior pituitary hormones 979 Parvocellular pathway 548 continues in ventral (temporal) pathway 549 550 projections 549–552 selective inactivation in lateral geniculate nucleus 551 to visual cortex 529–532 Patch clamp recording current flow in ion channels 111 demonstration of two conductance states of voltage-gated channels 162 measurement of current flow through ion channels 192–193 recording currents from single ACh-gated channel 195 current through GAB A- and glycine-gated channels 217 S-type K+ channel activity 245–246 245 refinement of voltage-clamp technique 152 See also Single-channel recording S-type K+ channels and modulation by FMRFamide 246 study of ion channels 109–110 synaptic transmission at central synapses 201 use of planar lipid bilayers in 111 patched gene, effects of mutations in 1029 Patched, interaction with sonic hedgehog 1027 Pathfinding, axonal See Axon guidance Patrick, James 300 Pattern direction-sensitive neurons 554 556 Pattern generator, locomotor, hypothetical 746 Pattern recognition 493 Patterning, induction of in nervous system 1019–1040 Pauling, Linus 867 Pavlov, Ivan 11 382 1240 1248 PCP See Phencyclidine PCR See Polymerase chain reaction PDGF See Platelet-derived growth factor PDS See Paroxysmal depolarizing shift PDZ class proteins See PSD-95 PDZ domains in postsynaptic protein 221 protein class that facilitates clustering of NMDA-type glutamate receptors 1103 Peduncles 8 Peduncolopontine nucleus in ascending arousal system 900 in basal ganglia-thalamocortical circuit 860–861 cholinergic cell groups in 894 control of sleep 941 Pelizaeus-Merzbacher disease, results from proteolipid PLP mutation 83 P.1384 Pelvic ganglion 964 Pemoline, treatment, narcolepsy 951 Pendular reflexes 844 Penetrance 53 Penetrating arteries, occlusion 1308–1309 Penfield, Wilder 12 344 387 925 911 1229 Penicillin, produces generalized epilepsy in cats 923 Peptide A, precursor structure 291 Peptide hormones, released by hypothalamic parvocellular neurons 979 PER protein circadian rhythm 44 dimerization with TIM protein 46 Percept, pain as 472–491 Perception 407–649 473 beginning in receptor cells 407 as constructive process 383 contributions of M and P cells 532 different modalities processed similarly by different sensory systems 381–382 functional organization 337–348 holistic nature 493 internal cellular representation required for 381–303 internal construction of world 412 motion, depth, and form 548–571 multimodal association areas of cerebral cortex as anatomical substrate for 350 nature of 408 neural representation 383 pain 472–491 pathway of processing 319 space See Vestibular system spatial, impairment after middle cerebral artery infarction 1307–1308 visual 492–506 See also Visual perception weakness in empiricist argument 412 Perceptual correlates, posture 829–830 Perceptual functions, role of cerebral hemispheres 322

Perforant fiber pathway, hippocampus 1257 Perforant pathway hippocampus 1259 long-term potentiation is associative 1260 Performance, affected by arousal level 983 Periaqueductal gray matter 482 in autonomic response control pathway 975 behaviorally coordinated patterns of autonomic response 973 inhibitory descending pathway, pain 486 pathway of sensory information 974 Periglomerular interneurons inhibitory synapses with mitral cell dendrites in glomerulus 632 of factory bulb 630 631 Perilymph 803 Perilymphatic duct 802 period gene circadian rhythm in flies 45 flies, role in circadian rhythm 44 fly, molecular polymorphisms in and circadian rhythm 42 Periodic limb movement disorder, sleep pathology 955 Peripersonal space 384 402 Peripheral motor axons, conduction velocities in neuropathies 699 Peripheral myelin protein 22 duplication of gene causes Charcot-Marie-Tooth disease 83–84 mutations of gene for in hereditary peripheral neuropathies 709 Peripheral nerves afferent fiber groups in 444 conduction velocities 444 cutaneous innervation map 734 diseases, acute or chronic 701–704 provide permissive environment for regeneration of central axons 1112 Peripheral nervous system 335 anatomical but not functional distinction from central nervous system 334–335 dependence on neurotrophic factors 1059 factors contributing to regenerative capacities 1110 greater capacity for nerve regeneration 1109–1110 myelination in 81 somatic and autonomic divisions 335 Peripheral neuropathies 696 Peripheral neuropathy inherited, Charcot-Marie-Tooth disease 83–84 symptoms 702 Peripheral receptors, in motor system 667 Peripheral sensors, fragment tactile information about object 452 Perirhinal cortex 1232 Peristalsis, control by enteric nervous system 968 Perisylvian language areas, damage to connections with transcortical sensory area 1181 Perivascular space, cerebrospinal fluid 1294 Periventricular fiber system, hypothalamus 978 Periventricular nucleus 976 Permeability 135 changes in during signaling 138–139 membrane to ion, calculation 132–134 membrane 135 use in Goldmann equation 132 Peroxisomes importation of proteins synthesized in cytosol 93–94 neuron 70 role in protein synthesis 91 Persephin, neurotrophin receptor 1057 Persistent vegetative state, as result of bilateral forebrain damage 900 901 Personal neglect syndrome 393 393–394 Personal space 384 internal representation explored by study of touch and proprioception 385 modifiable by experience 388–391 orderly representation in brain studied at cellular levels 384–388 Personality anatomical localization of affective traits and aspects 14–15 disorders 1192 twin studies 42 PET See Positron emission tomography Petersen, Steve 846 Petit mal seizure See Seizure, absence Petrosal ganglion innervation of taste buds 643 taste information pathway 642 Pettigrew, Jack 561 Pfaffkinger, Paul 248 Pfeiffer, Carroll 1134 PGO spikes See Pontogeniculo-occipital spikes PGO-on cells, patterns of activity during REM sleep 940 Phalangeal cells, organ of Corti 596 598 Phantom limb pain 473 479 Phantom limb syndrome, imaging studies of 390 Pharynx, taste information pathway 642 Phase lag, in feedback systems 656–657 Phase locking, cochlear nerve 603 Phe-Met-Arg-Phe-amide activates S-type K+ channels 243 precursor structure 291 neuroactive peptide 289

slow synaptic action mediated by opens same S-type K+ channel closed by serotonin 246 Phencyclidine inhibits NMDA receptor-channel 213 molecular targets and effects 1206 Phenelzine, antidepressant, structure 1213 Phenobarbital, as anticonvulsant 911 Phenothiazines, treatment, schizophrenia 1197 1197 Phenotype 38 relationship with genotype 38–40 Phenylethylamines, as false transmitters 286 Phenylketonuria, example of interaction of genes and environment 36–37 37 Phenytoin, treatment, prolonged repetitive seizures 919 Pheromone receptors 634 pattern of expression in vomeronasal organ 635 635 P.1385 Pheromones, chemical messengers 633–634 Phineas Gage, reconstruction of injury to temporal lobes 353 Phoenix, Charles 1136 Phonemic paraphasias, in Wernicke aphasia 1179–1180 Phonological store, left supramarginal gyrus 360 Phonology, grammar 1171 Phosphatase-1 249 Phosphatidylinositol4, 5-bisphosphate, hydrolyzed phospholipid 236 Phosphene 418 Phosphoinositol system 231 Phospholipids, hydrolysis of in cell membrane 236 237 Phosphoprotein phosphatases, regulate levels of phosphorylation 249 Phosphorylation cascade, in hippocampus 249 hydroxyl group in Ser, Thr, or Tyr residues by protein kinases, post-translational protein modification 93 ion channels, effect on funtional state 251 levels regulated by phosphoprotein phosphatases 249 neuronal, dopamine role in 249 of proteins in Golgi complex 96 receptor 230 sequence, and specificity of protein kinases 235 Photopigments, cones 573 575 576 as transmembrane proteins 576 Photoreceptors absorption of light by visual pigments in 510 activation of pigment molecules reduced cytoplasmic concentration of cGMP 512–514 dark current 513 531 hyperpolarization 513 514–515 interneurons relay signals from to ganglion cells 520–521 retina 508–510 508 rod and cone 417 slow adaptation to changes in light intensity 515–517 transduction of light into electrical signals 521 stimulus energy into neural activity requires intracellular second messengers 417 types of in color vision 573–575 Phototransduction closing of cation channels during in photoreceptors 512 mechanism 510–515 role of calcium 514 cGMP 521 G protein 521 Phrenology 7 map of skull 7 Physical stimulus, transformation into electrical activity 30 Physiological monitoring methods, sleep 949 Physostigmine, reverses symptoms of myasthenia gravis 299 Pigment epithelium, eye 508 508 Pillar cells, organ of Corti 596 P1P2 See Phosphatidylinositol 4, 5-bisphosphate Piriform cortex, olfactory information processing 633 Pitch, sense of, tonotopic maps underlying 1127 Pituitary, anterior, control of hormone release by peptides of parvocellular neurons 979 Pituitary gland 367 anterior hormone-dependent sex difference 1134 hormones and hypothalamic substances regulating 980 hormonal secretions regulated by hypothalamus 322 and hypothalamic control of endocrine system 978–979 pathways of control by hypothalamus 977 posterior absence of blood-brain barrier 1293 hormones 979 PKA, ACh receptor as substrate for 248 PKA See Protein kinase A PKC, ACh receptor as substrate for 248 Place cells firing patterns 1267 hippocampus 1264–1267 long-term potentiation fine-tunes properties of 1267 Place code 603 Place cues 992 Place field, hippocampus 1264 Place-preference 992 Planning

behavior, tests of 358 behavioral, disturbed by lesions of prefrontal association area 361–362 motor, affected by lesions in prefrontal association area 356–357 prefrontal association area 356 role of frontal lobe 9 and voluntary movement 756 Plasma cell diseases, chronic neuropathy in 702 Plasmalemma membrane in bulk endocytosis 98 maintenance in steady state by endocytosis 97 manufacture on rough endoplasmic reticulum 103 membrane anchor on proteins destined for 96 neuron 69 synthesized and modified in endoplasmic reticulum 94–96 vesicles that fuse with 97 Plasmapheresis, treatment of symptoms of autoimmune myasthenia gravis 306 Plasticity chemical synapses 34 hypothesis, in nervous system 34 Plateau potentials 743 744 Platelet-derived growth factor, and diversification of glial cells in rat optic nerve 1048 Plato 897 1317 Pleasure, effect on motivational states 1007 1009 Plexiform layers, retina 520 Plexins, receptors for semaphorins 1081 PMP22 See Peripheral myelin protein 22 Poggio, Gian 562 Poisons, ion channels as site of activity 105 Polarity, surface electroencephalogram, and location of synpatic activity in cortex 915 Poliomyelitis 701 and motor neurons 33 Polyamines, as blocking molecules in ion channels 112 Polygenic trait 55 Polymerase chain reaction, method for identifying polymorphisms 56–57 Polymodal nociceptors 443 474 Polymodal sensory association areas, cerebral cortex, lobes and location 351 Polymorphic variation, rate of 38 Polymorphisms allelic 38 genetic 38 methods of identifying 56–58 Polymyositis syndrome acquired myopathic disease 701 inflammatory myopathy 705 Polyneuropathy 732 Polypeptide See also Protein Polypeptides, signals for attachment to ribosomes 94 Polyprotein 288 Polyribosomes, in dendrites 90 Polysaccharide chain, complex, addition to protein during glycosylation in endoplasmic reticulum 95 Polysomes association of mRNA molecules with 90 free and membrane-bound 93 role in protein synthesis 91 Polysomnograms, electrophysiological measures 949 Polysynaptic circuits 26 P.1386 POMC See Proopiomelanocortin Pons 9 320 324 367 369 671 activation of GABA-ergic cells during REM sleep and loss of muscle tone 942 function 7 8 8 322 hemorrhage, effects 1315 infarction, PET scan 1311 junction with midbrain, location of nuclei that regulate REM sleep 940–943 lesions destroying ventral locus ceruleus in cats, and dream enactment 956 lower anatomy 1310 vascular lesion syndromes of 1310 noradrenergic neurons in 891 part of brain stem 320 role in control of smooth pursuit 795–796 upper anatomy 1310 vascular lesion syndromes of 1310 Pontine arteries 1303 Pontine flexure 1022 Pontine gaze centers, lesions 792 Pontine nuclei 347 Pontine reticular formation 885 887 generates horizontal saccades 789–791 Pontine, right lateral lesion, ocular reflexes characteristic 907 Ponto-geniculate-occipital-on cells control of sleep 941 regulated by REM-off cells in raphe nuclei of brain stem 942 Ponto-geniculo-occipital spikes, during REM sleep 938 Population codes 423 Population coding, superior colliculus 793 Population vector 766 Pore-forming region, ion channel, subunits 116 Position invariance 564 Positional cloning 705

Positive symptoms, schizophrenia 1192 Positivism 411 Positivism, influence on behaviorist psychology 412 Positron emission tomography (PET) 13 336 fetal dopaminergic cells implanted in Parkinson's disease brain 378 identification of regions of cerebral cortex involved in language processing 14 imaging of somatotopic functioning of cortex 458–459 infarction cerebral arteries 1305 1306 pons 1311 measurement of glucose consumption pattern in brain 376–377 measurement of local changes in cerebral cortex blood flow during processing of visual information 378 physical basis of 375 scan of patient with temporal lobe epilepsy 929 study of language 379 study of seizures with 927 technique 376–377 Posner, Michael 13 400 504 Post-saccadic drift 795 Post-traumatic stress disorder, symptoms 1222 Post-traumatic stress syndrome, genetic component, alteration in gene expression 1276 Postassium channel, electrical properties of 133 Postcentral gyrus 9 482 pathway of sensory information 446 Posterior association area, cerebral cortex 350 Posterior cerebral arteries, inferior temporal and medial occipital lobes, corpus callosum 1304 Posterior cerebral artery 1303 infarction 1308 PET scan of infarction 1306 Posterior commissure 788 Posterior communication artery 1303 Posterior fossa, aneurysms, effects 1316 Posterior inferior cerebellar artery 1304 infarction, brain stem syndromes produced 1311–1312 Posterior language areas, damaged in gloval aphasia 1181 Posterior nuclei, thalamus 343 Posterior parietal areas 5 and 7, inputs to primary motor cortex 760–761 Posterior parietal association area, projections 361 Posterior parietal association cortex 402 receives input from hippocampus 392–395 representation of imagined and remembered extrapersonal space in 392–395 Posterior parietal cortex 453 501 757 areas 5 and 7, integrative somatosensory responses for movement 465 area 7, integration of tactile and visual stimuli 465 effect of lesions in on visual system 498 function 351 lesions produce complex sensorimotor abnormalities 469 motion, depth, spatial information 502 and neural mechanisms of selective attention 400 401 roles 453 somatosensory cortical area 452 and visual attention 565 Posterior parietal cortical areas, mental rehearsal of movement 771 Posterior parietal lobe, damage to produces agnosia 392–393 Posterior parietal pathway cross talk with inferior temporal pathway 567–568 visual 500–501 Posterior pial arteriolar plexus 1314 Posterior radicular artery 1314 Posterolateral fissue, cerebellum 833 Postganglionic fibers, peripheral autonomic effector organs 962 Postganglionic neurons pathways 963 See also Autonomic motor neurons Postganglionic sympathetic neurons ATP as cotransmitter with norepinephrine 970 release of norepinephrine 970 Postherpetic neuralgia 473 Postictal period 913 Postspike facilitation 767 Postsynaptic cell 23 axo-axonic synapses inhibit or facilitate transmitter release 276 Postsynaptic density protein, PSD-95 221 Postsynaptic inhibition 275 Postsynaptic membrane 188 Postsynaptic neuron, impact of inhibitory current 225 Postsynaptic potential, high rate of stimulation of presynaptic neuron produces gradual increase in amplitude 275 Posttetanic potentiation 274 Postural changes, conscious ideas about have physiological consequences 830 Postural disturbances, learning of appropriate anticipatory responses 820 820 Postural equilibrium 817 Postural reflexes 816 817 Postural set 819 Postural system, functions 816 Posture 816–831 adjustment, contribution of vestibular system 824 contributions of neck 821–824 control adaptation to specific behaviors 819–820 adaptive learned during locomotion 821 requires intact cerebellum 820–821

feed-forward and feedback components 819 goals 830 by medial brain stem pathway 668 by medial descending systems 663 destabilizing effect of optokinetic stimulation 828 P.1387 disturbance, anticipatory motor action in response to 819 and equilibrium 817 feed-forward control in motor systems for control of 657 and locomotion, adaptability 822 maintained by cerebellum 322 modulation by medial and lateral reticulospinal pathways 896 and movement 817–821 perceptual correlates 829–830 readjustment preceded by anticipatory motor action 817–818 818 stability, collaboration of vestibulospinal and cervicospinal reflexes to maintain 823–824 823 vertical, maintained by vestibulospinal reflexes 810 vestibular contributions 821–824 Potassium activation of nociceptors 480 astrocytes main correct ion concentration 20–21 chemical intermediary for pain 442 extracellular, effect on excitability of neurons in seizure focus 919 permeability of synaptic channels at end-plate to 192 time course of concentration in cerebral cortex 1291 Potassium channel depolarization-activated and Ca2+ -activated, molecular structure 168 inactivating, molecular structure 168 noninactivating, molecular structure 168 electrical properties of 133 inward-rectifier, molecular structure 168 several, as single equivalent electric structure comprising a battery in series with a conductor 134 Potassium current calculation of voltage-gated K+ conductance from 154–155 hyperpolarization of thalamic relay nuclei 898 passive, balanced by active K+ fluxes driven by Na+ -K+ pump 135 Potassium equilibrium potential 128 Potassium ion channel passive, as equivalent electrical circuit 134 substances that block 154 Potassium ions channels permeable to opened by ACh binding in postsynaptic muscle cell 199 conducted along with Na+ in glutamate-gated channels 212 contribution of efflux of to transmitter release 254–255 diffusion out of cell 128 diffusion out of glial cells 128 distribution across cell membrane 128 distribution across neuronal cell membrane at rest 128 and electric potential of nerve cell membrane 27 flux across cell membrane 129 free energy of binding 109 increased permeability for in falling phase of action potential 151 model for selectivity of ion channels for 106–107 nerve cells permeable to at rest 129 passive flux balanced by active pumping of ions 131 resting ion channels in glial cells selective for 128–129 nerve cells selective for, in addition to Na+ and CI- ions 129–131 simultaneous flow with Na+ produces end-plate potential 193 Potassium-selective ion channel, structure solved by X-ray crystallography 120–123 122 Potential difference circuit analysis 1284–1285 electrical parameter 1280 factors affecting 1282 Potentiation 274 Potter, Lincoln 300 Power grip activity of single neuron during 772 control by descending pathways 769 770 Practice, movement, shift of neural control from supplementary motor area to primary motor cortex 774 Preattentive process, visual perception 502–503 Preattentive scanning 503 Precentral gyrus 9 Precerebellar nuclei 842 Precision grip activity of single neuron during 772 population of primary motor cortex cells active during 769 Precursor RNA, transcribed and spliced in nucleus 89 Prefrontal association area dopaminergic innervation 361 effect of lesions of 356–357 functions 356 illustrate function of association cortex 356–362 lesions of disturb behavioral planning 361–362 Prefrontal association cortex common output targets of 363 inputs to premotor cortex 355 prominence of particular cell layers 328 Prefrontal circuit, basal ganglia, links thalamus and cerebral cortex 858 Prefrontal cortex 757 attentional signals that modulate neurons in visual system originate in 401 delayed response task testing 359

disorders of action associated with 866 dorsolateral, increased blood flow in cocaine craving 1008 and episodic knowledge 1237–1239 evaluative component of emotion 985 left, in encoding of epidsodic memory 1238 projections of mesocortical system to 1202 right, in retrieval of episodic memory 1238 subgenual region abnormality of function in depressions 1212–1213 1212 effects of lesions in 1213 and visual attention 505 Prefrontal region, contains map of contralateral visual field that is used for working memory 359 Preganglionic neuron 962 Preganglionic sympathetic neurons, column in intermediolateral horn of spinal cord 963 Prehension 846 Premamillary preparations, study of stepping 738–739 Premotor areas 775 Premotor areas 775 contributions to motor planning 770–777 direct electrical stimulation stimulates movement 760 mental rehearsal of movement 771 motor maps of face and extremities in 760 movement-related neurons in 779 number of 760 projections 663 to primary motor cortex, and spinal cord 760 role in coordinating and planning complex movement 663 Premotor cortex 347 347 756 757 758 761 function 355 inputs to 355–356 761 location 671 Premotor neurons 696 degeneraton in amyotrophic lateral sclerosis 700 Premotor-cerebello-rubrocerebellar loop, role in mental rehearsal of movements and motor learning 846 Preoptic area baroreceptors in 1006–1007 hypothalamus 977 Preparations, spinal, types used in study of stepping 738–739 740 P.1388 Preparatory potential, negative potential in supplementary motor area 771 Preparatory set activity, primary motor cortex neurons 764–765 Preprohormone 288 Presenilin 1 and 2 genes, genetic risk factors in Alzheimer disease 1156 Presupplementary motor area learning motor programs 773 role in learning sequences of movements 771–774 Presynaptic bouton, structure 189 Presynaptic cell 22 Presynaptic contacts, on primary dendrites of motor neuron 76 Presynaptic differentiation, factors that organize 1100 Presynaptic facilitation 275 mechanisms of 275–276 Presynaptic inhibition 275 mechanisms of 275 Presynaptic membrane 188 Presynaptic neuron, high rate of stimulation produces gradual increase in postsynaptic potential 275 Presynaptic terminal 22 23 182 active zones 261 all-or-none transmitter release from active zones 261 axo-axonic synapses on regulate intracellular free calcium 275–276 blocking voltage-sensitive Na+ and K+ channels in 255 boutons 188 Ca2+ influx triggers neurotransmitter release 256 depolarization of regulates neurotransmitter release 253–255 exocytosis events 265 neuronal 21 sensory neurons, structural changes in long-term habituation and sensitization 1256 Pretectum controls pupillary reflexes 527–528 optic nerve projections to 517 retinal projections to 523 527 Prevertebral ganglia 963 Primary afferent fiber 431 Primary auditory cortex 604 columns in 609 left, affected in conduction aphasia 1180 parallel processing and conformal mapping in 609 tonotopic maps in 609 Primary cortex, two different meanings for term 350 Primary fissue, cerebellum 833 Primary motor cortex 326 346 355 756 757 758 761 775 adaptation of movements to new conditions 764–770 blood flow in during finger movements 773 comparisons of somatotopic organization in monkey and human 757 corticomotoneuronal cells in 765 distribution of sites controlling individual muscle 759 execution of movements 764–770 fibers originating in and terminating in ventral horn of spinal cord 346 functional organization changed after transection of facial nerve in rat 762 hand-control area 768 771

highest level of motor control 663 increased representation of movement with practice 763 individual movement of fingers 767–770 inputs from primary somatosensory cortex and posterior parietal areas 5 and 7 760–761 levels of functional organization 770 lobes and location 351 location 671 magnetic stimulation 759 motor map in 323 neurons can be activated by peripheral stimulation 767 organization of voluntary movement 758–759 populations of neurons in encode movement direction 765–766 premotor cortical areas project to 760 projections of thalamic neurons to 843 prominence of particular cell layers 328 relationship to association regions 352 representations of individual muscles overlap 759 somatotopic organization 347 Primary sensory cortex ascending dorsal column-medial lemniscal pathway 342 lobes and location 351 relationship to association regions 352 variation of body surface maps of among individuals 1274 Primary somatic sensory cortex 757 area 2, feature-detecting neurons 466 effects of lesions 468 integrates information about touch 452–458 location and projections 452 processing of sensory information in cerebral cortex 345 properties of neuronal receptive fields due to convergent and divergent connections in relay nuclei 456 receptive fields of cells comprising column in 456 neurons in 455 Primary somatosensory cortex 326 contains body map for each submodality of sensation 387–388 each area has complete representation of body surface 389 increased use of fingers enlarges representation of hand in 390 inputs to premotor cortex 355 primary motor cortex 760–761 mapping of 387 modification of cortical representation of hand 389–390 pattern of connections genetically programmed and also develops through learning 388–389 representation of hand with fused and nonfused digits 391 somatic sensory information conveyed to in parallel pathways 449 vestibular projection to 813 Primary spindle endings 720 Primary visual cortex 326 775 anatomical layers 533 blobs, stripes, and interblobs 501 cells in converge on cells in association cortex 324 columnar units linked by horizontal connections 540–543 combines information from two eyes 560–561 complex cells, feature abstraction by progressive convergence 535–537 each half of visual field represented in contralateral 532 information flow 533 input and output 533 interconnections with V2 549 intracortical connections 533 lesions, blindsight 1318 links between columns and horizontal connections 542 neurons not in distinct color classes 582–583 organization 549 of blobs in 539 into functional modules 537–543 of orientation columns, ocular dominance columns, and blobs 541 of retinal input into building blocks of visual images 532–537 orientation columns in 538 outlines of visual image decomposed into short line segments 533–535 prominence of particular cell layers 328 response of cells to moving plaid pattern 554 retinal projections to 543 See also Ocular dominance columns separation of function of dorsal and ventral pathways 549–550 structure 532 P.1389 two types of cells 533–535 visual system 496 Priming 1230 Principal neurons 323 Principal sensory trigeminal nucleus 881 function 882 Principal sulcus cortex surrounding and tasks that require working memory 357–361 memory fields in neurons of 359 neurons in track working memory 361 Principal trigeminal nucleus, pathway of sensory information 446 Pro-opiomelanocortin, precursor structure 291 Proctolin, neuroactive peptide 289 Prodromal signs, schizophrenia 1192 Prodynorphin 487 Proenkephalin 487

Programmed cell death 1041 See also Apoptosis Progressive bulbar palsy 700 Prohormone 288 Projection interneuron, functional regions 28 Projection neurons 323 329 330 335 afferent connections with in spinal cord 667 dorsal horn of spinal cord, nociceptive afferent fibers terminate on 474 inhibition in sensory relay nucleus enhances contrast between stimuli 427 Projections from cell layers of neocortex 329 retinal 526–529 Prolactin inhibitory control 979 neuroactive peptide 289 precursor structure 291 Prolactin release-inhibiting hormone, hypothalamic 980 Prolactin-releasing factor, hypothalamic 980 Proneural genes 1045 Proneural region, ectodermal 1043 Proneural strips 1046–1047 Proopiomelanocortin 487 neuroactive peptide 288 precursor polypeptide of opioid peptides 485 Propagation 145 factors affecting velocity of during action potential 147–148 Propranolol effect on storage of emotional events 992–993 treatment, post-traumatic stress disorder 1222 Proprioception 430 443 dorsal column-medial lemniscal system is pathway for perception 447–448 mediated by dorsal root ganglion neurons with encapsulated peripheral terminals 431 mechanoreceptors in skeletal muscle and joint capsules 443 study of to explore internal representations of personal space 384 timing and amplitude of stepping patterns 748 749 Proprioceptive reflexes, role in voluntary and automatic movements 726–730 Proprioceptors, automatic regulation of stepping 747 Propriospinal interneurons, short and long 668 Propriospinal neurons afferent connections with in spinal cord 667 organiziation of axons in spinal cord 667 Prosencephalon 1021 1022 1022 Prosencephaly 1029 Prosody 14 1171 Prosomeres 1035 Prosopagnosia 499 500 994 1237 lesions causing 499–500 Prostaglandin D2, hypnogenic properties 943 Prostaglandins action at synapses 262 effect on nociceptors 481 mediation of 237 and nociceptor sensitization 477–478 480 Prostigmine, enhance and prolong miniature end-plate potentials 257 Protanopia 584 Protection hypothesis, brain development 1139 Protein coats, generation of transport vesicles 96 Protein folding, role of chaperones 91–92 Protein kinase A (PKA) activation in ax on growth cones 1078 long-term potentiaton 1260 in long-term facilitation 1257 pathways of action in sensitization 1250–1251 role in learning and short-term memory in Drosophila 1258 sensitization 1250–1251 Protein kinase C isoforms 238 regulation 235 Protein kinases activation by second messengers 251 modification of gating by changing phosphorylation state 159 See also cAMP-dependent protein kinase specificity 235 Protein phosphorylation, effect on ion channel gating 114 Protein tyrosine kinases, and neurotrophin mechanism of action 1058 Proteins cellular organelles responsible for synthesis and processing of 91 cotranslational modifications 92–93 cytosolic enzymes that catalyze metabolic reactions 90 fibrillar elements of cytoskeleton 90 importation by nucleus, mitochondria, and peroxisomes 93–94 phosphorylation and dephosphorylation 93 ubiquitination 93 export signals 93 function defined by amino acid sequence and secondary and tertiary structure 91–92 kinases, similar regulation of 235 membrane, synthesis and modification in endoplasmic reticulum 94–95 modification during or after synthesis 92–93 nuclear localization signals 93 organelles responsible for synthesis and processing 93

post-translational modifications 90 92–93 reversibility of post-translational modifications 93 secretory method of formation in endoplasmic reticulum 95 processing in Golgi complex and export 96–97 synthesized and modified in endoplasmic reticulum 94–96 signal for mitochondrial import 93 structure, role of formation of intramolecular disulfide linkages 96 glycosylation 96 modifications 103 synthesis in cell body and dendrites 88–92 103 in consolidation of long-term implicit memory 1256–1257 occurs in cytosol 89 transmembrane, method of formation in endoplasmic reticulum 95 transport along axon 99–103 types of modifications in endoplasmic reticulum 94–95 in Golgi complex 96 vacuolar apparatus, synthesized and modified in endoplasmic reticulum 94–96 P.1390 Proteolipid PLP mutations of 83 protein component of central myelin 83 Proteolytic cleavage, of proteins in Golgi complex 96 Protoanomaly 584 Protopathic sensations 431 432 Proust, Marcel 406 407 Proximal stump, peripheral nerve 1109 PSD-95, and clustering of neurotransmitter receptors at central neuron synapses 1104 Pseudobulbar palsy, bilateral lesions of corticospinal tract 1313 Pseudoconditioning See Sensitization Pseudounipolar neurons, in spinal cord 340 Psychiatric disorders insight into provided by neuronal changes in learning 1275–1277 See Mental disorders Psychoanalytic theory 4 Psychodynamics 4 Psychology distinct from philosophy 411 focus on cognition 313 Gestalt 493–494 Psychometric function 421 Psychophysical parallelism, and consciousness 1318 Psychophysical studies 659 Psychophysics 412 Psychotherapy changes in behavior and gene expression 1275 1277 monitoring progress of with brain imaging techniques 1275 1277 treatment obsessive-compulsive disorder 1224 Psychotic behavior, drugs that induce 1206 See also Psychoactive drugs Psychotic episode, schizophrenia 1193 Pterygopalatine ganglion 964 Ptosis 788 in mysasthenia gravis 299 PTSD See Post-traumatic stress disorder Pulvinar thalamus 343 343 and visual attention 505 Pupil, eye consensual response to light 527 direct response to light 527 state of reflects balance between tone in parasympathetic pupilloconstrictor system and sympathetic pupillodilator pathway 904 Pupillary dilation, regulation by descending pathway from hypothalamus 905 Pupillary light response, in structural coma 904 Pupillary reflexes clinical importance 528 controlled by pretectum of midbrain 527–528 Pupillary response, nature of and level of nervous system dysfunction in coma 906 Purinergic receptors, in autonomic nervous system 971 Purinergic transmission, locations of 285 Purkinje cells cerebellar cortex 835 836 excitatory and inhibitory inputs 835–839 cerebellum GABA as major transmitter 285 multipolar neuron 24 dendrites of excited by beams 837 high level of cGMP-dependent protein phosphorylation in 240 inhibition of activity 839 projections, lesions, effect on vestibular system 841 selection of to program or correct eye or limb movements 848 simple and complex spikes recorded from 839 synaptic effects of climbing fibers 837 synchronization of complex spikes 839 vestibular labyrinth inhibitory influence on vestibular nuclei 825 828 parallel fiber input 827 828 Purkinje neurons cerebellar hemisphere, projections to interposed nucleus 843 inhibitory effect on medial and lateral vestibular nuclei 841 lateral cerebellar cortex, projections to dentate nucleus 845 spinocerebellum, somatotopic projections to deep nuclei that control descending motor pathways 843 Putamen 332 333 347 833

basal ganglia 331 855 855 in basal ganglia-thalamocortical circuit 860–861 hemorrhage, PET scan 1315 integration of movement, and sensory feedback 858 left, and category-specific knowledge 1236 lesions, effects 1315 output neurons 858 projection of skeletomotor circuit to 858 somatotopic organization of movement-related neurons in 858 Putamen/globus pallidus 368 369 Putnam, Tracey 911 Pycock, Christopher 1203 Pyramid 346 876 877 Pyramidal cells in cerebral cortex 922 connections with GABA-ergic neurons in neocortex 331 hippocampal affected in Alzheimer disease 1153 CA1 region dendritic spine shapes 80 excitatory input 85 CA3 region, form synapses on dendrites of CA1 cells in stratum radiatum 79 encode location of animal in particular space 1264 1266 inhibitory postsynaptic potential recorded from 923 multipolar neuron 24 premotor areas, project to spinal cord 760 in primary visual cortex 532–533 533 Pyramidal decussation 346 671 842 876 lateral corticospinal tract 670 Pyramidal neurons cell body 69 cerebral cortex, more extensive dendritic trees than spinal motor neurons 85 glutaminergic, neocortex and entorhinal area, affected in Alzheimer disease 1153 in precentral gyrus 758 preferential loss due to prolonged seizures 928 Pyramidal tract 323 347 347 control of sleep 941 Pyramidal tract syndrome 854 Pyramis, cerebellum 833 Pyridostigmine, treatment of symptoms of autoimmune myasthenia gravis 306

Q QTL See Quantitative trait locus Quadriceps muscle, stretch reflex circuit 208 Quadrigeminal cistern 367 Quadriparesis, bilateral lesions of corticospinal tract 1313 Quadriplegia, bilateral lesions of corticospinal tract 1313 Qualia 398 Quanta 257 fixed increments for neurotransmitter release 260 Quantal synaptic potential 257 Quantitative trait locus 57 Quinn, William 1258

R ra See Axial resistance, 144d Rab3A and -3C mediates vesicle targeting 277 proteins involved in neurotransmitter release 270 P.1391 Rabies virus, effect on emotional state 987 Radial glia 20 Radioactive isotopes, use in PET 375 RAGS See Repulsive axon guidance signal Raichle, Marcus 13 846 Ramachandran, Vilayanur 390 Ramon y Cajal, Santiago 6 7 23 34 175 335 390 1017 1070 Ranson, Stephen 986 Ranson, Stephen Walter 1002 Raphe complex, abnormalities in Alzheimer disease 1153 Raphe magnus nucleus, serotonergic neurons in 893 Raphe nuclei brain stem REM-off cells of regulate PGO-on cells 942 serotonergic neurons in 893 893 dorsal and medial, in ascending arousal system 900 serotonergic neurons in 893 896 serotonergic pathways arising in 1214 1216 synthesis of serotonin 50 Rapid eye movements (REM), sleep 936 See also Sleep, rapid eye movement Rapsyn, role in clustering of acetylcholine receptors at synaptic sites in muscle fiber 1093 1094 Reaching accuracy improved by learning 666 mediated by parieto-premotor channel 777–778 motor cortical cells code force needed to maintain trajectory 770 movement, pathways for 775 parallel dorsal visual pathways for visuomotor transformations 775 parameters for movement 778 See also Power grip; Precision grip Reaction time, variables 662 Reactive time, voluntary movement 661–662

Reading acquired disorders of 1183–1184 developmental dyslexia 1184–1185 disability, genetic component 58 See also Language; Speech versus language, 1170 Receptive field 418 bipolar cells, center-surround structure 521 cells comprising column in primary somatic sensory cortex 456 cells with similar fields are organized into columns in primary visual cortex 537 center 517 center-surround in bipolar cells of retina 518 complex cell or primary visual cortex 536 concentric cells of retina and lateral geniculate nucleus 535 cortical neurons 454–456 properties due to convergent and divergent connections in relay nuclei 456 cortical altered by experience 461 magnification 460–461 neurons in primary somatic sensory cortex 455 neurons in primary visual cortex 582–583 neurons in striate cortex 583 P cell, spatial organization allows conveying both brightness and color information 580 relay nuclei 427 retinal ganglion cells 529 concentrically organized 582 response to contrast 516 structure 517–518 sensory neurons, define spatial resolution of stimulus 418–419 sensory receptors in retina, and density determine resolution of visual image 420 simple cells in primary visual cortex 533–534 535 in skin mechanoreceptors 436–437 differences in size vary throughout body 436–437 touch receptors, structural basis of 419 Receptor cells, perceptions begin in 407 Receptor potential 29 414 characteristics 31 in hair cell 616 in knee jerk 29 in reflex 32 mechanical deflection of hair cells bundle in organ of Corti transduced into 598–599 Receptor proteins 295 Receptor specificity 414 Receptor tyrosine kinases activation 251 indirect gating of ion channels 230 Receptor-channels 185 in central nervous system 221–222 nicotinic acetylcholine functional model 201 three-dimensional model 200 transmembrane subunits 200 NMDA, opening of and plateau potentials 745 open and Na+ enters postsynaptic cell at chemical synapse 183 See also specific types Receptor-mediated endocytosis, endothelial cells 1289 Receptors, chemical acetylcholine, conduct ions across channels 108 action potentials conducted at different rates by afferent fibers 444 447 adaptation rates and temporal coding 423–425 autonomic nervous system 971 axon, as modality-specific line of communication 416 different among neurons 33 direct gating 230 for chemical transmitters, common biochemical features 185 as filter 416 G protein-coupled, include opiate receptors 484 GAB A, as transmembrane proteins 219–222 glutamate as transmembrane proteins 219–222 structure 219–221 glycine, as transmembrane proteins 219–222 indirect gating 230 ionotropic 185 mediate direct gating of ion channels 184 and metabotropic, differing physiological actions 240–248 produce fast synaptic actions 185 ligand-gated, conduct ions across channels 108 metabotropic 185 mediate direct gating of ion channels 184 produce slower synaptic actions 185 neurotransmitter classes 250–251 types 230 novel opioid-like orphan 486 opioid peptides 483–489 organ of Corti 596 phosphorylation 230 postsynaptic chemical transmitters bind to 183–185 gate ion channels with directly or indirectly 185 as integral membrane proteins 185 in postsynaptic cell 32 synaptic, types 229

transmitter, types 173 Receptors, sensory cell-surface, effect of endocytosis on 97–98 classes 416 density determines how well sensory system can resolve detail of stimulus 418–419 distribution of types in hand 436 each one responds to narrow range of stimulus energy 416–418 hearing, hair cells 590 information from transmitted by modulation of frequency of electrical impusles 430 P.1392 input to each region of somatic sensory cortex 459 inputs from arranged somatotypically in brain 408 morphology influences adaptation 425 nature of 414 organ of Corti 596 population codes 423 See also Mechanoreceptors; Merkel disk receptor; Nociceptors; Peripheral sensor; Thermal receptors See also specific types sensitivity of limits sensory threshold 421 for physical events 382 sensory dorsal root ganglion neuron for somatic sensory system 431–432 tuning curves 418 skin, topographic arrangement preserved in central processes of dorsal root ganglion neurons 447 skin and joints, maintenance of somatotopic organization throughout ascending somatosensory pathway 448 in somatic sensation 432 spatial properties processed by populations forming parallel pathways to brain 452 specialization for particular forms of energy 428 specialized, mediate somatic sensations 441–444 surface, inductive signals for neural cell differentiation 1022–1023 touch, structural basis of receptive field of 419 transduction of specific types of energy into electrical signal 416 Reciprocal innervation 715 Recognition, binding of feature and saliency maps 567 Recording, experimental, from cells in stretch reflex circuit 208 Rectifier, behavior of some ion channels as 112 Rectifying synapses 180 Recurrent artery of Heubner cerebellum and diencephalon 1304 effects of occlusion 1309 Red nucleus 347 369 669 contralateral, projections from cerebellar hemisphere 842 lateral corticospinal tract 670 midbrain 668 Red-green mechanism, in cones 580 Red-green variation, component function of reflectance function 578 reeler mice, animal model for seizures 930 Reese, Thomas 264 Referred pain 475 and convergence of somatic and visceral nociceptive input to lamina V neurons 477 Reflectance function 573 Reflex action coordination by inhibitory interneurons 722 Ib afferent fibers and Golgi tendon organs 724 sequence of signals producing 32 Reflex circuits, in visceral motor system 962 Reflex pathways divergence amplification of sensory inputs 721 coordination of muscle contractions 721 inferring number of synpases in 721 interneurons in 735 principles of 715 sites of modification 724 725 Reflex responses characteristic alterations in caused by damage to central nervous system 730–735 complexity 713 flexibility, convergence of inputs on interneurons 721–724 purposeful integration of and neuronal networks in spinal cord 717–724 Reflex sympathetic dystrophy 473 Reflexes 654 adaptability 714–715 conditioned flexion-withdrawal 715 control of movement in purposeful manner 714–715 crossed-extension 715 716 flexion 716 flexion-withdrawal 715 knee jerk 25 25 limb muscles, mediated by spinal and supraspinal pathways 727–728 long-loop 727–728 728 modulation by stimulus properties 715 muscle spindle, modulated by gamma motor neurons 734–735 nature of 735 spinal 25–26 713–736 stretch 25 32–33 716 717 study of with decerebrate preparations 717 Reflexive behavior 873–888 Refractoriness, following action potential 157 Refractory state, ion channels 114 Reh, Thomas 1121 Reissner's membrane, cochlea 592 592

Relative refractory period 157 Relay neurons cerebral cortex, morphology 457 convergence to produce direction sensitivity 467 receptive fields, stimulus features 467 Relay nuclei 335 brain stem, mediate localization of sound 606–608 convergent and divergent connections in and properties of cortical receptive fields 456 inhibitory interneurons in sharpen contrast between stimuli 427–428 inhibitory mechanisms control flow of information through 427 processing of sensory information 427 Relays 323 Release phenomena 666 REM See Rapid eye movements REM behavior disorder parasomnia 955–956 pathophysiology unknown 956 polysomnogram of patient with 957 REM sleep See Sleep, REM stage REM-off cells patterns of activity during REM sleep 940 regulated by PGO-on cells of raphe nuclei in brain stem 942 REM-on cells in nucleus reticular pontis oralis, types 943 patterns of activity during REM sleep 940 REM-waking-on cells, in nucleus reticularis pontis oralis, firing during REM sleep and non REM-waking-on cells, patterns of activity during REM sleep 940 Remapping of referred sensations 390 Remembered space 384 Renshaw cell inhibitory input to motor neurons 78 inhibitory interneurons 720–721 motor cortex reflex circuit 765 pathway of motor neuron inhibition 722 Repolarization 132 effect on Na+ channel gating 155 and termination of action potential 132 Representational neglect 394 Reproduction, hypothalamic control 975 Reproductive system, sexual differentiation of as fundamental characteristic of development 1131–1134 Repulsive axon guidance signal, same as ephrin A5 1081 Reserpine effect on depression 1217 inhibits uptake of amine transmitters 286 Resistance axial 144 effect on rate of spread of depolarization during action potential 147 P.1393 intercellular, as passive electrical property of neuron 140 input and magnitude of passive changes in membrane potential 140–142 relation between current and voltage 141 membrane 144 and axoplasmic, affect on efficiency of signal conduction 143–145 resting membrane, as passive electrical property of neuron 140 specific membrane 141 synaptic potentials originating in dendrites 144 Resistors acetylcholine-gated ion channels as 193 196 ion channels as 134 single K+ channel as 133 Resonance 1064 Respiration, role of pons 322 Respiratory pattern, evaluation of in structural coma 902–903 Resting ion channels 125 selective for several ion species in nerve cells 129–131 Resting membrane potential (V r) 27 126 approaches K+ equilibrium potential 132 balance of ion fluxes for is abolished during action potential 132 calculation using equivalent circuit model 136 136 central neurons 217 contribution of Cl- to 131–132 depolarization away from K+ equilibrium potential 131 determination by relative proportion of type of ion channels and value of their equilibrium potentials 130 resting ion channels 126–132 effects of depolarization near 242 and ion channels 149 quantification of contributions of different ions to using Goldman equation 132–134 results from separation of charges across the cell membrane 126 126 separation of charges across cell membrane 126 126 steady state of 131 Resting membrane resistance, as passive electrical property of neuron 140 Resting state, ion channels 114 Restriction fragment length polymorphism 705 detection of genetic polymorphisms 52–53 Reticular formation brain stem 320 873 coordinates reflexes and behaviors mediated by cranial nerves 885–887 functional regions 885 at level of medulla 887

and sleep 936 long projection systems of 889 medulla 482 midbrain 482 stimulation promotes the waking state 939 pons 482 role in emotional facial expression 887 Reticular nucleus reciprocal interaction of GABA-ergic inhibitory interneurons with thalamic relay nuclei 898–899 thalamus 343–344 343 ventral corticospinal tract 670 Reticular thalamic nucleus, role in primary generalized seizures 926 Reticulospinal pathways medial and lateral, modulation of posture, gait, and muscle tone 896 transmits descending signals that initiate locomotion 751–752 Reticulospinal tract 669 medial brain stem pathway 668 Retina axons of ganglion cells form topographic representation at termination in optic tectum 1064 of spontaneously active in utero 1123 bipolar neurons in 24 circular receptive fields of cells of 545 classes of neurons, structure 515 color-opponent signals 588 concentric cells, receptive fields 535 density of sensory receptors and size of receptive field of each receptor determine resolution of visual image 420 detection of contrast 519 diseases of affect color vision 585 dopaminergic neurons in 893 eye 508 fixation plane 560 fixation point 560 560 ganglion cells concentrically organized receptive fields 582 opponent mechanisms 579 identification of S cones on 585 input to superior colliculus 792 thalamus, and neural activity in utero 1123 movement of image on 813 814 output conveyed by ganglion cells 517 as part of central nervous system 507 pathway axons follow to optic tectum 1067 photoreceptors 508–510 508 preferential response of optic tract nuclei to stimuli moving across 813 projections 523 primary visual cortex 543 subcortical regions 526–529 527 representations in extrastriate regions 497 responses of horizontal cells to light 579 rod cells, cGMP acts directly on specific ion channels in 239–240 role of gaze system in keeping image still on 783 segregation of axon terminals of in lateral geniculate nucleus 1124 sensory transduction in 507 spontaneous waves of activity in 1124 stable images on and vestibulo-ocular reflexes 808–809 structure 508 synaptic connections in 521 synaptic contacts in 520 termination of axons in lateral geniculate nucleus 528–529 three-cone system in 575–577 types of ganglion cells 501 visual processing by 507–522 visual system 496 Retinal disparity 785 and stereopsis 561 Retinal image correspondence with visual field regions 525 inversion of visual field 524–525 526 Retinal pigment in cones 573 structure 511 512 Retinitis pigmentosa, disturbance of color vision 585 Retino-geniculate-cortical pathway, lesions in, associated with gaps in visual field 543–545 Retinohypothalamic tract, circadian rhythm 937 Retinoic acid induction of posterior neural tissue 1030 neural induction 1024 Retinotopic frame of reference 496 498 Retinotopic map 496 498 contralateral half of visual field, in each lateral geniculate nucleus 528 contralateral visual field, in superior colliculus 526 in lateral geniculate nucleus 545 optic tectum, ephrins and eph kinases required for formation of 1083 Retinotopy 496 P.1394 Retrieval, processing of explicit knowledge 1238 1238 Retrograde 100 Retrograde axonal transport 103 fast, rate of 103

organelles involved 102 Reuniens nucleus, thalamus 343 Reversal potential 191 acetylcholine-gated channel, role of conductance 193 of end-plate potential 194 for EPSP 210–211 Reward, and dopaminergic neurons 1010 RFLP See Restriction fragment length polymorphism Rhesus monkey, animal model for Alzheimer disease 1157–1158 Rhodopsin during phototransduction 512 photoactivation, biochemical cascade initiated 514 visual pigment in rod cells 511 511–512 Rhombencephalon 1021 1022 1022 Rhombomeres 1031 Rhopdopsin, mechanism of activation 512 Rhyming task, brain areas of significant change in activity during 1184 Rhythm-generating networks building blocks of 744 See also Central pattern generator Rhythmic behaviors 654 Ribosomal DNA, and cellular senescence 1150 Ribosomal RNA mitochondrial 89 staining of 91 transcribed in nucleoli 89 Ribosomes in cell body and dendritic arbor 90 free, manufacture of proteins of cytosol and cytoskeleton 103 role in proteins synthesis 93 See also Polysomes signals for polypeptide attachment to 94 Richmond, Barry 567 Right cerebral hemisphere convexity infarction, after middle cerebral artery infarction 1308 role in intonation and pragmatics in language 1182–1183 Right occipital-parietal area, human, lesions in produce deficits in smooth-pursuit eye movement 556 Right optic nerve, lesion, loss of vision in right eye 544 544–545 Right parietal lobe, injury to and representational neglect 394 Right posterior parietal cortex lesions to and memory 398–399 neglect of space after injury to 396 Righting reflexes 817 Rigor mortis 678 Rin See Resistance, input Rinne text, conductive hearing loss 593 Risperidone, treatment for some cases of schizophrenia 1206 RKA-R1, Drosophila learning mutant 1257 Robinson, David 828 Robinson, David A. 790 Rod and cone photoceptors 417 Rodbell, Martin 231 Rods detection of dim light 509 differences from cones 509 functional regions 510 retinal photoreceptor 508–509 spectral sensitivities 577 structure 510 515 Roof plate, neural tube 1027 Rosenbaum, David 665 Rosenthal, David 1193 1212 Rostral 321 Rotational vestibulo-ocular reflex 809 Rotenberg, Alex 1267 Rothman, James 270 Rough endoplasmic reticulum manufacture of secretory, plasmalemma, and vacuolar apparatus proteins 103 neuron 68 69 role in protein synthesis 93 Round window 591 802 cochlea 592 Rubin, Edgar 493 Rubrospinal projection, motor cortex reflex circuits 765 Rubrospinal tract lateral brain stem pathway 668–669 lateral corticospinal tract 670 Rudin, Donald 109 Ruffini ending 432 433 433 434 436 rutabaga, Drosophila learning mutant 1257

S S cones 576 577 identification on retina 585 S-I See Primary somatic sensory cortex S-II See Secondary somatic sensory cortex S4 region, visual cortex sodium channel 164 voltage sensor in voltage-gated ion channels 166 Saccades 180 783 activity of extraocular motor neuron during 788 control modified by experience 795 by superior colliculus 526–527

controlled by cerebral cortex 792–795 by oculomotor circuit 861 eye 797 eye position plotted against time 784 horizontal generated in pontine reticular formation 789–791 motor circuit for in brain stem 791 lateral intraparietal area 567 linked with visual attention 794 motor circuits in brain stem 789–792 motor neurons signaling eye position and velocity during 790 neural integration of velocity signal 790 vertical, generated in mesencephalic reticular formation 792 vestibular memory-contigent 830 Saccadic system, eye 784 Saccule 802 cochlea 592 detection of linear acceleration 804–805 reports linear accelerations 802 sensitivity to vertical acceleration 805 Sachar, Edward 1220 Sacral regon, spinal cord 338–340 339 Safety factor 302 Sagittal plane 321 Sakmann, Bert 111 193 Saliency map image 567 visual information 504 Salivary glands, control by sympathetic and parasympathetic systems 968 Salivary nuclei, superior and inferior, preganglionic parasympathetic nucleus in brain stem 963 Salivatory nucleus 881 Saltatory conduction 148 148 Saltatory movement 101 Salty, taste quality 640 Salty tastant, mechanism of transduction 639 Sarcoglycanopathies 708 Sarcoglycans muscle transmembrane protein 708 mutations of gene for in dystrophin-normal and limb-girdle muscular dystrophy 707–708 Sarcolemma, muscle fiber 676 677 Sarcomere 677 organizational unit of muscle fibers 676–683 structure 676 678 Sarcoplasmic enzymes, in serum, for diagnosis of muscle diseases 697 699 Sarcoplasmic reticulum 680 muscle fiber 677 Satiety center, lateral hypothalamus 1002 Satiety signals, effect on hypothalamus 1004 Saxitoxin blocks voltage-gated Na+ channel 154 structure 154 P.1395 Scala media 595 cochlea 592 592 Scala tympani 595 802 cochlea 592 592 596 Scala vestibuli 595 802 cochlea 592 592 595 Scanning speech, lesions of vermis 850 Schachter theory, emotion 984–985 Schachter, Stanley 984 Schaffer collateral pathway CA1 pyramidal neurons 85 hippocampus 1257 1259 long-term potentiation is associative 1260 NMDA-mediated synaptic plasticity and spatial memory 1272 Scheller, Richard 270 Schizophrenia 1192 abnormalities in dopaminergic synaptic transmission 1200–1204 anatomical abnormalities in brain 1195–1196 auditory-verbal hallucinations, PET results 1191 brain activity during verbal tests 1204 cost of 1191 defect in NMDA receptor function 213 disordered modulated of prefrontal circuits 866 disorders of thought and volition 1188–1208 disturbances of dopaminergic system 362 dopaminergic pathways involved in positive and negative symptoms 1203 familial nature 1195 genetic component 58 alteration in gene expression 1276 genetic factors 1194 genetic predisposition 1193–1195 hallucinations, functional neuroanatomy 1190 1190 in homeless people 1191–1192 model for pathogenesis 1196–1197 models of transmission 59 multigenic disease 55 multiple causality 1194 neuroanatomical model 1204

polygenic disease 1194 1195 possible role of NMDA receptors 1204–1206 risk of developing as function of pedigree 58 role of mesolimbic and mesocortical tracts 283 several related disorders 1189–1192 symptoms 1192–1193 treatment, antipsychotic drugs acting on dopaminergic systems 1197–1200 types 1193 Schizotypal personality disorder 1190 1194 Schleiden, Jacob 23 Schultz, Wolfram 1009 Schwab, Martin 1111 Schwann cells 85 develops from neural crest cells 1047 expression of myelin-associated glycoprotein 83 gap junctions enhance communication 182 myelin production by 20 at neuromuscular junction 1089 promote neurite outgrowth 1110 regulation of expression of myelin genes by 85 secrete chemotropic factor that attract axons to distal stump 1109 sheath 188 structure 21 type of glial cell 20 Schwann, Theodor 23 Scotomas 359 Scoville, William 1229 Searle, John 396 397 1318 Sechenov, Ivan 654 Second messenger systems calcium modulation of ion channel gating 159 noradrenergic receptors linked to 1216 in olfactory signal transduction 629 629 serotonin receptors linked to 1215 1220 See also Cyclic guanosine 3′-5′-monophosphate synaptic common, plan 231 Second-messenger cascades, activation in cell membrane 237 Second-messenger pathways activation by metabotropic receptors 230–240 interactions with each other 248–250 Second messengers activation of protein kinases 251 and axon growth cone motility 1074 gaseous, stimulate cGMP synthesis 239–240 intracellular, generate receptor potentials in chemoreceptors and photoreceptors 416 417 long-lasting consequences of synaptic transmission 249–250 modulation of synaptic transmission 229–253 modulatory synaptic actions involving, sites of action 241 in photoreceptors 510–511 production stimulated by activation of metabotropic receptors 185 role in emotional states 251 in taste cells 637 Secondary active transport 132 Secondary somatic sensory cortex, location and projections 452 Secondary spindle endings 720 Secondary visual area projects to V4 583 receives output from primary visual cortex 583 Secretins family of neuroactive peptides 290 neuroactive peptide 289 Secretion, at axon terminal 99 Secretory granules neuron 68 role in protein synthesis 93 Secretory pathway, transport of proteins from rough endoplasmic reticulum to vacuolar apparatus and cell surface 103 Secretory proteins manufacture on rough endoplasmic reticulum 103 method of formation in endoplasmic reticulum 95 processing in Golgi complex and export 96–97 synthesized and modified in endoplasmic reticulum 94–96 Seeburg, Peter 221 Segmental artery, spinal cord 1314 Seizure focus characteristic activity of neurons in 917 919 conductances underlying paroxysmal depolarizing shift 920 factors affecting excitability of neurons in 919 location and surgical treatment of epilepsy 925–927 mechanism of spread of seizure activity from 924 MRI imaging 925 origination of partial seizures 917–922 spatial and temporal organization 921 spread of activity through normal cortical circuitry 920 synchronization results from breakdown of surround inhibition 919–920 Seizures 910–935 absence 913 contribution of T channel in thalamic relay neurons 924 role of T-type Ca2+ channels and GABA-B receptors 924 spike and wave activity 926 activation of c-fos 933 animal models for 930 chronic, genetic susceptibility 930–931

classification of 911–913 911 complex partial, atrophy and cell loss in mesial portions of hippocampus 925 example of collective electrical behavior of brain 933 focal 910 P.1396 generalized 911 911 913 activation of stress response 927 evolve from thalamocortical circuits 922–925 systemic complications 927 types 913 hippocampal, dentate gyrus as gatekeeper of 931–933 932 metabolic mapping study in 927 negative signs 911 partial 911 911 913 auras preceding 913 and generalized, differing patterns of cortical neuron activity 933 loss of hyperpolarization and surround inhibition accompanies onset 924 origination in seizure focus 917–922 pathways of propagation 925 removal of temporal lobe reduces or cures 925 pathways for propagation 925 positive signs 911 positron emission tomography study in 927 primary generalized contribution of calcium-dependent K+ conductance 925 contribution of norepinephrine 925 generation of 926 generation in thalamus 924 pathways of propagation 925 role of thalamic connection for sleep spindles 926 synchronization of cortical neurons and thalamic relay neurons 926 prolonged brain damage by 927–930 repetitive, drugs for treatment 919 See also Status epilepticus secondarily generalized tonic-clonic 913 secondary generalization, pathways of propagation 925 study with single photo emission computed tomography 927 Selective attention basal nucleus of Meynert modulatory role in 334 brain stem modulatory role in 334 cellular interactions contributing to 427 effect on sensory machinery 401 enhances responses of neurons in many brain areas 401 limits amount of information reaching cortex 504–505 modification of firing patterns of S-II neurons 468 modifies response to effective visual stimulus by V4 neurons 568 neural mechanisms of in posterior parietal cortex 400 401 testable component of consciousness 400–402 Selective serotonin reuptake blockers, antidepressants, structure 1213 1214 Selective serotonin reuptake inhibitors 295 effect on serotonergic neurons 1218–1219 Selectivity, ion channels 107 for K+ in glial cells 128 Selectivity filter, and voltage-gated Ca2+ channel 163 Self-awareness loss of in personal neglect syndrome 393 neural representation 16–17 Self-image, deficits in with astereognosis 393 Self-stimulation, electrical drugs of abuse enhance pleasure produced by 1011 pathways of in rats 1009 1010 Semantic knowlege See Knowledge, semantic Semantic paraphasia, in Wernicke aphasia 1180 Semaphorins binding to neuropils, repulses growing axons 1080 inhibitory molecules for axon growth cone guidance 1081 receptors for 1081 Semicircular canals 802 cochlea 592 detect accelerations by inertia of internal contents 804 detect angular acceleration 805–806 horizontal 808 measure angular accelerations 802 organization of ampulla 806 orientation within head 807 Senescence See Aging Senile dementias 1151 1151–1153 1192 See also Alzheimer disease Senile plaques, Alzheimer disease 1154 1155 Senile plaques, cerebral cortex topography of in Alzheimer disease 1153 Sensation intensity determined by stimulus amplitude 419–425 modulation by brain stem 889–909 pain 472–491 somatic 430–450 mediated by variety of specialized receptors 441–444 modalities mediated by terminals of dorsal root ganglion cells 444 receptors in 432 See also Receptors, sensory two classes of, 431–432 thermal, types 444 Senses chemical 625–647 common steps in 412

complex qualities and activation of large groups of receptors acting in parallel 428 each mediated by distinct neural system 407–408 See also Hearing somatic 430–450 Sensitization 1250 central 479 gill-withdrawal reflex in Aplysia 1250–1251 long-term persistent synaptic enhancement with 1254–1255 structural changes in presynpatic terminals of sensory neurons 1256 long-term storage of implicit memory 1254–1259 nociceptor 477 by chemical mediators 481 nonassociative learning 1240 presynaptic facilitation of synaptic transmission 1250–1252 Sensorimotor transformations, lateral premotor areas 774–777 Sensory aphasia, after damage to Wernicke's area of temporal lobe 355 Sensory bristle, Drosophila 1043 Sensory cells, bipolar neurons in 24 Sensory cortex, projections to 973 Sensory cortices, blood flow in during finger movements 773 Sensory decussation 342 446 Sensory experience and fine-tuning of synaptic connections 1115–1130 refinement or modification of connections in auditory system 1127 Sensory experiences, natural stimuli versus stimuli used on neurological examination 441 Sensory fibers extensor, excitatory pathways of information from to extensor motor neurons 748 muscle classification 720 selective activation 720 propagation of action potentials in and perception of pain 473 Sensory function integration with motor function 349–380 role of midbrain 8 temporal and spatial contrast 425 Sensory information ascending pathways from limbs and trunk to thalamus and cerebral cortex 446–447 coding of 411–429 compared with biological set points by hypothalamus 975 P.1397 features of 428 from unimodal areas of cerebral cortex, converges in multimodal areas 354–355 gating and modulatory role of thalamus 322 hierarchical processing of by somatosensory system 338–341 moving limbs, regulate stepping patterns 747–750 parallel and serial processing in primary somatic cortex 452 parallel processing of 319 processed sequentially and in parallel 352 354 in stages in central nervous system 428 processing of emotional information 990 principles 352–362 by spinal cord 8 and regulation of movement 713 See also Receptors, sensory; Stimulus spatial and temporal judgments, activity of dentate nucleus during 848 supplied to hypothalamus 975 transmission to thalamus 448 visceral, distributed by nucleus of the solitary tract 966 Sensory initiation, role of posterior parietal cortex 453 Sensory inputs transient, difficulty in processing quickly in dyslexia 1185 unimodal, converge on neurons in prefrontal cortex, parietotemporal cortex, and limbic cortex 355 Sensory loss areas of after middle cerebral artery infarction 1307–1308 diffuse hypoperfusion 1313 after occlusion of carotid artery 1309 Sensory maps, in spinocerebellum 842–843 Sensory modality, determined by stimulus energy 414–418 Sensory neurons adaptation 424–425 anatomy 76 axonal path in spinal cord 77 conducts information from periphery to central nervous system 76–77 connections with motor neurons in spinal cord 74 develops from neural crest cells 1047 diseases attacking 33 ending in soleus muscle 74 frequency of action potentials encodes stimulus intensity 421–423 firing rates encode stimulus magnitude 423 and intensity of stimulation over time 424 functional regions 28 hearing, spatially organized according to sensitivity 419 higher-order, receptive fields have both excitatory and inhibitory regions 427 information flow to motor neurons is divergent and convergent 79 and nuclei, in gray matter of dorsal horn of spinal cord 338 populations of convey sensory information 426 receptive fields define spatial resolution of stimulus 418–419 require neurotrophins for survival 1057 S-type K+ channels closed by slow synaptic action mediated by serotonin 244

sensitization 1256 smell, spatially organized according to sensitivity 419 spatial distribution conveys information about stimulus 418–419 structural changes in presynaptic terminals in long-term habituation and synapse selectively on motor neurons 1106 in reflex 32 taste, spatially organized according to sensitivity 419 transformation of physical stimulus into electical activity 30 Sensory pathways different usage of and variation of cortical body surface maps among individuals 1274 modulated by descending pathways from brain stem to spinal cord 896 Sensory perception as constructive process 1239 influence of locus ceruleus 896 Sensory physiology 412 Sensory processing networks, hierarchical organization 416 not distributed symmetrically in cerebral hemispheres 363–365 Sensory psychophysics 412 Sensory receptors 414 density in retina and size of receptive field determine resolution of visual image 420 density of innervation and neural map 323 tuning curves 418 Sensory representations, direction of behavior 653 Sensory signals, role in reflex 32 Sensory signs, spinal cord lesions 732–734 734 Sensory stimulus change in membrane potential produced by transformed into digital pulse code 421 fidelity of in somatic sensory cortex 461 463 Sensory system, somatic dorsal root ganglion neuron as sensory receptor for 431–432 somatic, modalities 430 Sensory systems 416 attributes of stimulus mediated by 412–414 413 common plan 425–128 peripheral receptive surface and topographical representation 323 process information in serial pathways 426–427 Sensory threshold 421 modified by psychological and pharmacological factors 422 Sentence, deep structure versus surface structure 1171 Septum pellucidum 367 Septum, developing forebrain 1036 Serial pathways sensory systems process information in 426–427 in visual system 505 Serial processing attentive visual system 503 basal ganglia-thalamocortical circuits 859 See also Parallel processing stimulation of brain's higher-level cognitive processes 34 Serine proteases, biosynthesis of neuroactive peptides 288 Serine-threonine kinases, activation by bone morphogenetic protein 1029 Serine-threonine phosphatases 249 Serotonergic cell groups, midline of brain stem 893 Serotonergic neurons effects of antidepressant drugs on 1218–1219 and food intake in Aplysia 1005 location 283 in raphe nuclei 896 Serotonergic pathways drugs effective in treatment of depression act on 1216 from raphe nuclei 1214 1216 Serotonergic receptor, mutation in gene encoding and impulsive behavior 50 Serotonergic system, long-term effects of antidepressant drugs 1217 1217 Serotonin 50 activation of nociceptors 480 biosynthesis and structure 283 biosynthetic enzyme 281 chemical intermediary for pain 442 class of ligand-gated channels in central nervous system 221–222 closes S-type K+ channels 243 drugs that block reuptake 295 P.1398 mediated slow synaptic action that closes S-type K+ channels in sensory neurons 244 and nociceptor sensitization 477–478 receptors blockade by clozapine 1206 types 1215 reuptake inhibitors, treatment, obsessive-compulsive disorder 1224 sensitization of gill-withdrawal reflex in Aplysia 243 small-molecule neurotransmitter 283 Serum, comparison with cerebrospinal fluid 1296 Servo-control systems motivational states modeled as 1000 See Feedback control Servomechanism 729 1000 Set point 1000 biological, deviation from determined by hypothalamus 975 body weight 1002 alteration by hypothalamic lesions 1002 1002 calcium, for axon growth cone motility 1074 temperature control 1001 water intake 1006 Set related activity

primary motor cortex neurons 764 location 774 777 Set-related neuron, dorsal premotor area 775 Set-related neurons 779 Severin, Fidor 750 Sex chromosomes 38 Sex determination, process 1132 Sex differences brain, and control of behavior 1141–1143 central nervous system, produced by exposure to testicular hormones during development 1136–1137 cognitive performance 1142 structural, human central nervous system 1143 Sexual behavior, role of periventricular fiber system 978 serotonergic neurons 896 Sexual differentiation brain, hormonally dependent 1134–1140 clinical syndromes regarding 1134 external genitalia, depends on hormones produced by testes 1132–1134 genital ducts 1133 in nervous system 1131–1148 reproductive system, as fundamental characteristic of development 1131–1134 Sexual dimorphism central nucleus of bed nucleus of stria terminalis 1145 four interstitial nuclei of anterior hypothalamus 1144 nucleus of preoptic area 1137 See also Sex differences and sexuality, 1143–1146 Sexual reflexes, parasympathetic and sympathetic system control 969 Sexuality multifactorial nature 1146 and sexual dimorphism 1143–1146 Sexually dimorphic nucleus of the preoptic area, human 1142 estradiol prevents apoptosis in 1140 SGOT See Glutamic-oxaloacetic transaminase Shaffer axon collaterals, hippocampus 78 Shaker phenotype, mutations in K+ channel gene 169 Sham rage, in cats without cerebral cortex 984 Shape, object, information about signaled by populations of mechanoreceptors 438–441 Shatz, Carla 1123 Shellfish poisoning, amnestic, overactivation of glutamate receptors in 930 Sherrington, Charles 29 175 222 414 494 654 674 695 713 717 747 816–817 1229 1248 Shik, Mark 750 shiverer mutant, reduced production of myelin basic proteins in mice 82–83 Shock See Hypoperfusion Short circuit 138 Short-circuiting effect 217 Shunting effect 217 Sib-pair analysis 57–58 Sickle cell anemia, explained as molecular disease 867 Siegelbaum, Steven 1264 Sight See Vision; Visual system Sign language 612 Signal conduction, effect of membrane and axoplasmic resistance on 143–145 Signal recognition particles, mediates attachment of polypeptide to ribosomes 94 Signal sequences attachment of polypeptide to ribosomes 94 on proteins 90 Signal transduction, olfactory 629 629 Signal transmission, instantaneous in electrical synapses 177–182 Signaling between neurons 175 capabilities increased by variations in properties of voltage-gated ion channels 158–160 changes in membrane potential and cell membrane permeability to ions 138–139 chemical substances for 281 chemical See Neurotransmitters; Synaptic vesicles conductile component 31 effect of neuronal geometry on 145 functions of voltage-gated ion channels related to their molecular structure 160–164 input component 28–29 local control of neuronal cell fates 1047–1049 passive electrical properties of neruon 140–149 at nerve-muscle synapse 187–206 nerve and muscle cells specialized for over long distances 110 networks, neural, mediate specific behaviors 25–27 neuronal activation of classes of ion channels is basis of versatility 107 and rapid changes in electrical potential difference 105 ion channels as site of in nervous system 105–107 organization in nerve cells 27–33 output component 31 propagated, action potential 150–170 role of membrane potential in 28 transcellular, and retrograde synaptic transmission, evidence for 239 trigger component 29–30 Signals attenuation in propagation 144 conducting, features that convey information 31 delivered to cell body by retrograde transport 102 inductive, for differentiation of neural cells 1022–1027 local versus propagated 31 sequence producing reflex 32 transformation in stretch reflex pathway 32–33

Silent nociceptors 473 474 Silver staining, determination of coherent structure of the neuron 23 Simon, Herbert 383 Simple cells, primary visual cortex 533–534 Simple spike, Purkinje cells 839 Simpson, John 300 Singer, Wolfgang 567 Singing behavior, birds, effect of gonadal hormones on brain 1141 Single photon emission computed tomography imaging technique for biochemical processes 375 379 study of seizures with 927 Single-channel recording, study of ion channels 109 Site-directed mutagenesis, method for testing proposed ion channel structure 117–118 P.1399 Size perspective depth perception 558 monocular depth cue 559 Size, object, information about signaled by populations of mechanoreceptors 438–441 Skeletal muscle 674 affected in autoimmune myasthenia gravis 298 atonia of during REM sleep 938 diseases, inherited or acquired 704–705 interactions with motor neurons organizes development of neuromuscular junction 1089–1091 1089 loss of tone during REM sleep 942 943 weakness and wasting in diseases of motor unit 695 Skeletofusimotor efferents 725 Skeletofusimotor system 725 Skeletomotor circuit basal ganglia, links thalamus and cerebral cortex 858–861 neuronal function depends on direction of limb movement and movement preparation 859–861 Skew deviation 788 Skilled walking 753 Skin innervation density correlates with spatial resolution in somatic sensory cortex 459–461 mechanoreceptors in mediate touch 432–441 rate and amplitude of cooling coded by firing rates of cold receptors 442 sensory input from and adjustment of stepping 749–750 tactile sensory system represented in somatic sensory cortex 469 temperature, coded by warmth and cold receptors 441 two-point discrimination 464 types of mechanoreceptors in 433–435 Skinner, B.F. 382 1242 Sleep 936–947 apnea 943 methods for documenting 949 apnea syndrome See Obstructive sleep apnea syndrome amount needed is genetically determined 954 amount of 937 arousal from, disorders 955–958 behavioral definition 937 brain stem and forebrain regions that control 941 changes in over life span 943–944 and circadian rhythm 937 circadian rhythm controlled by suprachiasmatic nucleus of hypothalamus 946 deep, and rhythmic and synchronous firing of thalamic relay neurons 899 deprivation and cognition 944 and neural maturation 944 See also Chronic insufficient sleep syndrome disorders of 948–959 disturbances of in depression 948 drunkenness, confusional arousal 956 EEG patterns during 938 endogenous substances that affect 943 fragmentation in obstructive sleep apnea syndrome 952 functions of 944–945 functions 946 genetic control of 944 insomnia 954–955 monitoring physiological activity 937 non-REM, stages 937–938 recall of dreams after awakening from 945 regulation 940 organization into cycles of non-REM and REM stages 937–943 offset paralysis 949 paralysis, symptom of narcoleptic syndrome 949 peptide, neuroactive peptide 289 parasomnias 955–958 patterns in elderly 1151 percentages for each stage of 939 periodic limb movment disorder 955 phases 936–937 phylogenetic variations 944 produced by destruction of histaminergic neurons of posterior hypothalamus 939 promoted by different neural system than that of arousal 939 rapid eye movement (REM) sleep 938–939 atonia during 896 behavior disorder 956 and dreaming 946 generation of 946 neuronal connections that control 942 patients with narcolepsy begin sleep with 949

patterns of activity of key cell groups during 940 physiological responses during 938 recall of dreams after awakening from 945 regulation 940–943 relationship to circadian rhythms 937 role of pons 322 slow-wave, signaling activity of thalamic relay neurons 899 spindles EEG activity during sleep 938 rhythmic EEG activity in sleep 923 thalamocortical connections for also essential for primary generalized seizures 926 states, methods for documenting 949 terrors, confusional arousal 956 violent enactment of dreams during 956 Sleep-onset REM period, in narcolepsy 950 Sleep-walking, parasomnia 955 Sleepiness, excessive daytime 948 medical disorders associated with 949–954 Sleeptalking, parasomnia 955 Sleepwalking, confusional arousal 956 Sliding filament hypothesis, muscle 678 Sloviter, Robert 931 Slow axonal transport 100 for cytosolic proteins and cytoskeletal elements 103 faster component 103 rate and amount in dorsal root ganglion cells 102 Slow wave epilepsy mice 930 Slow-channel syndrome 307 Slow-twitch muscle fibers 684 686 Slow-wave sleep 938 SMAD transcription factors, dorsal neural tube cell development 1029–1030 Small cardiac peptide, neuroactive peptide 289 Smell 625–647 See also Olfactory system Smith, Eliot 184 Smooth endoplasmic reticulum, neuron 68 71 role in protein synthesis 93 Smooth muscle controlled by autonomic nervous system 960 develops from neural crest cells 1047 Smooth pursuit eye movements 556 556 783 784–785 797 controlled by cerebral cortex, cerebellum, and pons 795–796 eye position plotted against time 784 pathways for 796 Smooth, muscle 674 smoothened gene, effects of mutations in 1029 SNAP See Soluble NSF attachment protein, 271 SNAP-25 271 role in synaptic vescle docking and fusion 277 SNARE hypothesis, synaptic vesicle fusion and exocytosis 273 SNARE proteins, role in synaptic transmission 270 Snider, Ray 842 Snoring, in obstructive sleep apnea syndrome 951 Social behavior, critical period in formation of 1127–1128 Social cues, role of lateral orbitofrontal circuit of basal ganglia 866 P.1400 Social development, studies of early social interactions 1128 Social factors, biological aspect in mental disturbances 1275 Social isolation, consequences of 1128 Sodium channel See Ion channels, sodium Sodium current calculation of voltage-gated Na+ conductance from 154–155 passive, balanced by active Na+ fluxes driven by Na+ -K+ pump 135 Sodium ions channels permeable to opened by ACh binding in postsynaptic muscle cell 199 conducted along with K+ in glutamate-gated channels 212 distribution across cell membrane 128 neuronal cell membrane at rest 128 during phototransduction 512 and electric potential of nerve cell membrane 27 free energy of binding 109 influx depolarizes presynaptic membrane to generate action potential for transmitter release 254 lower external concentration reduces amplitude of action potential 151 model for selectivity of ion channels for 106–107 nerve cells permeable to at rest 129 passive flux balanced by active pumping of ions 131 permeability of synaptic channels at end-plate to 192 resting ion channels in nerve cells selective for, in addition to Cl- and K+ 129–131 role in generation of action potential 29–30 simultaneous flow with K+ produces end-plate potential 193 Sodium lactate, induction of panic attacks 1221 Sokolowski, Marta 42 Solitary nucleus 881 Soluble factors, attract and repel axon growth cones 1081 Soluble NSF attachment protein 271 Soma 430 neuron 21 Somasomatic synapses 223–224 Somatastatins, family of neuroactive peptides 290 Somatic division, peripheral nervous system 335 Somatic motor nuclei, in developing hindbrain 1031

Somatic nervous system compared with autonomic nervous system 960 organization of motor pathways 961 Somatic sensation See Sensation, somatic Somatic sensory cortex 342 accurate representation of spatial detail 461 463 contains multiple body maps 469 cortical map of body surface represents density of innervation 469 detailed representations of embossed letters in area 3b 464 465 disruption of synaptic transmission effect on finger coordination 469 distinct areas process stimulus features in parallel 465–468 each of four regions contains complete body map 460 functional modules of cortical processing 457 inhibitory responses generated by interneurons in dorsal column nuclei, thalamic ventral posterior lateral nucleus, cortex 461 input organized in columns by receptive field and modality 456–458 of receptors to each region of 459 lesions produce sensory deficits 468–469 major divisions 453 neurons have complex feature-detecting properties 463–468 parallel processing of information for stereognosis 467 postcentral gyrus, pathway of sensory information 446 See also Cortical neurons; Primary somatic sensory cortex; Secondary somatic sensory cortex spatial resolution correlated with innervation density of skin 459–461 synchronized firing in different areas to bind stimulus features 468 topographic representation of body in each of four Brodmann's areas 458 Somatic sensory system 319 information conveyed in parallel pathways to primary somatosensory cortex 449 modalities 449 See Sensory system, somatic Somatic 430 Somatosensory cortex 345 347 453 Brodmann's area 3b, termination of axons of ventral posterior lateral nucleus of thalamus 344 contains several somatotopic maps of body surface 345 language 1174 neural representations of specific body areas in, maps from evoked potentials 385 relationship of S-I to S-II cortex 453 representation of whiskers in 462 role in processing pain 481–482 somatotopic representation of portions of body is according to degree of innervation 344–345 thalamic input and barrel organization in rodents 1037 1037 Somatosensory information brought to spinocerebellum by direct and indirect mossy fiber pathways 841–842 carried by parallel and hierarchical pathways to spinal cord and brain 341 medial lemniscus as major afferent pathway for 342 species differences 388 Somatosensory processing, feature-detecting cortical neurons 469 Somatosensory system hierarchical organization 416 hierarchical processing of sensory information 338–341 receptive field of sensory neurons defines spatial resolution of stimulus 418–419 Somatostatin neuroactive peptide 289 neurons releasing 979 980 Somatotopic map 672 altered by experience 461 body surface, in spinal trigeminal nucleus 881 complete in each of four regions of somatic sensory cortex 460 in motor cortex 671 oral cavity and face, in spinal trigeminal nucleus 882 produced by learning, and biological expression of individuality 1274–1275 spinocerebellum 841 842–843 Somatotopic organization basal ganglia-thalamocortical motor circuit 859 putamen, movement-related neurons 858 Somatotopy, fractured 842 in spinocerebellum 841 Somatotropy 340 Sonic hedgehog induction of distinct classes of ventral neurons 1029 morphogen 1027–1029 patterning of neural tube 1025 1026 ventral neural tube 1027–1029 Sonic hedgehog gene, effects of mutations in 1029 Sound deconstruction by cochlea 594 each hair cell sensitive to specific frequency 598–599 P.1401 energy amplified in cochlea 599–600 frequency, basilar membrane as mechanical analyzer 593–597 frequency code 603 localization of mediated by relay nuclei in brain stem 606–608 nature of 591 place code 603 processing of in bats 609–610 609 representation of intensity 593 of stimulus frequency of in cochlear nucleus 605 See also Echolocation; Pitch Sour, taste quality 641 Sour tastant mechanism of transduction 639 signal transduction and blockade of K+ channels 641

Source amnesia 1237 Spasticity 666 pathophysiology 730 produced by interruption of descending pathways to spinal cord 730 Spatial awareness, perceptual abilities involved 418 Spatial differences coarse in skin, Pacinian corpuscles and Ruffini endings roles 436 fine in skin, Meissner's corpuscle and Merkel disc roles 436 Spatial event plots, area 3b of somatic sensory cortex 465 Spatial frequency, P and M cells 530 Spatial neglect 393–394 393 394 395 Spatial representation, role of hippocampus 1233 Spatial resolution accuracy of in somatic sensory cortex 461 463 increased by pattern of excitation and inhibition in receptive field of dorsal column nuclei neuron 463 Spatial summation 145 223 224 Specific anosmia 634 Specific language impairment syndrome 1172 SPECT See Single photon emission computed tomography Spectral composition 573 Specular reflections 573 Speech and left hemisphere of cerebral cortex 10 initiation and maintenance, role of frontal cortices of left hemisphere 1182 insula important for planning and coordinating articulatory movements for 1182 involvement of each cerebral hemisphere in aspects of 364 left-hemisphere for right-handed people and most left-handed people 364 motor and sensory programs of 11 production, brain areas involved in 1174 Spemann, Hans 1023 Spencer, Alden 1248 Spermine, as blocking molecule in ion channels 112 Sperry, Roger 16 364 1064 1083 Spike trains, code vibration sense in skin mechanoreceptors 437 Spike-triggered averaging technique 767 detection of single cortical neuron on motor units 767 identification of primary motor cortex neurons projecting directly to motor neurons 765 Spikes, single electrical transients, field potentials 913 Spinal accessory cranial nerve (XI) in developing hindbrain 1031 function and dysfunction 874–875 function 880 Spinal and bulbar muscular atrophy, type of trinucleotide repeats involved in 56 Spinal animals 654 Spinal cat, immobilized, reciprocal pattern of motor activity 746 Spinal cord 9 320 324 347 367 administration of morphine 487–489 blood supply 1314 central pattern generator 743 circuits for repetitive rhythmic motor patterns 656 complete transection, sensory and motor effects 732–733 connections between sensory and motor neurons in 74 cross sections at different regions 339 damage to, sensory deficits 733 descending pathways from brain stem modulate sensory and motor pathways 896 development 1021 of cell types 1027 differences in organization from brain stem 885 diseases and injuries 468 distinct terminal patterns in by afferents carrying somatic sensory information 447–449 dorsal and ventral roots 340 dorsal horn laminae 475–477 local-circuit interneurons integrate descending and nociceptor afferent pathways 488 nociceptive afferent fibers terminate on neurons in 475–477 opioid receptors in 487–489 projection neurons, nociceptive afferent fibers terminate on 474 substantia gelatinosa, synapses of primary nociceptive neurons with 476 embryonic development 1025 1026 function 7 8 320 gray matter afferent connections with local interneurons, propriospinal neurons, projection neurons, and motor neurons 667 functional regions 447 hyperexcitability of dorsal horn neurons and hyperalgesia 479 infarction 1313 interruption of descending pathways produces spasticity 730 ipsilateral dorsal horn, neurons mediating sensations of pain and temperature terminate in 448 major anatomical features 338 major division of central nervous system 319–320 major regions of 338–340 339 medial-lateral arrangement of motor nuclei 668 methylprednisolone treatment of trauma 1111 motor circuits 663 motor neurons modulated by cerebral cortex 669–671 motor pattern for stepping produced at 740–748 742 motor patterns generated in absence of sensory signals input 746 motor pool 1069 1070 neural networks of and purposeful integration of reflex responses 717–724 neuronal networks generate rhythmic alternating flexor and extensor muscles 742–743 partial transection, sensory and motor effects 732–733 premotor cortical areas project to 760

projections to gray matter 668 See also Medial brain stem pathway; Lateral brain stem pathway rhythm-generating system and complex motor patterns 743 746–747 sacral, contains preganglionic cells of parasympathetic nervous system 963 See also Neural tube; Spinal reflexes sensory and motor signs of lesions 732–734 734 similarity of structure to brain stem 873 somatosensory information from trunk and limbs carried to 338–340 sympathetic pathways outputs to ganglia alongside 963 P.1402 transection 739 hind leg stepping after 740 742 spinal shock followed by hyperreflexia 730–735 and walking 753 variation in size of dorsal and ventral horns 340 variety of reflex circuits 663 Spinal interneurons, in motor system 667 Spinal matter See also Gray matter; White matter Spinal motor circuits, action modulated by brain stem 668–669 Spinal motor neurons 337 dendritic structure in 76 direct and indirect connections of corticospinal axons 763–764 execute movement 667–668 inhibitory effects of corticospinal projections 764 mechanism of IPSP 215 217 study of central synaptic mechanisms 209 Spinal muscular atrophy 700 symptoms 700–701 Spinal nerve roots 340 Spinal nerves 319–320 339–340 contain postganglionic fibers innervating body 963 role of cranial nerves homologous to 876 Spinal nucleus of the bulbocavernosus, absent in female rat 1141 Spinal pattern generators, in human walking 753–754 Spinal preparation central locomotor activity 754 study of stepping 738–739 types used in study of stepping 738–739 740 Spinal reflex pathway sensory signals produce reflex responses involving supraspinal regions 728 transmission altered by centrally generated motor commands 724–725 Spinal reflexes 25–26 671 713–736 coordinated contractions of muscles 716 coordinated patterns of muscle contraction 715–717 strength modulated by changes of transmission 725 regulation by tonic and dynamic mechanisms 724 Spinal shock, following spinal cord transection 730–735 Spinal trigeminal nucleus 342 881 location and functions 881 sensory input to 881 Spinal trigeminal nucleus and tract, pathway of sensory information 446 Spinal trigeminal tract 448 Spindle waves, cause of 940 Spinocerebellar ataxia type 1 type of trinucleotide repeats involved in 56 trinucleotide repeats in 55 Spinocerebellar tracts, ventral and dorsal recordings from decerebrate cats 842 somatosensory information from legs to cerebellum 842 Spinocerebellum 834 direct and indirect mossy fiber pathways bring somatosensory information 841–842 feed-forward mechanisms to regulate movement 844 modulates descending motor systems in brain stem and cerebral cortex 843–844 regulation of body and limb movements 841–844 sensory maps in 842–843 two somatotopic neural maps of body 841 Spinohypothalamic tract, ascending pathway for nociceptive information 480–482 Spinomesencephalic ascending pathway, nociceptive information 482 Spinomesencephalic tract ascending pathway for nociceptive information 480–482 ascending pathway of anterolateral tract 449 pathway of sensory information 446 Spinoreticular ascending pathway, nociceptive information 482 Spinoreticular tract ascending pathway for nociceptive information 480–482 ascending pathway of anterolateral tract 449 pathway of sensory information 446 Spinoreticulothalamic tract 481 Spinothalamic ascending pathway, nociceptive information 482 Spinothalamic neurons, cool stimuli of 485 Spinothalamic tract ascending pathway of anterolateral tract 449 ascending pathway for nociceptive information 480–482 pathway of sensory information 446 Spiny nonpyramidal cells, connections with GABA-ergic neurons in neocortex 331 Spiny stellate cells, in primary visual cortex 533 Spiral ganglion cells cochlea 592 596 601 802 organ of Corti 602 Spitz, Rene 1128 Split-brain patient dissociation in 363

language in 1182 See also Corpus callosum test of independent function of cerebral hemispheres in 365 vision versus language in 365 SPMs See Statistical parametric maps Squire, Larry 1230 1233 STA See Spike-triggered averaging Stance phase, stepping 740 741 Stapes 591 591 595 802 Startle, fear potentiated 990 Startle disease, mutations in alpha-subunit of glycine receptor 219 Startle response, and PGO spikes 938 State-dependent reflex reversal 724 Static equilibrium 817 Statistical parametric maps, imaging of working memory 360 Status epilepticus glutamate toxicity in 214 medical emergency 927 Stellate cell cerebellar cortex 836 cochlear nucleus 605 606 Stellate ganglion, neuropeptides in 972 Stepping adjusted by externoreceptors 747 ascending pathways to cerebellum 753 automatic transformation into functional 753 complex sequence of muscle contractions 740 741 control of initiation of swing phase 749 in decerebrate animals 754 hip extension control of transition from stance to swing 748 motor pattern for produced at spinal level 740–748 742 movements, adaptations via motor cortex neuron activity and visual system inputs 752 pathway of descending signals from brain stem and motor cortex 750 750–753 patterns regulated by sensory input from moving limbs 747–750 phases of cycle in 740 741 precise, motor cortex control 752–753 preparations used for study of 738–739 proprioception regulates timing and amplitude of 748 749 role of proprioceptors 747 sensory input from skin and adjustment 749–750 Stereocilia 614 615 615 hair cells in vestibular labyrinth 803 803 organ of Corti 597 P.1403 Stereognosis 431 452 parallel processing of information for in somatic sensory cortex 467 Stereopsis 560 role of primary visual cortex 560–561 separate from object vision 561–562 Stereoscope 560 Stereoscopic cues, in near-field depth perception 560 Stereoscopic vision, neuronal basis 561 Stereotropism 1064 Steropsis 1127 Stevens, Charles 1264 Stevens, Stanley 421 Stimuli association of two in classical conditioning 1240–1242 body surface, two-point discrimination 436 contrast between sharpened by inhibitory interneurons within relay nuclei 417–418 and generation of changes in membrane potential 105 novel, role of locus ceruleus in responsiveness to 896 spatial resolution of and density of skin mechanoreceptors 436 Stimulus amplitude determines intensity of sensation 419–425 attributes of mediated by sensory systems 412–414 conscious and unconscious evaluation 985 energy determines sensory modality 414–418 each receptors responds to narrow range of 416–418 requires intracellular second messengers 417 transduction into neural activity in photoreceptors and mechanoreceptors 417 features bound together by synchronized firing in different areas of somatic sensory cortex 468 processed in parallel by distinct areas of somatic sensory cortex 465–468 See also Feature-detecting neurons fearful, role of amygdala in response to 992 information must be represented as series of action potentials to convey sensory message to brain 421 information about conveyed by spatial distribution of sensory neurons 418–419 location and spatial dimensions conveyed topographically 428 magnitude encoded by firing rates of sensory neurons 423 modality, neural coding of 414–416 noxious, dual effects 995 pleasurable dual effects 995 role of amygdala in response to 992 sensory, changed in membrane potential produced by is transformed into digital pulse code 421 sensory nerves, intensity of encoded by frequency of action potentials 421–423 spatial resolution defined by receptive fields of sensory neurons 418–419 temporal features signaled by dynamics of spike train 428 transduction 414 Stop-transfer signal, cotranslational transfer of protein through endoplasmic reticulum membrane 94 Storage, processing of explicit knowledge 1238

Strabismus, effects on development of visual perception and clinical treatment 1129 Stratum pyramidale 78 Stratum radiatum 78 Stream of consciousness 1318 Streptomycin, toxic effect on hair cells 809 Stress induction of analgesia 489 response, activation in generalized seizure 927 sympathetic system of peripheral nervous system 335 Stretch, depolarizes muscle spindle mechanoreceptors 415 Stretch reflex 32–33 circuit for knee jerk 208 quadriceps muscle 208 information carried by electrical signals 26 mediated by monosynaptic circuits 26 motor neuron conveys central motor commands to muscle fiber 77–78 muscle 654 muscles involved 716 nature of 717 neurons mediating differ in morphology and transmitter substance 76–85 physiological basis 717 reinforce central commands for movements 728–730 sensory neurons convey information about state of muscle contraction 76–77 servomechanism 729 use in clinical examination 730 Stretch-receptor neuron, inhibitory postsynaptic potential in 209 Stretch-sensitive free endings 432 Stria of Gennari 532 Stria terminalis 987 central nucleus of bed nucleus, sexual dimorphism 1145 projections 992 Striatal nuclei, in hallucinations in schizophrenia 1190 Striate cortex 532 4C, projections from magnocellular and parvocellular layers 545 cells responsive to binocular disparity 561 layer 4B, directional selectivity of cells in 553 layers and connections 545 receptive fields of neurons in 583 See also Primary visual cortex and visual attention, 565 Striations, skeletal muscle fiber 676 Striatum 761 basal ganglia, inputs and outputs 855 developing forebrain 1036 dopamine receptors in output pathways 857 early appearance of Huntington disease pathology 865 heterogeneous function and structure 856 parallel direct and indirect pathways 856–857 projections 856–857 Striatum radiatum, effect of estrous cycle on density of synapses on dendritic spines in 1142 Strick, Peter 848 1190 Striola, utricle 804 805 Stripes in secondary visual area 583 visual cortex 501 Stroke 1302 1306 and autonomous control of facial expression 887 causes 1306 central pain syndrome 484 damage to visual cortex 585 effect on vascular physiology of brain 1316 face recognition after 499 glutamate toxicity in 214 hemorrhagic 1315 impairment of color vision 583 intraparenchymal, rupture of microaneurysms 1315 See also Aphasia; Language disturbance; Perception; Sensory loss; Weakness types 1306 Strychnine, effect on retention of learning 1245 Stumbling-corrective reaction, stepping in cats 749 Stuperous 901 P.1404 Subarachnoid space 368 cerebrospinal fluid 1294 1295–1296 Subcortical regions, retinal projections to 526–529 Subfornical organ, sensitivity to angiotensin II 1006 Subiculum 1232 Submaxillary ganglion 964 Submodalities 416 Submucous plexus 964–965 965 Substance K, neuroactive peptide 289 Substance P chemical intermediary for pain 442 effect on nociceptors 481 and inflammation symptoms 478–179 localization in terminal of C fiber afferent in dorsal horn of spinal cord 476 and nociceptor sensitization 477–478 precursor structure 291 release from C fibers 477 sensitization of nociceptors 480 striatum 856 Substance P and K, precursor structure 291 Substantia gelatinosa, dorsal horn of spinal cord 475 476

Substantia nigra 332 basal ganglia, inputs and outputs 855 855 dopaminergic neurons in 896 dopaminergic synapses 857 inhibitory input from caudate nucleus in saccades 793 midbrain, location of dopaminergic tracts 283 nucleus in midbrain 322 Substantia nigra pars compacta degeneration of dopaminergic neurons in Parkinson disease 862 dopaminergic neurons in 892 Substantia nigra pars reticular, convergence of basal ganglia circuits 858 Subthalamic nucleus basal ganglia 855 855 glutaminergic cells of 855 dopaminergic synapses 857 excessive activity and production of parkinsonian signs 862–863 functional inactivation in Huntington disease 865 and infarction of posterior cerebral artery 1308 lesions, and dyskinesias 864 surgical intervention at in Parkinson disease 863 863 Subvocal rehearsal system, Broca's area 360 Sulcal artery, spinal cord 1314 Sulci 9 324 widened in schizophrenia 1195 Sulcus limitans neural tube 880 relationship to cranial nerve nuclei 881 Sulfation, of proteins in Golgi complex 96 Summation and action potential in central neuron 227 columns, in primary auditory cortex 609 spatial 223 224 temporal 222 224 Sunlight, and circadian rhythm 937 Superior 321 Superior and inferior colliculus 367 Superior cerebellar artery 1303 1304 Superior cerebellar peduncle 833 Superior cervical ganglion 964 neuropeptides in 972 in pupillary dilation 905 Superior colliculus 482 788 control of saccadic eye movements 526–527 cortical inputs 526 cranial nerve nuclei at level of 884 inhibited by basal ganglia 793 lesions 793 795 movement signal to from frontal eye field 794–795 movement-related neurons in 792 projection of optic nerve to 517 retina to 523 projections through thalamic pulvinar nucleus to cerebral cortex 526 responses of neurons enhanced by selective attention 401 retinal projections to 527 role in eye movements 797 rostral, and visual fixation 793 See also Tectum structure 792 and visual attention 565 visuomotor integration of saccades 792–795 Superior mesenteric ganglion 964 Superior olivary complex, auditory pathway 606 Superior olivary nuclei, auditory pathway 604 Superior orbital fissure 877 cranial nerves passing through 878 Superior saccular ramus 802 Superior salivatory nucleus, location and function 885 Superior temporal cortex, lesions, effect on response to facial features 989 Superior temporal gyrus 333 damaged in global aphasia 1181 Supplementary eye field, motor cortex 794 Supplementary motor area 757 760 761 damage after infarction of anterior cerebral artery 1308 internally initiated movements 770 language 1174 left, damaged in transcortical motor aphasia 1180 preparation of movement sequences from memory 773 role in learning sequences of movements 771–774 Supporting cell, olfactory epithelium 627 Suppression columns, in primary auditory cortex 609 Suppressor of hairless protein, transcription factor and neuronal cell fate 1043–1044 Suprachiasmatic nucleus 976 hypothalamus, control of circadian rhythm of sleep 45 322 946 internal clock site in hypothalamus 937 larger in homosexual than in heterosexual men 1145 Supramarginal gyrus, language 1174 Supraoptic nucleus 976 Surface reflectance curves 577 reflectance function has component functions 578 Surround 517

Surround inhibition 463 breakdown of in seizure focus 919–920 loss of accompanies partial seizure 924 seizure focus 921 Survival, and drive states 999 Sustance P, neuroactive peptide 289 Swaab, Dick 1145 Sweat glands control by sympathetic and parasympathetic system 968 exocrine, establishment of neurotransmitter phenotype 1051–1052 Sweet tastant, mechanisms of transduction 639 taste quality 637–639 Swets, John 422 Swimming, lamprey pattern of muscle contractions in 745 rhythmic locomotor pattern for 745 Swing phase, stepping 740 741 Sylvian fissure, of cerebral cortex 325 Symbolic behavior 364 Sympathethic neurons, establishment of neurotransmitter phenotype 1051–1052 Sympathetic apraxia 355 Sympathetic chain 963 964 Sympathetic crisis 1221 Sympathetic division, autonomic nervous system 961 neurons and projections 964 Sympathetic nerve trunk 962 Sympathetic neuron develops from neural crest cells 1047 require neurotrophins for survival 1057 P.1405 Sympathetic pathways 963 Sympathetic preganglionic and postganglionic axons, anatomical organization 962 Sympathetic system, autonomic division of peripheral nervous system 335 Synapatic potential, in knee jerk 29 Synapses 22 22 173 175 action of membrane-permeable substances at 262 central neuron, grouped according to function 223–226 225 central nervous system, ultrastructure 1100 in cerebral cortex 85 chemical 173 175–177 amplification of signals 182–185 and electrical, functional properties 176 excitatory actions at result from opening of channels permeable to be Na+ and K+ 210–211 high density of voltage-gated Ca2+ channels 160 nerve-muscle, signaling at 187–206 neuromuscular 676 plastic capabilities, role of regulation of free calcium concentration in presynaptic terminal 276 plasticity of 34 See also Neurotransmitters short-term versus long-term physiological changes 34 synaptic delay 182 synaptic transmission at, process 183 transmission at 280 current flow in chemical and electrical 176 electrical 173 175–177 depolarizing current generated by voltage-gated ion channels of presynaptic cell 177 evidence for 178 at gap-junction channels 177 178–179 provide instantaneous signal transmission 177–182 transmission is graded 178 transmission of depolarizing and hyperpolarizing currents 178 transmission of metabolic signals 180 elimination of some after birth 1099 1100–1101 en passant 85 excitatory, distinctive ultrastructure 209–212 formation establishes information-processing circuit 1087 in central nervous system similar to that at neuromuscular junction 1101–1104 key steps 1087 and regeneration 1087–1114 formed by motor neuron with muscle cells 78–79 81 85 pyramidal cells in CA3 region of hippocampus on dendrites of CA1 cells in stratum radiatum 79 selectivity of and target recognition molecules 1112 inferring number of in reflex pathways 721 inhibitory, distinctive ultrastructure 209–212 location on neuronal surface and function of cell 335 in visceral motor system 962 related to efficiency 227 nerve-muscle, signaling at 187–206 neuromuscular 676 neuromuscular junction, substances organizing 1100 primary nociceptive neurons with neurons of substantia gelatinosa of spinal cord 476 rectifying 180 those on axon terminals often modulatory 226 those on cell bodies often inhibitory 224 those on dendritic spines often excitatory 224–225 Synapsin binds vesicles to cytoskeleton 271 277 proteins involved in neurotransmitter release 270

Synaptic action, slow modulatory, release of neurotransmitters from dense-core vesicles 261 Synaptic boutons 187 motor neuron 73 78 Synaptic cleft 22 23 176 182 188 central and neuromuscular synapses compared 1103–1104 neuromuscular junction 189 removal of neurotransmitter terminates synaptic transmission 294–295 neurotransmitters from 287 Synaptic connections changes in strength at and memory 1254 effect of neurotrophins on survival 1124 fine-tuning, and sensory experience 1115–1130 growth associated with activation of CREB-1 1257 and pruning, in consolidation of long-term implicit memory 1256–1257 morphological types of in brain 209 210 212 pruning of in long-term habituation 1257 visual cortex, model for fine-tuning 1126–1127 Synaptic current, reversal potential for 210–211 Synaptic delay, calcium role in 277 Synaptic excitation, comparison of that produced by opening and closing of ion channels 240 Synaptic inhibition associated with opening of K+ channels in cells with GABA receptors 217 cerebral cortex 922 control of spontaneously active nerve cells 209 209 short-circuiting effect 217 shunting effect 217 Synaptic input influence properties of postsynaptic cell 1107 neuronal response to 160 Synaptic integration 207–228 Synaptic mechanisms, underlying habituation 1249–1250 Synaptic membranes, study with freeze-fracture technique 263 Synaptic plasticity associated with kindling 932–933 fine-tuning 1277 genetic control 1277 molecular alphabet for 1272–1274 NMDA-mediated, and spatial memory 1272 Synaptic potential 29 characteristics 31 end-plate, method of production 190 fast and slow in ganglionic transmission 970 in knee jerk 29 muscle, passive propagation 191 originating in dendrites, and resistance 144 quantal 257 reversal potential for 210–211 summation of as neuronal integration 222 Synaptic receptors, types 229 Synaptic regeneration, required for restoration of function after axon growth 1111–1112 Synaptic stripping, after axotomy 1108 Synaptic targets, specificity of axon recognition of 1105–1108 Synaptic terminal changes in membrane potential effect on intracellular calcium 274 retraction, after axotomy 1109 Synaptic transmission 173–310 activity-dependent presynaptic depression of in habituation 1248–1250 at chemical synapses, process 183 P.1406 autonomic nervous system 962–963 central nervous system 207–228 changes in effectiveness in short-term storage of implicit memory 1248–1254 strength and learning 1250 chemical 280 genetically determined defects in depression 1224 transmitting and receptive steps 183 cholinergic 241 abnormalities in narcoleptic dogs 951 decrease in synaptic strength due to decrease of number of transmitter vesicles released from presynaptic terminals 1249 effect of residual calcium 274 electrical, demonstration in giant motor synapse of crayfish 177 fast and slow in autonomic ganglion neurons 242 long-lasting consequences endowed by second messengers 249–250 long-term depression, cGMP cascade role in 240 longest-lasting, changes in gene transcription 251 mechanisms for 176 modulation by second messengers 229–253 monoaminergic, abnormalities in narcoleptic dogs 951 overview 175–186 presynaptic facilitation of in classical conditioning 1252 sensitization 1250–1252 process 182 retrograde, evidence for 239 return of organelle membranes involved in to cell body 97 role of SNARE proteins 270 second messengers in 230–231 terminated by removal of neurotransmitter from synaptic cleft 294–295 Synaptic vesicles 182 188 189

calcium mobilization 277 clear-core, in hair cells 622 623 clustered at active zones 182 control of mobilization, docking, and function 272 discharge neurotransmitter by exocytosis 262–264 electron-translucent, in afferent terminals of nociceptive neurons 477 fusions 265 molecular machinery for fusion and exocytosis 273 neuron 68 neurotransmitter 31 neurotransmitter release from through opening of fusion pore 267 precursor membranes, anterograde transport to axon 101 proteins involved in neurotransmitter release from 270–273 and postulated receptors 271 recycling of 267 269–270 269 by endocytosis 99 release small-molecule transmitters 295 store and release neurotransmitter 261–267 question of assembly 97 Synaptobrevin 271 role in synaptic transmission 270 Synaptogenesis, highly interactive process 1112 Synaptophysin 271 Synaptotagmin 271 isoforms 272–273 membrane protein of synaptic vesicle 272 Syndactyly cortical representation of hand after surgical correction 392 use of to study cortical representation of hand 389–390 Syndenham, Thomas 1189 Syndrome 1189 Synergistic muscle 77 Syntactic processing, difficulties in Broca aphasia 1177 Syntactical processing 13 Syntax grammar 1170 principles of 1170–1171 Syntaxin 271 role in synaptic transmission 270 role in synaptic vesicle docking and fusion 277 Syringomyelia, cysts in spinal cord 733

T t-SNARE proteins docking and fusion of transport vesicles with target membranes 96 role in synaptic vesicle docking and fusion 277 Tabes dorsalis 468 and sensory neurons 33 Tabula rasa 411 Tachykinins, family of neuroactive peptides 290 Tacrine, treatment, Alzheimer disease 1158 Tactile information, object, fragmented by peripheral sensors and integrated by brain 452 Tactile stimulation behavioral relevance modifies cortical response 468 integration with visual stimuli in area 7 of posterior parietal cortex 465 map of cortical responses to produced using evoked potentials 386 Tail-flip response, goldfish 180 Takahashi, Joseph 45 Talbot, Samuel 496 Tanji, Jun 764 Tanner, Wilson 422 Tanycytes 1293 Tanzi, Rudy 1157 Tardive dyskinesia 1201 Target cells, secrete neurotrophic factors 1055–1056 Target membrane SNARE proteins See t-SNARE proteins Target recognition molecules, selectivity of synapse formation 1112 Tastants 626 interaction with taste cells 637 sweet, binding to G protein-coupled receptors 638 Taste 625–647 brain stem is site of entry for information from 320 coding, nature of 644 four different qualities of 637–642 role of pons 322 sensory cells 625–626 sensory neurons for organized according to sensitivity 419 types of stimuli 626 Taste buds 626 detect taste stimuli 636–642 innervation 637 643 taste cells in 638 on tongue 636 transmission of taste information to cerebral cortex 642 types of cells in 636 Taste cells clustered in taste buds 636–637 ion channels in 637 response to bitter tastant 640 Taste information

pathway 642 relayed to cerebral cortex via thalamus 642–644 transmission from taste buds to cerebral cortex 642 Taste pore 637 638 Taste sensations, variations in patterns of activity in afferent fibers 644 Taste stimuli detected by taste buds 636–642 detection 645 mechanisms of transduction 639 transduction 645 Tau protein, Alzheimer disease 1154 TDF See Testis determining factor P.1407 Teaching line, adaptive adjustment in vestibulo-ocular reflex 826–827 828 Tectorial membrane cochlea 596 organ of Corti 596 598 and stimulation of hair cells 598 Tectospinal tract 669 medial brain stem pathway 668 Tectum 669 See also Superior colliculus Telencephalon, development 1021 1022 1035 Tello, Fernando 1099 Temperature compensation, and circadian rhythm in flies 42 control, set point in humans 1001 regulation integration of autonomic, endocrine, and skeletomotor responses 1000–1002 See Drive states sense 430 sensations of mediated by anterolateral system 448–449 Temporal bone, inner ear 592 Temporal coding, and receptor adaptation rates 423–25 Temporal cortex auditory areas, monkey 608 lesions in disrupt object recognition 498 multimodal association areas, lesions in affect explicit memory 1231 visual processing area, responses of neurons enhanced by selective attention 401 Temporal crescent 525 Temporal frequency, P and M cells 530 Temporal hemiretina 524 524 Temporal lobe epilepsy See Epilepsy, temporal lobe Temporal lobe 8 324 325 332 368 369 abnormal cortical connection in schizophrenia 1196 and category-specific knowledge 1236 of cerebral cortex 325 decreased blood flow in Alzheimer disease 1152 dorsal surface, auditory areas 608–609 electrical stimulaton produces experiential response 1229 epileptic, mossy fiber reorganization in 933 function 9 lesions, in patient H.M. 1228 limbic association areas, lesions of and distinction between explicit and implicit memory 1230–1231 medial, increased blood flow in cocaine craving 1008 removal reduces or cures partial seizures 925 See also Left temporal lobe signals about color conveyed to 583 Temporal operculum 332 Temporal summation 222 224 Tendon jerks 730 Tendon reflexes 730 Tendons, store mechanical energy during muscle contraction 678 TENS See Transcutaneous electrical stimulation Terminal arbor, axon 1067 Terminal cistern, muscle fiber 677 Terminal degeneration, after axotomy 1109 Terminal tremor 844 Testes, produces hormones for sexual differentiation of external genitalia 1132–1134 Testicular hormones, produced sex differences in developing central nervous system 1136–1137 Testis determining factor development of testes 1132 in sex determination 1132 Testosterone effects of exposure to during early development 1136 and neuronal death in spinal nucleus of the bulbocavernosus 1141 prohormone 1134 and sexual differentiation of genital ducts 1133 suppresses apoptosis 1140 Tetanic stimulaton 274 Tetanus toxin 271 targets SNARE proteins 270 Tetrabenzine, inhibits uptake of amine transmitters 286 Tetracycline, use to control timing of gene expression 1270 Tetraethylammonium blocks voltage-gated K+ channel 153 structure 154 permeability of end-plate ion channels to 192 Tetrodotoxin action in voltage-gated versus ligand-gated channels 197 blocks voltage-gated Na+ channel 153 effect on presynaptic action potentials 253 254 structure 154 study of Na+ channels 160

Texture, object encoded by firing patterns of mechanoreceptors 440 information about signaled by populations of mechanoreceptors 438–441 Thalamic nuclei, in hallucinations in schizophrenia 1190 Thalamic pain syndrome, after infarction of posterior cerebral artery 1308 Thalamic relay neurons activity synchronized with cortical neurons during primary generalized seizure 926 hyperpolarized by GABA-ergic interneurons 924 rhythmic firing during non-REM sleep 940 special Ca2+ channel in 924 and state of sleep or wakefulness 899 T channel contribution to absence seizures 924 transmission and burst modes of signaling activity 899 Thalamic relay nuclei hyperpolarization 898 reciprocal interaction with GABA-ergic inhibitory interneurons in reticular nucleus 898–899 role in primary generalized seizures 926 transmission and burst modes 898 voltage-gated calcium channels in 898 Thalamic syndrome 481 Thalamogeniculate arteries diencephalon 1304 effects of occlusion 1309 Thalamoperforate arteries diencephalon 1304 effects of occlusion 1309 Thalamus 332 333 347 367 368 369 761 833 842 855 anterior, abnormalities in Alzheimer disease 1153 in ascending arousal system 900 and ascending pathway of nociceptive information 480–482 basal ganglia parallel circuits link with cerebral cortex 857–861 positive feedback and indirect pathway negative feedback 857 direct and indirect pathways of anterolateral tract to 449 function 8 generation of primary generalized seizures 924 hemorrhage, PET scan 1316 and infarction of posterior cerebral artery 1308 information processing in 344 inputs to motor cortex 761 left, and category-specific knowledge 1236 link between sensory receptors and cerebral cortex for all modalities except olfaction 341 major subdivisions 343 motor nuclei inputs to premotor cortex 355–356 P.1408 neurons in project to primary motor cortex 843 normal wakefulness state 899 nuclei classification 341–342 relay nociceptive information to cerebral cortex 480–481 olfactory information processing 633 parvocellular region, projections to ipsilateral cerebral cortex, taste 643–644 pathway of sensory information 446 projections from to neocortex 341 receives return projection from neocortex 343 recorded electrical activity, nature of 897–899 relay of taste information to cerebral cortex 642–644 role in mediating emotion 984 sends sensory information to amygdala for processing emotional information 990 sensory modalities conveyed to in ascending pathways 449 subdivision of diencephalon 322 transfer of odorant information to from olfactory bulb 633 transmission of sensory information to 448 ventral posterior medial nucleus, taste information pathway 642 Thermal injury, sensitization of nociceptors 479 Thermal nociceptors 443 473 Thermal pain, activation of anterior cingulate cortex 484 485 Thermal receptors 416 432 444–445 Thermal sensations, mediated by dorsal root ganglion neurons with bare nerve endings 431 Thermoregulation effects of sleep 944 role of serotonergic neurons 896 Theta, electroencephalogram 916 Theta rhythm, in hippocampus 1266 Thiamine deficiency chronic neuropathy 702 effect on cerebellum 850 Thinking 1169 Thioacylation, protein modification 92 Thiol endopeptidases, biosynthesis of neuroactive peptides 288 Thirst See Drinking Thirst See Drive states Thompson, Richard 849 1243 1248 Thoracic intermediolateral cell column, in pupillary dilation 905 Thoracic region, spinal cord 338–340 339 Thoracic splanchnic nerve, contains preganglionic axons 963 Thorndike, Edgar 382 1242 Thought, disorders of, schizophrenia 1188–1208 Threshold 126 127 127 158 sensory determination 421

modified by psychological and pharmacological factors 422 Thryotropin, neuroactive peptide 289 Thunberg's illusion, pain 484 484 Thymectomy in myasthenia gravis patients 300 treatment, myasthenia gravis 306 Thymomas, in patients with myasthenia gravis 300 Thyrotropin-releasing hormone neuroactive peptide 289 neurons releasing 979 980 Tight junctions, endothelial cells in brain microvessels 1290 TIM protein circadian rhythm 44 light-dependent degradation and circadian rhythm in flies 46 Time constant, passive membrane property of neuron 222 Timed response paradigm, parallel processing in movement 664 665 timeless gene, Drosophila, role in circadian rhythm 42 44 Timing role of cerebrocerebellum 846 stimulus attribute conveyed by sensory system 412 414 413 Tinel sign 703 Tinnitus 807 Tip link, hair cells 615 617 Tissue injury, major ascending pathways for information 480–482 TMA See Tetramethylamonium Todd paralysis 922 Tolerance drug 1011 opioid peptides 489 Tolman, Edward 382 Tonegawa, Susumi 1266 Tongue spatial segregation in nucleus of solitary tract, thalamus, and cortex 644 taste information pathway 642 types of papillae on 636 637 Tonic neurons 790 Tonic phase, partial seizure 913 Tonic-clonic seizure 913 neuronal activity during 922 Tononi, Giulio 1318 Tonotopic mapping, hair cells 620 Tonotopic map on basilar membrane 594 formation of on neurons in cochlear nucleus, inferior colliculus, and auditory cortex 1127 in primary auditory cortex 609 Tonsil, cerebellum 833 Top of the basilar syndrome, bilateral brain stem lesions 1312–1313 Topognosis 431 Topographic map body surface, in each of four Brodmann regions of somatic sensory cortex 458 in brain 323 internal organ system, in anterior insular cortex 974 retinal, generated by synchronous activity 1127 See also Retinotopic map Topographic representation, axons of retinal ganglion cells at termination in optic tectum 1064 Torque, muscle 688 tottering mouse mutant, model for study of primary generalized seizures 925 930 Touch 451–471 dorsal column-medial lemniscal system is pathway for perception 447–448 information about integrated by primary somatic sensory cortex 452–458 mediated by dorsal root ganglion neurons with encapsulated peripheral terminals 431 mechanoreceptors in skin 432–441 model for principles of cortical organization that give rise to conscious perception 451 path of information for 341 structural basis of receptive field of receptors for 419 study of to explore internal representations of personal space 384 Tourette syndrome, and basal ganglia 1224 Tower of Hanoi, test of frontal lobe function 358 Tower of London task, test of frontal lobe function 358 Toxins as blocking molecules in ion channels 112 effect on functional state of ion channels 115 ion channels as site of activity 105 Tract of Lissauer 448 Training effect on functional organization of primary motor cortex 761–763 expansion of existing representation of fingers in cortex 1274 and increased representation of movement in primary motor cortex 763 massed and spaced 1250 P.1409 repeated, conversion of short-term into long-term memory 1254 trans -(1S, 3R)-1-amino-1, 3-cyclopentanedicarboxylic acid, activates metabotropic glutamate receptors 212 Trans-Golgi network 96 Transcortical motor aphasia brain areas damaged in 1180 characteristics 1176 nonfluent speech in 1180 Transcortical responses 767 Transcortical sensory aphasia brain areas damaged in 1180 characteristics 1176 Transcortical sensory area, fluent speech with impaired comprehension in 1180

Transcription, DNA conversion to mRNA 88–89 Transcription factors regulatory DNA-binding proteins 88–89 See also C/EBP; CREB segmental expression in hindbrain patterning 1033 Sox gene family, neural plate cell differentiation 1026 Transcutaneous electrical stimulation, relief of pain 482 Transducin, inactivation terminates light response in phototransduction 514 Transfer RNA, mitochondrial 89 Transformation, signal in stretch reflex pathway 32–33 Transforming growth factor beta, neural crest cell fate 1047 Transgenes expression, methods of regulating 1268–1270 1269–1270 introducing in flies and mice 43 methods for turning on and off 1268 Translation, messenger RNA 90–91 Translational vestibulo-ocular reflex 809 Transmembrane proteins cone photopigments 576 GABA receptor 219 glutamate receptor 219 glycine receptor 219 method of formation in endoplasmic reticulum 95 See also Receptors Transmission directly gated, at nerve-muscle synapse 187–206 electrical, rapid and synchronous firing of interconnected cells 180 synaptic, process 182 Transmitters 173 act through second messengers to stimulate local protein synthesis in specific dendritic spines of postsynaptic neurons 250 action through second messengers to mediate phosphorylation of transcriptional proteins 249–250 chemical 31–32 chemical common biochemical features of receptors for 185 short- and long-term effects on ion channels 250 release triggered by calcium influx at presynaptic nerve terminals 160 See also Neurotransmitters Transneural degeneration, after axotomy 1109 Transneuronal degeneration, after axotomy 1109 Transport systems, carrier-mediated, and blood-brain barrier 1290–1292 Transport vesicles docking and fusion with target membranes 96 for export of proteins 96–97 neuron 68 69 Transporters chloride 132 ion conductance across cell membranes 108 reuptake of transmitter substance 294–295 types 295 vesicle, for concentrating neurotransmitters 285–286 Transposable elements 48 Transsexualism 1143 Transverse tubules, muscle fiber 677 Trapezoid body, auditory pathway 604 606 cranial nerve nuclei at level of 884 Treisman, Anne 502 504 566 trembler mutation, mouse, identification of peripheral myelin protein 22 83 Tremor, cerebellar abnormality 849 Trial-and-error learning See Operant conditioning Tricyclic antidepressants block uptake of serotonin 295 treatment cataplexy 951 panic attacks 1221 effect on serotonergic and noradrenergic neurons 1218–1219 Tricylcic compounds, antidepressants 1214 Trifluopromazine, structure 1198 Trigeminal cranial nerve (V) function and dysfunction 874–875 877 lesion 878 motor and sensory roots 877 origin at brain stem 876 877 Trigeminal lemniscus, ascending somatosensory pathway 448 Trigeminal motor nuclei 671 Trigeminal motor nucleus 881 location and function 883 Trigeminal nerve areas of innervation 880 in developing hindbrain 1031 mesencephalic nucleus of, control of sleep 941 Trigger component generation of action potential 29–30 nerve cell signaling 29–30 Trigger signal 27 Trigger zone 30 30 223 high density of voltage-gated Na+ channels 160 motor neuron 78 Trinucleotide amplification, myotonic muscular dystrophy 710 Trinucleotide expansion and genetic anticipation 54 role in Huntington disease 54 Trinucleotide repeats in huntingtin gene for Huntington disease 865 neurological diseases involving 55 types involved in neurological diseases 56

Trinucleotide repeat diseases 704 Triplet repeat diseases 704 Tritanopia 584 trkA, B, and C, neurotrophic receptors 1056 1057 trkB receptors, interference with blocks formation of ocular dominance columns 1124 Trochlear cranial nerve (IV) function and dysfunction 874–875 877 origin at brain stem 876 877 Trochlear nerve in developing hindbrain 1031 innervation of extraocular muscle 787 lesion 788 Trochlear nuclei, location 883 Trochlear nucleus 881 Tropism 1080 Tropomyosin in muscle fibers 677 678 muscle contraction 679 Troponin, in muscle fibers 677 678 Trunk motor control and sensation mediated by spinal cord 320 somatosensory information conveyed from by dorsal root ganglion neurons 431 from carried to spinal cord 338–340 Tsien, Joe 1266 TTX See Tetrodotoxin Tuber, cerebellum 833 Tuberculoventral cell, cochlear nucleus 605 Tuberoinfundibular hypothalamic neuroendocrine system, dopaminergic neurons in 893 P.1410 Tuberomamillary nucleus in ascending arousal system 900 histaminergic neurons in 894 895 896 hypothalamus 977 Tubulin, in microtubules 72 Tufted relay cells, olfactory bulb 630 631 Tully, Tim 1259 Tulving, Endel 1231 Tumors affecting cranial nerves 877 brain, and blood-brain barrier function 1294 Tuning curve, frequency sensitivity of hair cell 599 599 Twin studies anatomical abnormalities in brain in schizophrenia 1195–1196 for evaluating role of genes and environment in complex behavior 40–42 41 homosexuality 1145–1146 1145 personality 42 schizophrenia 1193–1194 Twins monozygotic versus dizygotic 40 concordance rate for bipolar depression 1212 enlargement of lateral ventricle in schizophrenia 1197 sleep patterns in 944 Twitch contraction 681 Two-point discrimination and lateral inhibition 461 skin 464 Two-point threshold 438 Tympanic membrane 595 Tympanum 591 591 595 Tyrosine kinase ACh receptor as substrate for 248 regulation 235 dimerization 239 membrane-spanning, as neurotrophic receptors 1056 nonreceptor 230 pathway, receptor and cytoplasmic kinases in 238–239

U Ubiquitin, addition of as post-translational protein modification 90 93 Ubiquitin carboxyterminal hydrolase, in long-term facilitation 1254–1257 Umami, taste quality 642 Unconditioned response 1240 Unconditioned stimulus 1240 Ungerleider, Leslie 500 1237 Unimodal association areas 350 cerebral cortex 345 Unimodal association cortex, processing of sensory information in cerebral cortex 345 Unipolar disease See Depression, unipolar Unreality, ictal phenomenon 15 Unwin, Nigel 199 Upper contralateral quadrantic anopsia 544 Upper motor neurons 696 symptoms of disorders of 696 Urbach-Wiethe disease, amygdala 988–989 Urogenital reflexes, mechanism 968–969 Utricle 802 axis of mechanical sensitivity 805 cochlea 592 detection of linear acceleration 804–805 reports linear accelerations 802

structure 804 Uvula, cerebellum 833

V V See Potential difference Vm see Membrane potential V-SNARE proteins, docking and fusion of transport vesicles with target membranes 96 V1 See Primary visual cortex V2, visual cortex cells in respond to both illusory and actual contours 562–563 higher-level information processing of illusions of edges 564 interconnections with V1 549 organization 549 See also Secondary visual cortex stripes and interstripes in, 550 V4, visual cortex analyzes and represents color information in image 583 cells in respond to form 563–564 color-opponent neurons in 588 effects of visual attention on cells of 565–566 neurons, response to effective visual stimulus modified by selective attention 568 secondary visual area projects to 583 Vacuolar apparatus proteins manufacture on rough endoplasmic reticulum 103 synthesized and modified in endoplasmic reticulum 94–96 Vacuolar apparatus neuron 69 role in protein synthesis 91 Vagal nucleus, dorsal, preganglionic parasympathetic nucleus in brain stem, projections 963 Vagus cranial nerve (X) function and dysfunction 874–875 879–880 injury 880 origin at brain stem 876 877 Vagus nerve in developing hindbrain 1031 and homeostasis 965 Vagusstoff 966 Valium effect on gating of ion channels in response to GAB A 114 116 See Benzodiazepines Vallbo, Ake 729 Valproic acid, blocks absence seizures 924 VAMP in synaptic transmission 270 in synaptic vesicle docking and fusion 277 Van Essen, David 496 Vannilloid receptor, in nociceptors 474 Varicosities 962 Vascular lesions brain stem, syndromes 1310 See also Infarction; Occlusion Vascular syndromes, brain stem 1312 Vascular volume, regulation of drinking 1006–1007 Vasoactive intestinal peptide, co-release with ACh 290 Vasoactive intestinal polypeptide 972 neuroactive peptide 289 Vasogenic edema 1294 brain 1299 Vasopressin magnocellular endocrine neurons 987 neuroactive peptide 289 posterior pituitary gland 979 transmitter in neurons innervating antipyretic area of brain 1002 secretion by hypothalamic magnocellular neurons 979 Vegetative state, persistent, as result of bilateral forebrain damage 900 901 Venterolateral nucleus 761 Ventral amygdalofugal pathway 987 Ventral columns, white matter of spinal cord 338 338 Ventral corticospinal tract, pathway 670 Ventral horn, spinal cord 319 338 Ventral occipital cortex, localized damage to causes loss of color vision 563–564 Ventral posterior and ventral medial nuclei, pathway of sensory information 446 Ventral posterior lateral nucleus 342 thalamic 482 Ventral posterolateral nucleus 761 Ventral premotor area, individual cell active if monkey performs task or observes task being performed 777 Ventral root, spinal cord 320 Ventral striatum, basal ganglia 855 P.1411 Ventral sulcus, spinal cord 338 Ventral tegmental area, dopaminergic neurons in 896 Ventral 321 Ventricle 325 332 lateral and third, enlarged in schizophrenia 1195 1196 1197 third 369 Ventrolateral funiculus 751 Ventrolateral medulla in autonomic response control pathway 975 pathway of visceral sensory information 974 Ventrolateral medullary reticular formation 885 Ventrolateral nucleus, thalamus 347 Ventromedial hypothalamic nucleus 976 Ventromedial motor nucleus 668 Ventromedial nucleus, hypothalamus 977 Ventroposterior parvocellular nucleus, projections to 973–974

Verbal tasks, sex differences 1142 Vergence 797 movement system, eye 783 785 organized in midbrain 796 Vermis, cerebellum 833 834 lesions of 850 Vertebral artery 1303 branches supply blood to brain stem and cerebellum 1309 infarction, brain stem syndromes produced 1311–1312 Vertigo, cerebellar infarction 1313 Vesicles anterograde transport to axon 101 classes of 97 clathrin-coated, in endocytic traffic 98 coated, in exocytosis 265 concentrations of neurotransmitters in 285 dense-core contain neuropeptides and small-molecule neurotransmitters 281 store neuropeptides and neurotransmitters 261 large dense-core in afferent terminals of nociceptive neurons 477 anterograde transport to axon 101 storage of neuropeptides 290 store peptide neurohormones 97 targeted to axons 97 neurotransmitter, and quantal synaptic potential 277 package chemical messengers 296 precursors, neuron 68 secretion of proteins from Golgi complex 97 small lucent, contain small molecule neurotransmitters 281 SNARES, role in synaptic transmission 270 synaptic, question of assembly 97 transport, for export of proteins 96–97 transporters 287 for concentrating neurotransmitters 285–286 Vesicular SNARE proteins See v-SNARE proteins Vesicular-ATPase, vesicle transporter 285–286 Vestibular apparatus habituation 809–810 integration of vestibular, visual, and motor signals 810–813 Vestibular canals, disease in, nystagmus 812 Vestibular ganglia of Scarpa 802 Vestibular ganglion 803 Vestibular labyrinth 802 defects in, and loss of balance 824 effect of removal in cat 825 Meniere disease 807–808 parallel fiber input to Purkinje cells 827 828 Purkinje cells' inhbitory influence on vestibular nuclei 825 828 receptor organs 802–808 Vestibular movements, eye 797 Vestibular nerve 591 801 803 807 808 anatomical connections 812 cochlea 592 signals head velocity to vestibular nuclei 810–812 Vestibular nuclei 801 afferent inputs 810 lateral and medial 669 location and function 882 medial and lateral, inhibitory effect of Purkinje neurons on 841 optokinetic and vestibular peripheral inputs to 828 829 projections to oculomotor system 814 receive signals regarding head velocity from vestibular nerve 810–812 vestibulo-ocular reflex 811 811 812 Vestibular nucleus 808 881 ventral corticospinal tract 670 Vestibular nystagmus 809 resets eye position during sustained rotation of head 809 Vestibular projection, cerebral cortex, perception of rotation and vertical orientation 813 Vestibular receptors, lesions, cause disorientation and vertigo 807 Vestibular reflexes stabilize eyes and body when head moves 808–810 volitional control 822–823 Vestibular schwannoma, vestibulocochlear cranial nerve 879 Vestibular signals, covergence with vestibular signals during rotational movements 828–829 Vestibular system 801–815 contributions to postural control 821–824 824 projects information in top-down manner 830 Vestibulocerebellum 834 inputs and projections 840 regulates balance and eye movements 841 Vestibulocochlear cranial nerve (VIII) function and dysfunction 874–875 functions 879 origin at brain stem 876 877 Vestibulocochlear nerve 807 Vestibulocollic reflex, stabilizes head relative to space 822 Vestibulo-ocular control motor learning in 824–828 role of cerebellum in adaptation 825–828 Vestibulo-ocular eye movements 783 Vestibulo-ocular reflex 808

adaptive learning, memory of in brain stem 828 compensate for head movement 808–809 effect of magnifying lenses 825 826 prism glasses on 848 horizontal 812 hypotheses of adaptive adjustment 826–827 supplemented by optokinetic system 809–810 types 809 Vestibulo-ocular system 783 Vestibulospinal reflexes 808 collaboration with cervicopspinal reflexes to maintain postural stability 823–824 823 maintain vertical posture 810 Vestibulospinal tracts 669 medial brain stem pathway 668 Vibration sense, coded by spike trains in mechanoreceptors in skin 437 Vibrissae 462 Video microscopy techniques 101 Vigilance increased by ascending monoaminergic projections from brain stem and hypothalamus 896–897 role of locus ceruleus 896 Vilis, Tutis 844 Vincent, Angela 306 Violence See Behavior, aggressive VIP See Vasoactive intestinal peptide Virchow, Rudolf 1189 Virchow-Robin spaces, blood vessels in subarachnoid space 1296 Viscera innervated by dorsal root ganglion neurons 444 P.1412 mechanosensory and chemosensory receptors in 443–444 signals from nociceptors in and pain elsewhere in body 475 Visceral function, role of hypothalamus 8 Visceral motor cortex 974 Visceral motor nuclei, in developing hindbrain 1031 Visceral motor system reflex circuits in 962 synpases in 962 Visceral reflexes, and autonomic nervous system 961 Visceral sensory afferents 980 Visceral sensory information, pathways 973–974 974 Visceral sensory thalamus, projections to 973 Visible spectrum 574 Vision achromatic 579 color 572–589 depth, monocular cues and binocular disparity 558–562 disturbed, diffuse hypoperfusion 1313 guidance of movement 654 independence from language 364–365 object versus stereopsis 561–562 role of occipital lobe 9 posterior nuclei of thalamus 343 See also Depth; Form; Gaze; Motion; Object vision stereoscopic 560 neuronal basis 561 vestibular stabilization of eye relative to space 828–829 visuospatial sketch pad for in working memory 1239 Visual area 1 See Primary visual cortex Visual attention See Attention, visual Visual cortex cells responsive to binocular disparity 561 function MRI study 374 hierarchical pathways in two cortical pathways 552 information conveyed by magnocellular and parvocellular pathways 529–532 model for fine-tuning of synpatic connections 1126–1127 monkey, different disparity profiles in neurons 562 partial lesions, partial visual deficits on opposite side 544 projections to 1116 See also Primary visual cortex; V2; V4 serial pathways through 552 transformation of visual signals 581–583 Visual deprivation See Eye closure Visual field 524 binocular and monocular zones 524 correspondence of regions with retinal image 525 decomposition into short line segments 545 deficits in produced by lesions at various points in visual pathway 544 each half represented in contralateral primary visual cortex 532 gaps in associated with lesions in retino-geniculate-cortical pathway 543–545 one region of, hypercolumn representation of visual properties of 539–540 optic flow 553 perception of motion in 551 retinal image inversion of 524–525 526 visual information 504 Visual hemifield, left and right 525 Visual image background versus foreground 497 built up from inputs of parallel pathways 502–504 construction 492–506 contrasts and rapid changes detected by ganglion cells 519–520 ganglion cells process different aspects 520

and interactions among areas of cerebral cortex 505 outlines of decomposed into short line segments in primary visual cortex 533–535 primary visual cortex organizes retinal inputs into building blocks of 532–537 receptive field of each receptor 420 requirement of focused attention on elements in visual field 502 Visual information areas of cerebral cortex dedicated to 499 carried by brightness variations 579 combination into coherent image, hypothetical model 504 and motor systems, role of parietal neurons 567 parallel pathways 500–501 517 processing in cerebral cortex, PET measurement of local blood flow changes during 378 multiple cortical areas 496–497 selective filtering by visual attention 565 subcortical processing by lateral geniculate nucleus 529 Visual neglect 498 Visual neurons, in frontal eye field 794 Visual orientation, disrupted by lesions in parietal cortex 498 Visual pathways central 523–547 early transformation of cone signals 577–581 functions mediated by 502 P and M 501 Visual perception activity of extrastriate cortex 500 development of 1116–1117 focal attention 503 frames of reference 498 preattentive scanning 503 requires sensory experience 1115–1117 and selective attention 400 sequential processes 502–503 winner-take-all perceptual strategy 494 Visual pigments absorption of light by in photoreceptors 510 in cones 512 genes encoding are on X chromosomes 584–585 Visual processing and developmental dyslexia 1185 by retina 507–522 Visual signals, transformation in visual cortex 581–583 Visual space, representation of body related to 402 Visual spatial agnosia 500 Visual stimuli development and role of orientation columns 1125 integration with tactile stimuli in area 7 of posterior parietal cortex 465 responses of neurons in area 17 of monkey visual cortex 1117 Visual system 492–506 anatomical pathways 496–197 binding problem 492 566–567 circuits refined by sensory experience 1115 cognitive function 492 components of in midbrain 322 confusion by artificial means 577 distributed processing 496 505 M and P pathways 581 magnocellular pathway, slower conduction in people with dyslexia 1185 molecular cues for development 1115 motion information processed in two stages 554 556 parallel pathways in 504–505 521 545 567–568 on-center and off-center ganglion cells 519–520 P.1413 receptive field of sensory neurons defines spatial resolution of stimulus 418–419 separate circuits for global versus local features of object 397 serial pathway 505 structure 1116 Visuomotor integraton, superior colliculus 792–795 Visuomovement neurons, in frontal eye field 794 Visuospatial buffer, localization 360 Visuospatial sketch pad localization 360 working memory 1239 Visuospatial tasks, sex differences 1142 Vitamin A, deficiency, night blindness 512 Vitamin B12 deficiency, chronic neuropathy 702 Vm See Resting membrane potential Vogt, Marthe 299 Volition, disorders of, schizophrenia 1188–1208 Voltage current in ion channel related to linearly 109–110 110 equal to membrane potential 143 relationship with current 141 Voltage clamp technique 169 calculate membrane conductance 155 current generator 152 determining origin of electrical resonance in hair cells 621 demonstrates rapid rate of Na+ channels turning on and off over range of membrane potentials 156 determine separate time courses of oppositely directed currents 153 electrical equivalent circuit of nerve cell undergoing 155 mechanism of 151 152

negative feedback system 152 study of end-plate potential 190 See also Patch-clamp technique, 152 study of Na+ and K+ conductance as function of membrane potential 151 study of Na+ and K+ currents with 151–154 Voltage response, passive neuronal process, and electrotonic conduction 145 Voltage-gated channel, structure 119 118 See Ion channel, voltage-gated Voltametry 266 Voluntary behavior, law of effect 1242 Voluntary movement 756–781 See also Movement, voluntary Vomeronasal organ mediates information about pheromones 634 olfactory information processing 633 pattern of expression of pheromone receptors 635 635 sensory transduction in 634 Vomeronasal receptors, layered 634 Vomeronasal system 634 von Bekesy, Georg 594 von Helmholz, Herrmann 6

W Wada test, for hemispheric distinction 364 Wagnor, Jackson 1134 Wake-sleep cycle with no cognitive content, as persistent vegetative state 900 role of serotonergic neurons 896 Wakefulness disorders of 948–959 increased by ascending monoaminergic projections from brain stem and hypothalamus 896–897 Waking, signaling activity of thalamic relay neurons 899 Waking state, promoted by stimulation of midbrain reticular formation 939 Walker, Mary 299 Walking central motor command for modifies transmission in spinal reflex pathways 724 human bipedal and demands on descending systems 754 spinal pattern generators in 753–754 proprioceptive signals in 727 role of descending pathways in initiation and adaptive control 750–753 750 See also Locomotion; Stepping spinal circuits in 717 Wallenberg syndrome, damage of cranial nuclei in lateral medulla 886 886 Wallenberg, Adolph 886 Waller, Augustus 88 Wallerian degeneration, after axotomy 1108 1109 Warm-sensitive neurons, hypothalamus 1001 Warmth, mediated by thermal receptors 444–445 Warrington, Elizabeth 1237 Water, shell of surrounding ions 108 Water balance, regulation by hypothalamus 1006–1007 Water intake, set point 1006 Water maze memory test 1267 1271 1272 test of spatial memory defects 1271 Water regulation, feedback signals for 1006 See also Drinking Water-soluble compounds, transport across blood-brain barrier 1292 Watson, J.B. 382 Weakness after occlusion of carotid artery 1309 areas of after middle cerebral artery infarction 1307–1308 infarcts of medial or lateral brain stem structures 1311 Weber syndrome, midbrain infarction 1312 Weber's law 421 Weber, Ernst 411 412 421 Weigert stain, layers of neurons in cerebral cortex 326 Weinberg, Stephen 398 Weinberger, Daniel 1203 Weischaus, Eric 1032 Weiskrantz, Lawrence 1318 Weiss, Paul 100 1064 Wender, Paul 1193 1212 Werner syndrome, premature aging, mechanism 1150 Wernicke aphasia after middle cerebral artery infarction 1308 characteristics 1176 damage to left temporal lobe structures 1179–1180 MRI of lesion 1179 phonemic paraphasias in 1179–1180 spontaneous speech, auditory comprehension, and repetition in 1178 Wernicke's area activation when words are heard 13 language 1174 1175 lesion, effect on speech 897 and speech 11 temporal lobe, damage to produces sensory aphasia 355 Wernicke, Karl 7 10–11 Wernicke-Geschwind model, language 1175 Wertheimer, Max 493 Wheatstone, Charles 560 Whiskers and developmental organization of barrels in somatosensory cortex of rodents 1037 1037 mapping in primary motor cortex and plasticity 761 representation on rodent cortex 460 462 See also Barrels

White communicating ramus 962 White matter, spinal cord 319 structure 338 White myelinated rami 963 Wide-dynamic-range neurons, in dorsal horn of spinal cord 475 Wiesel, Torsten 529 533 537 579 1116 Wilks, Samuel 299 Williams syndrome 1172 Wind-up phenomenon, C fibers 479 Winner-take-all perceptual strategy, visual perception 494 P.1414 Wisconsin Card Sorting Test blood flow to prefrontal areas in schizophrenic patients 362 test of frontal lobe function 358 Withdrawal reflexes, muscle 654 Wnt-1, differentiation of mesencephalon 1034 Wolffian ducts, sexual differentiation 1133 1133 Woodworth, Robert 662 Woolsey, Clinton 385 Word 1170 Words activation of different areas of cerebral cortex 13 PET identification 14 association, role of cerebellum 848 for categories of things, left temporal cortices contain neural systems for accessing 1182 open-class and closed-class vocabularies 1170 recall of in amnesiacs and normal subjects 1230 Working memory 357 and Broca aphasia 1179 components 357 cortex surrounding the principal sulcus 357–361 imaging of 360 modular nature 359 nonverbal 360 and prefrontal association area 357 See also Memory tracked by neurons in principal sulcus 361 verbal 360 Worm See Caenorhabditis elegans Writing acquired disorders of 1183–1184 motor equivalence in 657 versus language 1170 Wundt, Wilhelm 411 1317 Wurtz, Robert 400 565

X X chromome L and M pigment genes on 585 locus of genes encoding visual pigments 584–585 See also Duchenne muscle dystrophy; Mental retardation X-linked spinal and bulbar muscular atrophy, trinucleotide repeats in 55 X-ray computerized tomography, functional imaging of brain 366 X-ray crystallography structure of extracellular glutamate binding domain 220 study of ion channels 109 used to solve structure of K+ -selective ion channels 120–123 122 X-ray diffraction studies, three-dimensional structure of gap-junction channel 179 XX individual, formation, phenotypic female 1132 1132 XX male, formaton 1132 1132 XY female, formation 1132 1132 XY individual, formation, phenotypic male 1132 1132

Y Y chromosome location of testis determining factor 1132 in sex determination 1132 Yellow-blue mechanism, in cones 580 Yellow-blue variation, component function of reflectance function 578 Yeo, Christopher 849 Yin, Jerry 1259 Yohimbine induces panic attack in patients with post-traumatic stress disorder 1222 induction of panic attacks 1221 Young, Thomas 575

Z Z disk, sarcomere 677 678 Zeitgebers, timing cures 937 Zeki, Semir 496 505 583 587 Zona limitans intrathalamica, forebrain 1035 Zotterman, Yngve 421 430 Zurif, Edgar 13