Autonomic Nerves

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Wilson-Pauwels Akesson Stewart Autonomic Nerves Beginning in 1997 every Decker book will be accompanied by a CD-ROM. The disk will appear in the front of each copy, in its own sealed jacket. Affixed to the front of the book will be a distinctive “BCD” sticker - “Book cum Disk.” The disk contains the complete text and illustrations of the book, in fully searchable PDF files. The book and disk are sold only as a package. Neither are available independently, and no prices are available for the items individually. B.C. Decker Inc. is committed to providing high-quality electronic publications that will complement traditional information and learning methods. We trust you will find the book/disk package invaluable and invite your comments and suggestions.

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Front cover: Release of neurotransmitters from postganglionic autonomic varicosities resulting in stimulation of secretory cells. Cover design and illustration by Linda Wilson-Pauwels with technical assistance from David Mazierski.

LINDAWILSON-PAUWELS, A.O.C.A., B.Sc.AAM, M.Ed., Ed.D. Associate Professor and Chair Biomedical Communications, Department of Surgery Faculty of Medicine University of Toronto Toronto, Ontario, Canada

PATRICIAA. STEWART, B.Sc., M.Sc., Ph.D. Professor Department of Anatomy and Cell Biology Faculty of Medicine University of Toronto Toronto, Ontario, Canada

ELIZABETH 1. AKESSON,B.A., M.Sc. Assist ant Professor Department of Anatomy Faculty of Medicine University of British Columbia Va n co u ve r, Brit i sh Co1 u m b i a, Ca n a d a

1997

B.C. Decker Inc. Hamilton

London

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01997 Linda Wilson-Pauwels, Patricia Stewart, Elizabeth Akesson. 97 98 99 00 01 /PC/ 9 8 7 6 5 4 3 2 1 ISBN 1-55009-030-5

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The autonomic nervous system is complex, both structurally and functionally, and research in the field is changing our understanding of autonomic function at a rapid pace. This book is designed to make learning about the autonomic nervous system easier for teachers, students, and practitioners in medicine and the allied health professions. To facilitate learning, we make extensive use of conceptual illustrations: neural pathways, transmitters, and receptors are color coded, and arrows are used to show the direction of impulses. Considerable care is taken to integrate the written a n d visual components of each chapter. W e attempt t o simplify our representation and discussion of autonomic pathways and functional mechanisms without over-simplifying important concepts. W e emphasize the major principles of autonomic function and resist the temptation to include a wealth of detail that might overwhelm the reader. For those who wish to delve deeper, we include a bibliography that lists several excellent publications that describe the autonomic nervous system in considerable detail. This book is divided into two parts. The first part describes the structure and function of the autonomic nerves, and the second part addresses autonomic control of individual organ systems in a problem-based learning format. In many other text books, the autonomic nervous system is narrowly defined as a motor system organized into two divisions: sympathetic and parasympathetic, whose effects are frequently antagonistic and whose balance of activities produces homeostasis. While this definition is simple and facilitates description of the autonomic nervous system, it ignores the important roles of sensory input, central integrating mechanisms, and the enteric nervous system. In this book, we define the autonomic nervous system much more broadly as the neurologic substrate that acts to maintain homeostasis in the body. We describe afferent (sensory) pathways, integrating structures and mechanisms, efferent (motor) pathways, and the autonomic effectors (smooth muscle cells, cardiac muscle cells, and exocrine secretory cells). We address the principles of autonomic neurotransmission with respect to the specialized morphology of the nerve endings and the variety of neurotransmitters and receptors that act in autonomic nerves and effector cells. The second part of the book consists of eight case studies. Each depicts a different aspect of the autonomic control of the organ systems, and each includes a history, a list of guiding questions, and a case discussion in which each of the learning objectives is addressed. The case studies are designed to be complete when isolated from the rest of the book. We are grateful to our colleagues, both in our home institutions and abroad, who were kind enough to answer burning questions, critique text and illustrations, and supply us with radiologic and photographic images. Their expertise was invaluable, and very much appreciated. They are: U. Ackerman, Ph.D., Department of Physiology, University of Toronto, Canada.

C.E.Bayliss, M.D., M.Ed., F.R.C.S.(C),Departments of Physiology and Surgery, University of Toronto, Canada. G. Burnstock, DSc., F.A.A., M.R.C.P.(Hon), F.R.S., Department of Anatomy and Developmental Biology, University College, London, U . K . M. Costa, F.A.A., Department of Human Physiology, Flinders University, South Australia.

J. Church, M.D., Ch.B., Ph.D., Department of Anatomy, University of British Columbia,

Canada. W.G. Dail, Ph.D., Department of Anatomy, University New Mexico, U.S.A. D. Dixon, M.D., F.R.C.P.(C),Ophthalmologist, B r a m p t o n , Ontario, C a n a d a . J.O. Dostrovsky, Ph.D., Department of Physiology, University of Toronto, C a n a d a . G. Downey, M.D., F.R.C.P.(C),Department of Medicine, University of Toronto, C a n a d a . D. Harrison, M.D., ER.C.P.(C),BC Cancer Agency, Vancouver Centre, Vancouver, BC, C a n a d a . K. Hayakawa, Technician, Department of Anatomy, University of Toronto, C a n a d a . S. Kraft, M.D., ER.C.S.(C),Department of Ophthalmology, University of Toronto, Canada. D. Mazierski, B.Sc.AAM, Biomedical C o m m u n i c a t i o n s , Department of Surgery, University of Toronto, C a n a d a . J. Mitchell, Ph.D., Department of Pharmacology, University of Toronto, C a n a d a M. Opas, Ph.D., Department of Anatomy a n d Cell Biology, University of Toronto, Canada. V. Palaty, Ph.D., Department of Anatomy, University of British Columbia, C a n a d a . J.A. Pearson, Ph.D., Department of Anatomy, University of British Columbia, C a n a d a . J. Saint-Cyr, Ph.D., Department of Anatomy a n d Cell Biology, University of Toronto, Canada. F. Silver, M.D., F.R.C.P.(C),Department of Medicine (Neurology),University of Toronto, Canada. E.L. Shorter, Ph.D., Departments of Medicine a n d History of Medicine, University of Toronto, C a n a d a . S. Spacey, M.B.B.S., Neurology Resident, University of British Columbia, Vancouver Hospital, C a n a d a .

D.A. Stringer, B.Sc, M.B.B.S.,F.R.C.R.,F.R.C.P.(C),Section of Ultrasound a n d General Radiology, Department of Radiology, BC Children’s Hospital, Vancouver, C a n a d a . I.M. Taylor, M.D., Department of Anatomy a n d Cell Biology, University of Toronto, Canada. C. Thompson, B.Sc., Department of Anatomy a n d Cell Biology, University of Toronto, Canada. D. Van d e r Kooy, Ph.D., Department of A n a t o m y a n d Cell Biology, University of Toronto, C a n a d a . A.W. Vogl, Ph.D., Department of Anatomy, University of British Columbia, C a n a d a M.J.Wiley, Ph.D., Department of Anatomy a n d Cell Biology, University of Toronto, Canada. H. Wolburg, Professor, Institut fur Pathology d e r Universitat Tubingen, Germany N. Wooolridge, B.F.A., B S c . AAM, M S c . , Biomedical C o m m u n i c a t i o n s , University of

Toronto, C a n a d a . Linda Wilson-Pauwels Patricia Anne Stewart Betty Akesson vi

BIBLIOGRAPHY / 229 INDEX / 237 vii

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Introduction

I INTRODUCTION The nervous system can be divided into two semi-independent systems: 1. The somatic nervous system allows us t o act on t h e external environment,

a n d can be defined as t h e neurologic substrate that allows t h e individual to respond voluntarily to consciously perceived sensory signals. 2. The autonomic nervous system allows us to act on t h e body’s internal

environment, a n d can be defined a s t h e neurologic substrate that acts t o maintain homeostasis (a steady state) in t h e body. For t h e most part, we a r e not aware of t h e workings of t h e autonomic nervous system in t h e s a m e way as we a r e aware of other neurologic activities, such a s seeing, feeling, or moving. Most autonomic sensory signals are not perceived consciously, a n d most autonomic motor activities are not under voluntary control. The n a m e “autonomic” (self-governing) reflects t h e i n d e p e n d e n t nature of this part of t h e nervous system.

Introduction

SOMATIC AND AUTONOMIC NERVOUS SYSTEMS ARE ORGANIZED IN A SIMILAR WAY Both somatic a n d autonomic nervous systems include sensory neurons that carry signals t o integrative neurons within t h e brain a n d spinal cord that construct a n a p p r o p r i a t e r e s p o n s e , a n d motor neurons t h a t carry t h e response back to t h e effector cells (Figure 1-1). Over short time spans, t h e nervous system can only respond to sensory input in two ways: it can cause a muscle, or group of muscles, t o contract, or it can cause glands to secrete. Our entire behavioral repertoire can be reduced t o combinations of t h e s e two actions: t h e somatic nervous system causes voluntary muscles to contract, whereas t h e autonomic nervous system causes or modifies involuntary muscle contraction a n d glandular secretion.

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THE SOMATIC AND AUTONOMIC NERVOUS SYSTEMS DIFFER MOST IN THEIR MOTOR COMPONENTS 1. Somatic effectors (skeletal muscle fibers) are innervated by a single

source: lower motor neurons in t h e brain stem or spinal cord. In contrast, most autonomic effectors (smooth muscle, cardiac muscle, secretory cells) are innervated by two autonomic sources: sympathetic and parasympathetic motor neurons (Figure 1-2).

2. Somatic motor neurons, whose cell bodies reside in the motor nuclei of the

brain stem and in the anterior horn of t h e spinal cord, project directly to their target cells, whereas autonomic motor neurons form two-neuron chains: preganglionic motor neurons, whose cell bodies reside in the central nervous system (brain stem or spinal cord), and postganglionic motor neurons, whose cell bodies reside in autonomic ganglia. This two-neuron arrangement has several advantages a s follows: Firstly, a single preganglionic neuron synapses on large numbers of postganglionic neurons, thereby allowing for a small number of central neurons to influence large areas of t h e body. This is t h e principle of divergence of stimuli (Figure 1-3); Secondly, since sensory (afferent) axons course through the ganglia, a certain amount of sensory-motor integration can take place at t h e ganglionic level, thereby giving t h e autonomic nervous system a degree of autonomy from the central nervous system; and

Introduction

Thirdly, a single preganglionic neuron can synapse o n both excitatory a n d inhibitory postganglionic neurons, thereby allowing for excitation a n d inhibition of various target cells t o produce a high d e g r e e of functional coordination.

Figure 1-3 The principle of divergence of stimuli is illustrated in the sympathetic nervous system. Preganglionic motor neurons in the spinal cord project to numerous postganglionic motor neurons in the coeliac ganglion. In humans, the ratio of pre- to postganglionic neurons averages 1 : 120. It is higher in sympathetic than in parasympathetic pathways.

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3. Somatic motor neurons activate skeletal muscle fibers only, whereas

autonomic motor neurons have a variety of targets including smooth muscle, endothelial cells, cardiac muscle, secretory cells, a n d chromaffin cells in t h e adrenal medulla. 4. Somatic motor n e u r o n terminals release their neurotransmitter a t discrete

sites close t o t h e target muscle fibers, whereas postganglionic autonomic motor neuron terminals release their transmitter much more diffusely a n d a t a distance from t h e effector cells (Figure 1-4). 5. Somatic motor n e u r o n s secrete acetylcholine a s their neurotransmitter, whereas autonomic neurons secrete mainly either acetylcholine or noradrenaline, plus o n e or more co-transmitters that modify and/or elicit a component of t h e response (see Fig. 1-4).

Figure 1-4 ( A ) A terminal bouton of a somatic motor neuron releasing acetylcholine to activate somatic muscle cells ( e g , striated muscle), ( B ) A postganglionic motor neuron releasing acetylcholine (or noradrenaline) plus co-transmitters to activate smooth muscle cells

SOMATIC AND AUTONOMIC NERVOUS SYSTEM COMPONENTS INTERACT WITH EACH OTHER S o m e somatic sensory signals, such a s t h o s e elicited b y t e m p e r a t u r e changes in t h e skin, or food odors, give rise to autonomic responses, such a s a change in blood circulation t o t h e skin, or a n increase in gastrointestinal activity. Conversely, s o m e autonomic sensory signals give rise to motor events that involve b o t h somatic a n d autonomic nerves. Often t h e somatic component of t h e s e activities proceeds in an unconscious, automatic way. These somatic events are fixed action patterns generated by central motor programs. They may be considered to be complex reflexes elicited by a single stimulus involving a chain of events proceeding in a predictable sequence, although t h e sequence is not absolutely fixed. The major combined somatic and autonomic functions are listed and discussed below. They are described in more detail in t h e appropriate chapters.

Introduction

Swallowing, Vomiting, and Defecating

Gut movement is controlled almost entirely by t h e autonomic nervous s y s t e m ; however, activity at t h e oral a n d anal e n d s is controlled b y t h e somatic nervous system. Swallowing, a voluntary thrusting of a bolus into t h e pharynx, elicits complex involuntary activity of t h e pharyngeal muscles which are controlled by t h e somatic nervous system. Contraction of t h e pharyngeal muscles propels t h e bolus into t h e u p p e r e n d of t h e esophagus. Once t h e b o l u s e n t e r s t h e e s o p h a g u s , t h e e n t e r i c c o m p o n e n t of t h e a u t o n o m i c nervous system takes over a n d peristalsis propels t h e bolus along t h e gut. Vomiting b e g i n s with a p r o l o n g e d b u r s t of a u t o n o m i c activity in t h e i n t e s t i n e distal t o t h e s t o m a c h , followed b y retching m o v e m e n t s as t h e somatic motor system stimulates t h e diaphragm, intercostal muscles, a n d abdominal muscles t o contract rhythmically. This process is coordinated by a vomiting, or emetic, center in t h e brain s t e m (Figure 1-5) (see also Case Study 3: Victoria a d the Vicious Hot Dog: Emesis). During defecation, a fecal mass in t h e lower rectum stimulates anorectal stretch receptors. These, in turn, elicit relaxation of t h e internal anal sphincter via t h e autonomic nervous system a n d contraction of t h e diaphragm a n d a b d o m i n a l wall m u s c l e s via t h e s o m a t i c n e r v o u s s y s t e m . T h e resulting increase in intra-abdominal pressure causes t h e fecal mass to begin t o move.

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Accommodation and Eye Movements

Accommodation is t h e adaptation of t h e e y e to allow for near vision (Figures 1-6 and 1-7). Accommodation has three components: constriction of t h e pupil via t h e constrictor pupillae muscle to d e c r e a s e spherical a n d chromatic aberration (parasympathetic motor response); rounding u p of the lens to bring t h e focal point of t h e e y e nearer (parasympathetic motor response); and convergence of the eyes so that t h e object of interest is in t h e direct line of sight of both eyes, i.e.,is projected onto the foveae of both eyes (somatic motor response). Convergence of t h e eyes is caused by t h e oculomotor nucleus a n d oculomotor nerve fibers t o t h e medial rectus muscles of both e y e s (see Chapter 4: Auto~omicIntegrutiug CompoMerzts, pg. 4 8 and t h e example, Accomodaion Reflex, pg. 50).

Introduction

Bladder Emptying

.

The bladder has two p h a s e s of activity, a storage p h a s e a n d a n expulsion phase. Each p h a s e is controlled by a different set of neural impulses. During expulsion, t h e autonomic nervous system causes smooth muscle in t h e walls of t h e b l a d d e r to contract a n d t h e internal urethral sphincter (also smooth muscle) to relax (Figure 1-8). At t h e s a m e time, t h e somatic nervous system causes t h e external urethral sphincter to relax; thereby allowing t h e passage of urine. T h e external urethral s p h i n c t e r is striated muscle a n d is u n d e r voluntary control in t h e conscious state, except in infants a n d young children. Contraction of t h e a b d o m i n a l m u s c l e s can also be e l i c i t e d to facilitate emptying of t h e bladder (see Case Study 4: Robert and his Klzocked-Out Bladder).

Figure 1-8 Autonomic and somatic motor nerves innervating the bladder.

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Breathing a n d Coughing

Although b r e a t h i n g a n d c o u g h i n g m o v e m e n t s are e x e c u t e d a l m o s t entirely b y t h e somatic musculature, control of t h e s e m o v e m e n t s is t h e responsibility of autonomic centers in t h e brain s t e m a n d , for t h e most part, breathing a n d coughing a r e not voluntary movements. The advantage of this is obvious since breathing must continue during sleep. Breathing involves rhythmic m o v e m e n t s of t h e diaphragm a n d of t h e intercostal a n d abdominal wall muscles-all striated muscle driven b y t h e somatic nerves (Figure 1-9). When breathing rates change, t h e caliber of t h e airway a n d pulmonary blood v e s s e l s also c h a n g e s d u e to contraction o r relaxation of t h e smooth muscle in their walls. These changes are controlled by t h e autonomic nervous system. Although we can voluntarily speed u p or slow down respiratory movements, a n d e v e n s t o p them for brief periods of t i m e , b o t h h y p e r - a n d h y p o v e n t i l a t i o n e v e n t u a l l y c a u s e a loss of consciousness that allows t h e autonomic centers in t h e brain s t e m t o assume control of t h e process. Coughing is elicited when food, liquids, or other foreign objects get into t h e w i n d p i p e , irritating t h e m u c o s a . T h e glottis is c l o s e d a n d a s t r o n g contraction of t h e diaphragm a n d t h e intercostal a n d abdominal muscles builds u p p r e s s u r e in t h e chest. T h e glottis is s u d d e n l y o p e n e d a n d t h e pressure propels air a n d t h e foreign matter out of t h e trachea (see Case Study 8: Patty’s Puffer).

Introduction

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Sexual Response

The sensory stimuli that elicit sexual responses are carried b y somatic s e n s o r y fibers a n d are consciously p e r c e i v e d . Sexual r e s p o n s e i n c l u d e s several autonomic e v e n t s , including increased glandular secretion, contraction of smooth muscle in t h e reproductive tract, relaxation of vascular s m o o t h muscle, a n d increased h e a r t a n d breathing rates. Contraction of striated muscle in t h e pelvic floor, a n d occasionally in t h e limbs, is driven b y t h e somatic nervous system a n d is automatic in nature (see Case Study 5: Glenn's Embavrassing Pvoblem). Heat Conservation

When t h e b o d y temperature begins t o d r o p , blood is s h u n t e d away from t h e s u r f a c e of t h e b o d y to d e c r e a s e h e a t loss, t h e a r r e c t o r e s p i l o r u m m u s c l e s c o n t r a c t c a u s i n g b o d y h a i r to s t a n d u p in a well m e a n t , b u t ineffective, a t t e m p t t o increase t h e insulating properties of t h e b o d y hair ( a n i n h e r i t a n c e from o u r h i r s u t e a n c e s t o r s ) a n d , w h e n t h e a m b i e n t t e m p e r a t u r e r e a c h e s a b o u t 23" C (73" F ) , t h e s o m a t i c m u s c l e s b e g i n to contract spasmodically (shivering) to generate heat. Shivering can increase heat production u p to t h r e e times t h e basal rate. While changes in blood flow a n d t h e action of t h e arrectores pilorum muscles a r e controlled b y t h e autonomic nervous system, shivering is driven b y t h e somatic motor system (see Case Study 7: Michael's Last Run).

Development of the Autonomic Nervous System

I1 DEVELOPMENT OF THE AUTONOMIC NERVOUS SYSTEM MORPHOGENESIS The morphogenesis of t h e autonomic nervous system can be considered in four stages: 1. Formation of t h e brain a n d spinal cord from t h e neural plate

(Figures 2-1 a n d 2-3); 2. Migration of neural crest cells away from t h e developing central nervous

system into t h e b o d y to form sensory, sympathetic, parasympathetic, a n d enteric ganglia (Figures 2-2, 2-4, a n d 2-6); 3. Outgrowth of axons of preganglionic neurons in t h e central nervous system that contact a n d innervate t h e autonomic postganglionic neurons (Figure 2-5); a n d 4. Outgrowth of axons of postganglionic neurons that innervate their target muscles a n d glands (Figures 2-6 a n d 2-8).

Formation of the Brain a n d Spinal Cord

1. During t h e third a n d fourth weeks of human d e v e l o p m e n t a flat, spoons h a p e d thickening called t h e neural plate (neurectoderm) develops in t h e e c t o d e r m along t h e main axis of t h e embryo. T h e “bowl” of t h e s p o o n eventually forms t h e brain a n d its “stem” t h e spinal cord. The cells along

t h e edges of t h e spoon are t h e neural crest cells. They will form a major component of t h e peripheral nervous system (see Fig. 2-1). 2. Shortly after t h e neural plate forms, its sides roll u p , a n d t h e flat plate

converts to a long tube. The anterior e n d of this t u b e forms three primary enlargements: t h e forebrain, t h e midbrain, a n d t h e hindbrain. Subsequently, t h e forebrain divides into t h e telencephalon ( t h e future c e r e b r a l h e m i s p h e r e s ) a n d t h e d i e n c e p h a l o n , which i n c l u d e s t h e hypothalamus. T h e midbrain remains a relatively simple structure, a n d t h e hindbrain b e c o m e s d i v i d e d into t h e p o n s a n d its outgrowth, t h e cerebellum, a n d t h e medulla. 3 . Neuronal cell bodies within t h e p o n s a n d medulla form reticular auto-

nomic centers, such as t h e cardiac a n d respiratory centers, a n d compact, recognizable autonomic nuclei such as t h e dorsal vagal nucleus a n d nucleus solitarius. Within t h e spinal cord, autonomic neuronal cell bodies form a column, t h e intermediolateral cell column, which extends throughout t h e thoracic spinal cord to t h e u p p e r two lumbar segments; it r e a p p e a r s in sacral segments S2 t o S4.

Development of t h e Autonomic Nervous System

Figure 2-1 Formation and folding of the neural plate t o form the neural tube. The anterior end of the neural tube forms the brain and the tapering posterior part the spinal cord (Stage 9, 20-21 days). The arrows show the direction of movement of the neural folds.

Specialist Information Most of what we know about the development of the autonomic nervous system comes from studies on avian (bird) embryos. The avian embryo is large and accessible and, therefore, suitable for experimental manipulation and study. Until recently, however, migrating neural crest cells were almost impossible to follow once they had migrated away from the neural folds because they could not be distinguished from surrounding body cells. If these cells were made to take up a radioactive marker they could be followed for a short while; however, during cell division, the marker was divided up among the daughter cells so that, after a few generations, the marker was so dilute that it could no longer be detected. These problems were solved when the cells of the Japanese quail were discovered to have a large, condensed mass of DNA in the nucleolus, which is reproduced during every cell division. Since the DNA content of the nucleolus in other avian species is much smaller than in the quail, the distinctive quail nucleolus can be used as a cell marker. Neural crest cells of the quail can be transplanted into a chicken embryo and can be found and identified days later after they complete their migration. Using this technique, the French scientist Nicole Le Douarin and her co-workers (Le Douarin 1973, Le Douarin et al 1973, 1974) made enormous strides in describing the migratory pathways, final resting sites, and the developmental fate of the neural crest cells that form the autonomic ganglia. In the description that follows, we assume that the developmental process described in human embryos is very similar to that in avian embryos.

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Migration of Neural Crest Cells

As t h e edges of the neural plate (the neural folds) meet, t h e neural crest cells migrate out of the folds into other areas of the embryo (Figs. 2-2, 2-3,

and Fig. 2-6). These cells form a variety of cell types in t h e embryo, including pigmented cells (melanocytes) in t h e skin and dorsal root (sensory) ganglion cells. Neural crest cells contribute to t h e formation of the mesodermal structures in t h e head and neck. A large group of them, however, is destined to form t h e peripheral parts of t h e autonomic nervous system, including t h e neurons within the gut, which form the enteric nervous system. Neural crest cells originating from different sites along t h e neuraxis form t h e following autonomic structures: Sy mpathe t ic Gang /ia

Neural crest cells from t h e lower cervical, thoracic, and lumbar levels (C3-L5) of t h e neuraxis migrate to a position, either lateral or anterior, to the forming vertebral bodies and aorta, where they form the sympathetic ganglia. These cells become t h e postganglionic neurons of t h e sympathetic system a n d s e n d their axons peripherally to target tissues. Paras y m pa t he tic Ga ng lia

Neural crest cells from the brain stem and cervical levels C1 to C3 of the neuraxis migrate to t h e following structures: I . Into the head, where they form the ciliary, pterygopalatine, submandibular, and otic ganglia, and 2. Into the walls of t h e thoracic and abdominal viscera, where they form visceral ganglia. Neural crest cells from sacral levels of the neuraxis (S2-S4) migrate into the walls of the pelvic viscera and caudal gut.


Figure 2-2 Transverse section of a developing embryo showing the migration of neural crest cells (Stage 10, 22 days of gestation).

Entevic Newous System Neural crest cells that form t h e enteric nervous system (i.e.,t h e s u b m u cosal [ Meissner’s] a n d myenteric [Auerbach’s] plexuses) migrate from t h e brain s t e m a n d u p p e r cervical levels of t h e neuraxis into t h e oral e n d of t h e gut a n d t h e n along t h e gut towards t h e anus. S o m e neural crest cells from sacral levels migrate into t h e postumbilical gut. Initially, n e u r o n s s e t tle b e t w e e n t h e forming circular a n d longitudinal muscle layers to form t h e myenteric plexus a n d , from t h e r e , s o m e neurons migrate d e e p e r to a s u b mucosal p o s i t i o n , w h e r e t h e y form t h e s u b m u c o s a l plexus. Within t h i s environment, t h e crest cells differentiate into glia a n d a variety of sensory and motor neurons that supply t h e absorptive epithelium, glands, a n d muscles of t h e gut wall. Subsequently, parasympathetic preganglionic, a n d sympathetic postganglionic axons grow into t h e gut, where they contact enteric neurons so that t h e activities of t h e enteric nervous system can be m o d u l a t e d b y central autonomic mechanisms.

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Sensory Ganglia From t h e entire length of t h e developing neuraxis neural crest cells migrate into t h e h e a d mesoderm a n d into t h e anteromedial aspect of somites in t h e trunk, where they differentiate into t h e paired dorsal root (sensory) ganglia associated with t h e cranial a n d spinal nerves. The cells b e c o m e t h e sensory neurons that extend processes to t h e periphery a n d into t h e CNS. A small proportion of t h e s e neurons are involved in transmitting sensory signals from t h e viscera to t h e central nervous system.

Figure 2-3 Panorama of development of the nervous system in the human embryo from Stage 9 to Stage 19 (20 to 48 days) of gestation. The embryo is transected to show the migration of neural crest cells into the body to form the autonomic ganglia.

Development of t h e Autonomic Nervous System

Adrenal Medulla Neural crest cells from lower thoracic a n d u p p e r lumbar levels migrate into t h e adrenal gland where they form t h e chromaffin cells of t h e adrenal medulla. Melanocy tes Neural crest cells from t h e entire length of t h e neuraxis migrate into t h e dermis. Here t h e y form melanocytes that p r o d u c e t h e characteristic color of t h e skin.

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Figure 2-4 Axial origin and migration of neural crest cells to form the autonomic ganglia (Stage 13, 28 days): ( 1 ) neural crest cells from the future midbrain and pons form the parasympathetic ganglia in the head; ( 2 ) neural crest cells from the future brain stem form all of the visceral ganglia and the enteric nervous system as far caudal as the future transverse colon; ( 3 ) neural crest cells from the thoracic spinal cord form the sympathetic ganglia; ( 4 ) neural crest cells from the sacral spinal cord form the pelvic and caudal enteric ganglia.


Outgrowth of Axons of Preganglionic Neurons As the migrating neural crest cells are reaching their final positions (Figs. 2-4, 2-5, and 2-6), the preganglionic neurons in t h e brain stem and spinal

cord s e n d their axons out into t h e periphery t o contact their ganglia a s detailed below. Interestingly, t h e pathway followed by the axons is similar to the pathway followed by t h e migrating neural crest cells that t h e preganglionic axons are destined to innervate. Sympathetic Ganglia

From t h e intermediolateral cell column in t h e thoracic a n d upper lumbar regions of the spinal cord (Tl-L2 or L3), preganglionic axons travel for a short distance with t h e ventral roots and then form white rami communicantes that connect with t h e developing paravertebral sympathetic ganglia. Some preganglionic axons terminate here; others continue on through the ganglia to the prevertebral (preaortic) ganglia, where they terminate. Still others turn within the paravertebral ganglia and travel cranially or caudally to terminate in other paravertebral ganglia. These axons link t h e sympathetic ganglia together forming the sympathetic chain (see Fig. 2-6B). Paras y m pa t he tic Ganglia

In the brain stem, the cells of the accessory (Edinger-Westphal) oculomotor nucleus s e n d their axons a s part of cranial nerve 111 (oculomotor) to synapse with postganglionic cells in t h e ciliary ganglion. Cells of t h e superior and inferior salivatory nuclei s e n d their axons a s parts of cranial nerves VII (facial) a n d IX (glossopharyngeal), respectively, to innervate t h e pterygopalatine and submandibular (VII) ganglia, and t h e otic (IX) ganglia, respectively. Cells of the dorsal vagal nucleus and nucleus ambiguus send their axons with cranial nerve X [vagus] to synapse with postganglionic cells of ganglia situated in the mouth, pharynx, larynx, viscera, and enteric neurons a s far caudal a s the splenic flexure. In sacral levels of the cord preganglionic axons form t h e pelvic splanchnic nerves (S2-S4) that terminate in t h e visceral a n d enteric neurons of t h e pelvic organs and hindgut.

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Figure 2-5 Outgrowth of preganglionic axons from the brain stem and spinal cord t o contact and innervate the autonomic ganglia (Stage 19, 48 days).


Figure 2-6 Migration and differentiation of neural crest cells that contribute to the autonomic nervous system ( A ) (Stage 9, 20 days),neural crest cells migrate away from the neural tube and aggregate to form ganglia; ( B ) preganglionic axons grow out from the neural tube to contact and innervate neurons in the ganglia ( C ) (Stage 19, 48 days),postganglionic axons grow out from the ganglia to innervate the target effector cells

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Outgrowth of Axons of Postganglionic Neurons

Sy m pat he tic Ganglia

In the case of the sympathetic ganglia, the postganglionic axons generally have to travel long distances to reach their target structures (see Figs. 2-6C and 2-7).

Within the Head. Sympathetic postganglionic axons mainly from t h e superior cervical sympathetic ganglion travel into t h e h e a d along t h e surfaces of the major blood vessels. Within t h e head, they innervate vascular smooth muscle, arrectores pilorum muscles, sweat, salivary, a n d lacrimal glands, and the dilator muscle of t h e pupil (Figure 5-7). Within the Trunk. Some of t h e sympathetic postganglionic axons form gray rami communicantes that rejoin t h e spinal nerves and travel with them into t h e body wall and limbs where they innervate vascular smooth muscle, arrectores pilorum muscles, and sweat glands. The remaining postganglionic axons form pulmonary and cardiac plexuses, and splanchnic nerves, which innervate the viscera both directly and via enteric neurons.

Parasympathetic Ganglia In t h e case of parasympathetic ganglia, t h e distance from t h e postganglionic cell to t h e target cell is usually quite short, especially for those ganglia located within the walls of the target organs (Fig. 2-7). Within the Head. Postganglionic parasympathetic axons from: The ciliary ganglion enter the e y e to innervate the ciliary muscle and t h e constrictor pupillae muscle of the iris. The pterygopalatine ganglion innervate the lacrimal gland causing secretion. The submandibular ganglion innervate the submandibular and sublingual salivary glands causing secretion. The otic ganglion are secretornotor to t h e parotid gland.

Within the Trunk. Postganglionic parasympathetic axons innervate cardiac muscle, smooth muscle, and glands of the thoracic viscera, abdominal viscera both directly and by enteric neurons, and pelvic viscera.


HISTOGENESIS Once t h e relatively undifferentiated neural crest cells have reached their final sites in t h e embryo, they begin to express their adult features. In t h e autonomic nervous system as in t h e somatic nervous system, at least t h r e e factors play a role in cell differentiation during development: (a) t h e environm e n t that they encounter a t their level of origin in t h e neuraxis, during migration, a n d a t their final site; (b) t h e synaptic connections t h e cells make with other neurons; a n d (c) t h e d e a t h of cells that a r e unsuccessful in competing for synaptic sites on target cells. Specialist Information

Transplantation studies have shown that cells from all regions of the neural crest can provide the entire spectrum of autonomic ganglion cells. Therefore, as development proceeds, the restriction of these potentialities is a result of extrinsic factors along the migration route and/or at the site of ganglion formation. Whether all neural crest cells are pluripotent and extrinsic factors induce the formation of appropriate phenotypes in them, or whether the cells are a mixed population of already committed cells and extrinsic factors merely select for those committed to an appropriate developmental path, is not known.

Sympathetic Neurotransmitters and Receptors

When neural crest cells destined t o form sympathetic postganglionic neurons reach their paravertebral a n d preaortic sites, they aggregate into ganglia a n d begin to elaborate t h e anabolic (synthetic) enzymes a n d uptake mechanisms for catecholamines (adrenaline, noradrenaline). Subsequently preganglionic (cholinergic) axons from t h e intermediolateral cell column make contact with t h e postganglionic neurons and induce t h e m to form nicotinic cholinergic receptors. The survival a n d differentiation of both t h e pre- a n d postsynaptic neurons d e p e n d o n this interaction. Preganglionic axons that terminate in t h e forming adrenal medulla, like other preganglionic axons, elaborate acetylcholine as their major transmitter a n d induce t h e formation of nicotinic receptors in t h e chromaffin cells. The chromaffin cells synthesize adrenaline, which is released into t h e blood during times of stress. Sympathetic postganglionic neurons s e n d their axons t o contact their targ e t organs in t h e viscera a n d b o d y wall. Those that contact enteric neurons or smooth muscle in t h e gut, or smooth muscle in most vessel walls a n d in t h e e y e , continue to elaborate noradrenaline a s their major transmitter a n d are, therefore, adrenergic postganglionic sympathetic neurons. Those that contact sweat glands a n d s o m e vascular smooth muscle, however, loose their a d r e n e r g i c p h e n o t y p e a n d b e g i n to s y n t h e s i z e acetylcholine. Therefore t h e s e are cholinergic postganglionic sympathetic neurons. In response t o t h e postganglionic neurons, t h e target cells synthesize either a or p adrenergic receptors, or in t h e case of sweat glands, muscarinic acetylcholine receptors (see Fig. 2-7).

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Autonomic Nerves Specialist Information Even after birth, the phenotype of autonomic neurons can be altered. If a sympathetic axon, which usually innervates smooth muscle and synthesizes noradrenaline, is made to innervate a sweat gland, it stops synthesizing noradrenaline and begins to synthesize acetylcholine (Stevens and Landis, 1987).

Figure 2-7 Formation of major sympathetic and parasympathetic neurotransmitters and receptors


Parasympathetic Neurotransmitters and Receptors

In neural crest cells, the cholinergic phenotype appears much earlier than the adrenergic phenotype and can be detected before the cells have left the neural crest (see Fig. 2-8). Within the parasympathetic ganglia, continued survival of the neurons and differentiation of the cholinergic phenotype are dependent on contact with both preganglionic neurons and with the target muscles and/or glands. Postganglionic parasympathetic neurons send their axons to target structures in the iris, salivary glands, and thoracic, a b d o ~ i n a l , and pelvic viscera (glands and smooth muscle). Postganglionic parasympathetic neurons synthesize acety~cho~ine as their major transmitter and induce the formation of muscarinic receptors in the target cell membranes.

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DEVELOPMENTAL DEFECTS Since t h e autonomic nervous system coordinates t h e life support systems, serious defects in its formation a r e incompatible with life. Developmental defects in t h e autonomic nervous system, therefore, are very rare, but they do occur. Two are described below, a n d a third forms t h e basis of Case Study 2: Megads Colon. Familial Dysautonomia (Riley-Day Syndrome)

Familial dysautonomia is a n exceedingly rare genetic disorder characterized b y problems in feeding a n d respiration, vasomotor instability, insensitivity to pain, a n d ataxia (an unsteady gait). Patients with this syndrome have a b o u t half t h e normal n u m b e r of sympathetic preganglionic neurons in t h e intermediolateral cell column of their spinal cords. A more dramatic decrease in neuron population is s e e n in sensory a n d autonomic ganglia. The pterygopalatine ganglion is particularly depleted, resulting in an inability to form reflex tears. The cause of this disease is not well understood, b u t it probably involves defects in production and/or survival of neural crest precursors of autonomic neurons. Neurofibromatosis (von Recklinghausen’s Disease)

Neurofibromatosis is characterized b y numerous benign tumors of t h e spinal a n d autonomic nerves a n d pigment abnormalities in t h e skin that a r e described as “cafe-au-lait” spots because of their “coffee-with-cream” color. Because neural crest cells form pigment cells (melanocytes) in t h e skin, as well as spinal a n d autonomic ganglia, all of t h e s e derivatives a r e affected. This disease is thought to be d u e to excess production of neural crest cells. Autonomic symptoms of t h e disease a r e highly variable a n d a r e believed to be d u e to hyperplasia of t h e autonomic ganglia.

Autonomic Sensory Components

111 AUTONOMIC SENSORY

COMPONENTS CHARACTERISTICS OF AUTONOMIC SENSORY FUNCTION 1 S e n s o r y information t h a t d r i v e s a u t o n o m i c activity a r i s e s from t h r e e

sources: t h e viscera (visceral sensory) (Figure 3-1A); t h e surface of t h e b o d y ( s o m a t i c s e n s o r y ) (Figure 3-1 B); a n d t h e external e n v i r o n m e n t (special sensory) (Figure 3- 1C). 2 The two t y p e s of sensory fibers a r e as follows: 0

The primary afferent fibers, t h e cell bodies of which reside in t h e dorsal root ganglia a n d in t h e sensory ganglia of t h e cranial nerves. The axons of primary afferent fibers carry information to t h e central nervous system.

0

The enteric afferent fibers, t h e cell bodies of which reside in t h e enteric nervous system. The axons of enteric afferent fibers carry information to t h e (sympathetic) prevertebral ganglia to mediate splanchnic reflexes.

3 T h e v a s t majority of visceral s e n s o r y signals r e c e i v e d b y t h e central nervous system a r e not consciously perceived. Their role is to m e d i a t e functional r e g u l a t i o n of t h e v i s c e r a . S o m e visceral s e n s o r y s i g n a l s , however, are consciously perceived (e.g., visceral pain, nausea, hunger, feelings of b l a d d e r fullness, a n d sexual tension). The role of t h e s e signals is to drive behavioral changes a i m e d a t dealing with t h e stimulus in an appropriate manner. 4. The density of sensory endings in t h e viscera is very low (approximately 10%) compared with t h e density of t h o s e in skin.

5. Visceral afferents are included in both sympathetic a n d parasympathetic nerves; however, parasympathetic nerves have, o n average, three times as many sensory axons as sympathetic nerves. The vast majority of visceral afferents a r e unmyelinated (Figure 3-2).

6 . w i t h s o m e e x c e p t i o n s , visceral pain is m e d i a t e d b y afferent axons in s y m p a t h e t i c nerves. Visceral sensation t h a t drives reflex regulation of viscera is mediated by afferent axons in parasympathetic nerves. 7. Conscious visceral sensation is difficult to localize, or is only localized to

large areas of t h e body. Visceral pain is often referred to (perceived as arising from) t h e surface of t h e body. Pain from certain organs is appreciated for felt) in localized areas of t h e b o d v fsee Referred Pain, DE. 421.


3I

Figure 3-1 Sensory (afferent)signals that drive autonomic activity may originate from (A) the viscera (visceral sensory); (B) the surface of the body (somaticsensory);and ( C )the external environment (special sensory).

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Figure 3-2 Sensory axons of the autonomlc nerves accompany the motor axons Together they form the mixed autonomic nerves ( A ) a parasympathetlc nerve depicting a preganglionic motor (efferent)axon (myelinated)and three sensory (afferent)axons, (unmyelinated),and ( B ) a sympathetic nerve showing one motor axon and one sensory axon (both unmyelinated)

VISCERAL SENSORY INFORMATION Visceral Receptors

Sensory signals that direct activities of the visceral organs arise primarily from stretch receptors, baroreceptors, and chemoreceptors. Sensory signals also arise from pain receptors and thermal receptors in the viscera. Bavoveceptors (Figure 3-3) Sensory information from baroreceptors does not evoke conscious sensation. T h e free nerve endings of baroreceptors are found in the walls of hollow organs, including blood vessels. Baroreceptors send signals to the central nervous system, for example: Baroreceptors in large arteries, such as the carotid sinus, signal changes in blood pressure; Baroreceptors in the atria of the heart signal changes in blood volume.


Figure 3-3 The bifurcation of the common carotid artery showing baroreceptors in the walls of the carotid sinus and chemoreceptors within the carotid body. The size of the carotid body is exaggerated to show structural detail.

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Other Stretch Receptors Stretch receptors in t h e lungs signal information a b o u t lung inflation a n d deflation; Stretch receptors in hollow organs, such as t h e gut a n d bladder, signal changes in organ wall distension. Chemoreceptors (see Fig. 3-3) Chemoreceptors detect a variety of molecules in t h e blood a n d in t h e internal environment. They trigger autonomic reflexes by sending signals to t h e brain s t e m a n d t h e hypothalamus to elicit autonomic responses, for example: Oxygen receptors in t h e carotid b o d y d e t e c t changes in blood oxygenation a n d signal cardiovascular a n d respiratory centers in t h e brain s t e m to produce alterations in heart a n d ventilatory rates. Chemoreceptors that respond to t h e products of anaerobic metabolism signal pain a n d elicit a cardiovascular response that increases blood flow to ischemic regions. Osmotic receptors in t h e hypothalamus monitor t h e osmotic pressure of t h e blood a n d modify secretion of vasopressin t o maintain blood osmolarity within physiologic limits. Glucose receptors in t h e hypothalamus monitor t h e concentration of glucose in t h e blood. They function t o drive eating behaviour a n d its associated visceral actions. Visceral Pain and Thermal Receptors Pain receptors, also called nociceptors, a r e free nerve endings of primary sensory neurons. They are activated by distension of hollow organs (greater than normal, physiologic distension), inflammation, or ischemia (inadequate blood s u p p l y ) . Unlike s o m a t i c nociceptors, visceral nociceptors a r e n o t activated by cutting a n d burning stimuli. Thermal receptors in t h e viscera are also free nerve endings of primary sensory neurons. Their role is to signal changes in core temperature as part of t h e thermoregulatory mechanism (see Case Study 7: Michael’s Last RUM). Specialist Information Some molecules that stimulate central chemoreceptors, for example CO2, are able to cross the blood-brain barrier and gain access to the brain by passing directly through capillary walls; others are excluded by the blood-brain barrier and gain access to the brain only in specialized areas where the barrier is absent. Because these specialized areas are located close to the walls of the ventricles, they are called circumventricular organs. Circumventricular organs (e.g., the area postrema) (see Case Study 3: Victoria and the Vicious Hot Dog: Emesis), form a component of some autonomic integrating centers, such as the hypothalamus and reticular areas in the brain stem.


Visceral Sensory Pathways

The two anatomic types of visceral sensory neurons a r e t h o s e that project t o t h e central nervous system a n d those that do not. Sensory Neurons that Project to the Central Nervous System Visceral afferent nerves that project t o t h e central nervous system are typical sensory neurons. Their nerve endings are free or encapsulated, a n d their cell bodies a r e pseudo-unipolar in s h a p e . They reside in t h e dorsal root ganglia of t h e spinal cord or in t h e sensory ganglia of t h e cranial nerves. Their central processes e n t e r t h e central nervous system along with t h e appropriate spinal or cranial nerves. Sympathetic Afferents Encode Visceral Pain. Visceral afferents, which are frequently termed sympathetic afferents, travel t o t h e sympathetic chain in t h e s a m e n e r v e b u n d l e s as t h e motor n e r v e s . They pass through t h e sympathetic ganglia without synapsing a n d travel through t h e white rami communicantes to t h e spinal nerves, t o e n t e r t h e dorsal roots. Their cell bodies reside in t h e dorsal root ganglia, a n d their central axons e n t e r t h e spinal cord with t h e dorsal roots to terminate in t h e dorsal horns within t h e s a m e , or n e a r b y , s p i n a l s e g m e n t ( s ) . P a i n s i g n a l s a r e c a r r i e d by t h e spinothalamic pathway to t h e contralateral thalamus a n d t h e visceral sensory areas of t h e cerebral cortex, where they are consciously perceived. Visceral pain is poorly localized a n d is often referred to (perceived a s coming from) t h e surface of t h e body (see Referred Pain, pg. 42), most likely because visceral pain signals excite spinal neurons that are also excited by pain signals from t h e skin. P a r a s y m p a t h e t i c Afferents E n c o d e Visceral S e n s o r y Information. Parasympathetic afferents from t h e h e a d , thoracic organs, a n d all of t h e abdominal organs, except for t h e distal e n d of t h e gut a n d pelvic organs, e n t e r t h e central nervous system via t h e glossopharyngeal (CN 1X) a n d vagus ( C N X) nerves. Their role is t o direct regulation of t h e internal environment. T h e c e l l bodies of p a r a s y m p a t h e t i c a f f e r e n t s r e s i d e in t h e i n f e r i o r glossopharyngeal ganglion a n d in t h e inferior ( n o d o s e ) vagal ganglion. Eighty percent of t h e axons in t h e vagus nerve are sensory in function. The central processes of t h e parasympathetic sensory neurons terminate primarily in t h e nucleus of t h e tractus solitarius. From h e r e information is s e n t to t h e brain s t e m centers that direct visceral function a n d higher centers in t h e cerebrum (e.g.,t h e hypothalamus a n d insular cortex) (Figure 3-4). Parasympathetic afferents from t h e distal e n d of t h e gut a n d from t h e pelvic organs e n t e r t h e central nervous system via t h e pelvic nerves that join spinal nerves S2 to S4. The cell bodies of t h e s e afferent nerves reside in t h e dorsal root ganglia of spinal nerves S2 t o S4, a n d their central p r o c e s s e s terminate in t h e dorsal horn within t h e s a m e sacral spinal segment, where they act to drive local reflex arcs (Fig. 3-4).

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Figure 3-4 Visceral sensory pathways project t o the brain stem and to the thoracic and sacral regions of the spinal cord.


Sensory Neurons that do not Project to the Central Nervous System Intestinofugal (fleeing t h e intestine) neurons a r e a group of sensory enteric neurons, t h e cell bodies of which r e s i d e in t h e myenteric plexus a n d t h e axons of which project to t h e prevertebral ganglia where t h e y s y n a p s e o n sympathetic motor neurons. These neurons are specifically associated with t h e innervation of t h e gut a n d its a p p e n d a g e s , a n d t h e information that they e n c o d e does not reach t h e central nervous system (see Fig. 3-4). Visceral Sensory Nuclei (Figure 3-5) Dorsal Horn of the Spinal Cord Sympathetic afferents that carry pain information from t h e viscera terminate in t h e dorsal horns of t h e spinal cord in s e g m e n t s TI to L2, primarily in l a m i n a e I a n d V a n d , t o a l e s s e r e x t e n t , in o t h e r l a m i n a e . C a u d a l p a r a s y m p a t h e t i c a f f e r e n t s carrying s t r e t c h , c h e m o r e c e p t o r , p a i n , a n d temperature information terminate in t h e dorsal horns of spinal segments S2 to S4. The organization a n d projections of t h e dorsal horn a r e well described in s t a n d a r d n e u r o a n a t o m y t e x t b o o k s a n d so t h e s e t o p i c s will n o t be a d d r e s s e d further here.

Nucleus of the Tractus Solitarius The nucleus of t h e tractus solitarius (NTS) is t h e major sensory nucleus of t h e autonomic nervous system. It is a paired structure found in t h e lateral area of t h e medulla, close to t h e paired dorsal vagal nucleus a n d nucleus ambiguus. T h e cranial part of nucleus solitarius receives special sensory information that e n c o d e s taste ( t h e gustatory nucleus). Cranial parasympathetic afferents carrying baroreceptor a n d chemoreceptor information from t h e viscera terminate in t h e main body parts of t h e nucleus solitarius. Primary visceral sensory axons e n t e r t h e brain s t e m with cranial nerves IX and X, turn caudally, a n d descend in t h e medulla where they form a prominent fiber bundle called t h e tractus solitarius. The nerve cell bodies of t h e nucleus solitarius surround t h e tract. This anatomic arrangement, which gives t h e tract t h e appearance of an isolated, or “solitary,” structure, suggested its name. Visceral afferents from t h e major organs a r e thought to terminate in t h e nucleus solitarius in a viscerotopic manner. In addition to primary sensory input from t h e periphery, t h e nucleus solitarius also receives afferents from t h e hypothalamus a n d cerebral cortex. The cells of t h e nucleus solitarius project widely in t h e central nervous system. Their major projections are: To t h e hypothalamus a n d higher subcortical a n d cortical centers where they regulate food intake a n d blood osmolarity, To t h e brain s t e m centers that control t h e gut a n d t h e cardiovascular a n d respiratory functions.

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Figure 3-5 Visceral and somatic sensory pathways and nuclei within the central nervous system. The organization of the nucleus solitarius is based on studies in mammals other than humans; however, it is likely that the nucleus solitarius in humans is similar in its functional organization.


SOMATIC SENSORY INFORMATION S e n s o r y information from t h e surface of t h e b o d y elicits a u t o n o m i c responses directed towards maintaining body temperature, reacting to pain, a n d affecting sexual behaviour. Somatic Receptors

Therrnoreceptors Thermoreceptors a r e free nerve endings of primary sensory neurons. The a x o n s of t h e r m o r e c e p t o r s a r e small in d i a m e t e r a n d c o n d u c t i m p u l s e s relatively slowly. They d e t e c t t h e temperature of t h e skin a n d transmit this information to t h e brain s t e m a n d appropriate areas of t h e hypothalamus. T h e s e central structures t h e n construct appropriate autonomic r e s p o n s e s t h a t modify t h e production a n d loss of h e a t in t h e b o d y (i.e.,changes in metabolic rate, shivering, changes in blood distribution in t h e skin, sweating, a n d piloerection). For d e t a i l s o n t e m p e r a t u r e control, see Case Study 7: Michael’s Last Run. Pain Receptors (Nociceptors) Somatic pain receptors, also called nociceptors, a r e free nerve endings of primary sensory neurons. The axons of somatic pain receptors are small in diameter a n d conduct impulses relatively slowly. Three t y p e s of nociceptors can be distinguished: ( 1 ) mechanical nociceptors, which a r e activated b y strong mechanical stimuli; ( 2 ) thermal nociceptors, which a r e activated b y damaging h e a t o r cold stimuli; a n d ( 3 ) polymodal nociceptors, which a r e activated by mechanical, thermal, a n d chemical stimuli. Activation of somatic nociceptors is associated with a sharp pricking, or a slow burning pain. Touch Receptors (Mechanoreceptors) Most of t h e information that reaches t h e central nervous system from touch receptors does not elicit activity in t h e autonomic nervous system, except in t h e c a s e of sexual behavior. Pleasurable sensations from t h e b o d y surface reinforce signals from t h e central nervous system that drive t h e autonomic events in t h e pelvic visceral a n d somatic musculature, which are necessary for several aspects of human sexuality (for details o n t h e autonomic aspects of sexual behaviour, see Case Study 5: Glenn’s Ern6arrassing ProGlern). Touch receptors are activated by mechanical stimuli. Their nerve endings a r e either free o r encapsulated. They can be classified as slowly adapting ( r e s p o n d i n g continuously t o a p e r s i s t e n t s t i m u l u s ) o r rapidly a d a p t i n g (responding at t h e onset a n d , often, also at t h e termination of a stimulus, b u t not throughout its duration).

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Somatic Sensory Pathways and Nuclei (see Fig. 3-5)

Sensory information from t h e surface of t h e b o d y r e a c h e s t h e central nervous system via t h e cranial a n d spinal nerves. Two anatomically distinct pathways transmit sensory information to t h e cortex. Pain a n d temperature sensation is transmitted via t h e spinothalamic pathway a n d other sensory modalities-such as touch, pressure, vibration s e n s e , a n d proprioception ( p o s i t i o n s e n s a t i o n ) - a r e t r a n s m i t t e d via t h e d o r s a l c o l u m n s . T h e s e pathways a n d their associated receptors a n d nuclei ( t h e trigeminal nuclei a n d t h e d o r s a l h o r n s of t h e s p i n a l gray m a t t e r ) a r e well d e s c r i b e d in standard neuroanatomy text books, a n d are not, therefore, a d d r e s s e d here. However, they are illustrated in Fig. 3-5. Visceral and Somatic Pain Signals Converge into a Common Pathway to the Brain (Figure 3-6)

Sensory information that mediates visceral a n d somatic pain is carried b y t h e sympathetic a n d spinal nerves, respectively. Afferent axons from both regions e n t e r t h e dorsal roots of t h e spinal nerves a n d pass along t h e m to t h e dorsal root ganglia, where their cell bodies reside. The central processes of t h e sensory neurons either terminate within t h e s a m e spinal cord segment or they e n t e r Lissauer’s tract a n d ascend, or d e s c e n d , o n e or two spinal cord segments before they terminate. When t h e sensory axons have reached t h e s p i n a l s e g m e n t w h e r e t h e y will t e r m i n a t e , t h e y d i v i d e a n d s y n a p s e o n second order sensory neurons in layers I a n d V of t h e dorsal horn. In many cases both visceral and somatic afferents synapse on the same secondary neurons. Therefore, a given secondary neuron in the spinal cord can be excited by either a visceral afferent, a somatic afferent, or both.

The axons of t h e s e second-order sensory neurons cross t h e midline a n d form t h e s p i n o t h a l a m i c tract. T h e s p i n o t h a l a m i c a x o n s a s c e n d via t h e thalamus to t h e sensory cortex.


Figure 3-6 Convergence of visceral and somatic sensory signals onto common spinothalamic neurons in laminae I and V of the dorsal horn (lamina V shown).

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Referred Pain Visceral pain is often referred to (perceived a s coming from) the surface of t h e body. This is because both visceral and somatic primary sensory neurons synapse on common secondary sensory neurons in t h e dorsal horn of t h e s p i n a l c o r d , which, in t u r n , s e n d s i g n a l s t o t h e b r a i n for c o n s c i o u s interpretation (Figure 3-8). The brain is unable to determine whether visceral o r somatic afferents stimulated t h e secondary neurons. The density of sensory nerves is much higher in the skin than in the viscera; approximately 90 percent of the sensory stimulation comes from the body surface, only 10 percent from the viscera. Pain from certain organs is generally referred to specific areas of t h e body surface related t o t h e d e r m a t o m e s r e p r e s e n t e d in t h e spinal s e g m e n t s where the visceral afferents terminate. For example, cardiac pain is generally referred to the left side of the chest, neck, and left arm (Fig. 3-7 and 3-8), although this pattern is highly variable among individuals. Other visceral organs such a s esophagus and gall bladder can occasionally be referred to t h e s a m e area a s cardiac pain, which suggests that visceral afferents from more than o n e organ converge on spinothalamic neurons.

Figure 3-7 Referred pain associated with some thoracic and abdominal organs: referred pain from the heart (A) varies. It can be referred to the left arm (pink),to a constricting band around the chest (blue), or to the midline (striped yellow). Referred pain from the esophagus ( B , yellow) can overlap that of the heart. Gall bladder pain ( C ) is referred to the right upper quadrant of the abdomen (purple),and pain from the duodenum to the midline of the upper abdomen (green).


Figure 3-8 Referred cardiac pain (angina).

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SPECIAL SENSORY INFORMATION Information a b o u t e v e n t s in t h e external environment reach t h e brain via special sensory receptors (Figure 3-9). Both inborn behavioral patterns a n d individual experience d e t e r m i n e how t h e autonomic nervous system responds to stimuli that may be threatening, exciting, pleasing, or anxietyproducing (see Case Study 1 : “Fight or Flight” - Anxiety: Margaret and Matthew). In addition, several autonomic reflexes are driven by signals from t h e external environment as detailed below. Salivation

Autonomic reflexes involved in t h e digestion of food (i.e.,salivation, gut motility, a n d secretion) can be elicited b y stimulation of t h e smell (olfactory) a n d taste receptors. Molecules in inhaled air bind with receptors on t h e olfactory epithelial cells in t h e a p e x of t h e nose. Olfactory epithelial cells, in turn, stimulate t h e cells of t h e olfactory nerve (CN I ) , which project to t h e olfactory regions of t h e brain ( t h e pyriform a r e a in t h e temporal lobe a n d insula a n d t h e medial olfactory area in t h e subcallosal region of t h e medial surface of t h e frontal lobe) for conscious appreciation a n d interpretation. From t h e olfactory areas, signals are s e n t by, as yet, unknown pathways to t h e brain s t e m to elicit t h e autonomic responses of salivation in t h e mouth via t h e salivatory nuclei a n d motility a n d secretion within t h e gut via t h e dorsal vagal nucleus. Taste is transduced by tastebuds on t h e tongue and, to a lesser degree, in t h e pharynx. Taste b u d s are innervated b y t h e facial (CN VII), glossopharyngeal (CN IX), a n d t h e vagus (CN X) nerves. The cell bodies of t h e neurons that e n c o d e taste reside in t h e geniculate, inferior glossopharyngeal, a n d inferior vagal ganglia, respectively. Gustatory axons of t h e facial nerve (CN VII), a n d t h e few gustatory fibers that travel with t h e glossopharyngeal a n d vagus nerves, e n t e r t h e brain s t e m with t h e i r r e s p e c t i v e n e r v e s a n d t e r m i n a t e in t h e gustatory nucleus ( t h e cranial part of t h e NTS). From t h e gustatory nucleus, taste information is s e n t to t h e insular cortex (via t h e parabrachial nucleus a n d t h e thalamus) for conscious interpretation a n d to t h e brain s t e m nuclei that innervate t h e salivary glands a n d produce gut motility a n d secretion. Fig. 3-9 demonstrates t h e structures a n d pathways that integrate sensory input a n d autonomic motor output in salivation. Nausea

S u d d e n or uncoordinated changes in balance can cause t h e autonomic nervous system to initiate nausea a n d t h e vomiting reflex. Balance receptors a r e l o c a t e d w i t h i n t h e s e m i c i r c u l a r c a n a l s of t h e i n n e r e a r . S e n s o r y information from t h e semicircular canals is transduced by hair cells within t h e ampullae. The hair cells stimulate t h e peripheral processes of t h e vestibular n e u r o n s , t h e cell bodies of which form t h e v e s t i b u l a r ganglion. Central p r o c e s s e s of t h e v e s t i b u l a r n e u r o n s form t h e v e s t i b u l a r portion of t h e vestibulocochlear nerve (CN VIII). T h e vestibulocochlear nerve carries t h e

Autonomic Sensory C o m p o n e n t s

Figure 3-9 Salivation is an autonomic response t o special sensory signals. This figure illustrates the sensory and motor pathways (sympathetic and parasympathetic) involved in the salivation reflex.

sensory signals to t h e brain s t e m , where t h e y terminate in t h e vestibular nuclei. From t h e vestibular nuclei, signals a r e carried by, as yet, unknown pathways, to t h e cortex t o produce t h e feelings of nausea a n d to t h e dorsal vagal nuclei t o elicit vomiting.

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Pupillary Dilation and Constriction

Light e n t e r i n g t h e e y e is t r a n s d u c e d i n t o n e u r a l i m p u l s e s b y t h e photoreceptor cells in t h e retina. Impulses are carried in t h e optic nerve to specialized nuclei (pretectal a n d Edinger-Westphal nuclei) in t h e midbrain. T h e s e nuclei increase o r d e c r e a s e t h e size of t h e pupil b y acting o n t h e smooth muscles of t h e iris to maintain a relatively constant amount of light striking t h e retina (Figure 3-1 0).

Figure 3-10 T h e pupillary light reflex is an example of an autonomic response (changes in pupillary size) t o an environmental stimulus (light).The insert shows the sensory pathway through the retina.

Autonomic Integrating Components

IV AUTONOMIC INTEGRATING COMPONENTS AUTONOMIC IMPULSES ARE INTEGRATED AT SEVERAL HIERARCHICAL LEVELS (Figures 4-1A a n d 4-1 B) 1 . The cerebral cortex a n d parts of t h e limbic system act to produce

behavioral components of autonomic responses over t h e full range of environmental challenges. 2. The hypothalamus acts to produce a n d integrate behavioral, autonomic,

a n d endocrine responses over t h e full spectrum of physiologic changes concerned with t h e survival of t h e individual a n d t h e species. 3. Reticular centers in the brain stem, such as cardiac a n d respiratory

centers, coordinate t h e activities of individual organ systems. 4. Preganglionic autonomic motor neurons modulate reflex autonomic

activity in large segments of t h e body. 5. Postganglionic autonomic motor neurons integrate reflex activity in

specific organs. 6. Local neurons integrate reflexes in local areas of organs. This level of integration is best understood within t h e gut (see Case Study 2: Megan’s Colou). Enteric neurons, which are color-coded yellow, include sensory

neurons (called enterofugal), motor neurons, a n d interneurons.

Autonomic Integrating C o m p o n e n t s

Figure 4-1B Levels of integration within the autonomic nervous system. Numbers 1 to 6 refer to the numbers used on page 48, and are for the major divisions in the text of this chapter.

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ACCOMMODATION REFLEX The accommodation reflex is a familiar example of autonomic integration a t several hierarchical levels. For example, t h e autonomic nervous system c o n t r o l s t h e s h a p e of t h e l e n s to a d j u s t t h e focal p l a n e of t h e i m a g e projected onto t h e retina (Figures 4-2 a n d 4-3). A s we scan our visual fields, we constantly switch from o n e object t o another. When we switch to viewing a new object, initially t h e new image is out of focus (unless t h e new a n d old objects are at t h e s a m e distance from t h e e y e ) . Sensory signals are t h e n s e n t t o t h e visual cortex via pathways shown in Fig. 4-3. T h e cerebral cortex recognizes t h e image as being out of focus a n d s e n d s return signals to t h e p r e t e c t a l region in t h e b r a i n s t e m , which, in t u r n , s i g n a l s t h e n e a r b y accessory oculomotor (Edinger-Westphal)nucleus. The accessory oculomotor nucleus is c o m p o s e d of preganglionic parasympathetic neurons that drive p o s t g a n g l i o n i c p a r a s y m p a t h e t i c n e u r o n s in t h e ciliary g a n g l i o n . T h e postganglionic neurons signal: ( I ) t h e ciliary muscle which, in turn, changes t h e s h a p e of t h e lens, bringing t h e image into focus; a n d ( 2 ) t h e pupillary constrictor muscle which, in turn, changes t h e size of t h e pupil to adjust for spherical aberration. Sympathetic nerves also play a role in determining pupillary size in that t h e y a c t to dilate t h e p u p i l u n d e r c o n d i t i o n s of low l i g h t , f e a r , a n d aggression. Signals from t h e cerebral cortex d e s c e n d through t h e spinal cord t o t h e preganglionic sympathetic neurons in t h e u p p e r thoracic spinal cord s e g m e n t s . Preganglionic axons p r o j e c t to postganglionic n e u r o n s in t h e superior cervical ganglion. Postganglionic axons leave t h e superior cervical ganglion a n d travel with t h e internal carotid artery into t h e cranium. They then e n t e r t h e orbit a n d e y e a n d terminate in t h e dilator pupillae muscles (see Fig. 4-2).

Autonomic Integrating C o m p o n e n t s

Figure 4-3 Pathways involved in the transmission of visual impulses to the cortex. Reflex autonomic pathways to the ciliary and pupillary muscles adjust the lens and pupil thereby changing focal planes. For clarity, part of the pathway between the lateral geniculate body of the thalamus and the visual cortex, the geniculocalcarine pathway, has been interrupted in the illustration.

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CEREBRAL CORTEX AND LIMBIC SYSTEM Although primitive drives such as hunger, thirst, a n d reproduction may be o r g a n i z e d in t h e h y p o t h a l a m u s , full i n t e g r a t i o n of t h e s e d r i v e s i n t o behavioral activities that regulate nutrient intake, elimination, a n d reproduction requires activity in large areas of t h e cerebral cortex. Several cortical a r e a s a r e thought to be directly involved in autonomic function (Figures 4-4, 4-5, a n d 4-6). Cerebral Cortex

Insular Cortex (see Fig. 4-4)

T h e i n s u l a ( i s l a n d ) is t h e deepest region of t h e l a t e r a l s u r f a c e of t h e cerebrum. T h e insula lies deep to t h e e d g e s of t h e lateral fissure a n d is overlain b y t h e frontal, parietal, a n d temporal opercula (lids). The dorsal part of t h e insular cortex plays a major role in taste, whereas t h e ventral part functions as a somatotopically organized visceral sensorimotor area. Gastrointestinal sensory a n d motor neurons are located rostrally, cardiovascular neurons most caudally, a n d arterial chemoreceptor n e u r o n s in a n i n t e r m e d i a t e position. Electrical stimulation of t h e insular cortex in a w i d e variety of animals, including h u m a n s , elicits autonomic responses such as piloerection, pupillary dilation, gastric motility, salivation, a d r e n a l i n e s e c r e t i o n , a n d c h a n g e s in blood p r e s s u r e , h e a r t r a t e , a n d respiration. The insular cortex has reciprocal connections with a number of structures in t h e cerebrum a n d brain s t e m . These structures a r e involved in autonomic function, a n d they include t h e thalamus, nucleus solitarius, t h e parabrachial n u c l e u s , t h e lateral h y p o t h a l a m i c a r e a , a n d t h e c e n t r a l n u c l e u s of t h e amygdala. Medial Prefvoutal, OrGitofuontal, and Cingulate Cortex (see Fig. 4-4)

The role of t h e medial prefrontal cortex in autonomic function, in humans especially, is poorly u n d e r s t o o d . It receives information from t h e insular cortex, limbic system, a n d brain s t e m a n d projects to a n u m b e r of autonomic structures, such as t h e nucleus of t h e tractus solitarius a n d t h e parabrachial nucleus. Stimulation of parts of t h e medial prefrontal cortex in experimental animals c a u s e s bradycardia, hypotension, a n d gastromotor changes. T h e orbitofrontal a n d cingulate cortices relay signals from t h e limbic system to t h e medial prefrontal cortex. Serzsorimotor Cortex (see Fig. 4-4)

T h e r o l e of t h e s e n s o r i m o t o r c o r t e x in visceral activity is a l s o p o o r l y understood in humans. Perception of visceral pain is likely mediated in t h e sensory areas. The motor area is undoubtedly involved in t h e production of somatic motor actions involved in autonomic activities, for example, chewing a n d swallowing.


Figure 4-4 The areas of the cortex (insular,medial prefrontal and orbitofrontal, and the sensorimotor cortex indicated in blue) that are thought to play a significant role in autonomic function.

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Limbic System

The limbic system forms links between cognitive activity a n d visceromotor r e s p o n s e s . Particular c o m p o n e n t s of t h e f o r e b r a i n a r e c o n s i d e r e d to constitute t h e limbic system (see Figs. 4-5 a n d 4-6). Its components are not universally a g r e e d u p o n , b u t t h e amygdala, hippocampus, d e n t a t e gyrus, parahippocampal gyrus, cingulate gyrus, a n d t h e septa1 area are included b y m o s t a u t h o r s . T h e r e g i o n s of t h e l i m b i c s y s t e m a r e e x t e n s i v e l y interconnected b y t h e pathways summarized in Fig. 4-6. The specific roles of different c o m p o n e n t s of t h e limbic s y s t e m in producing t h e a u t o n o m i c components of affective behavior a r e not well understood. Their extensive interconnections a n d widespread connections with other parts of t h e central nervous system make it difficult to investigate t h e system experimentally a n d to isolate autonomic functions from t h e behavioral a n d memory functions of t h e limbic system. It is reasonably well accepted, however, that t h e amygdala is an important autonomic limbic structure. The amygdala mediates behavior important t o survival of t h e individual a n d of t h e s p e c i e s , such as flight, aggression, feeding, a n d reproductive behavior. The visceral components of t h e s e behaviors are elicited through its influence on t h e hypothalamus a n d autonomic centers in t h e brain stem. Am ygdaloid Complex (Amygdala)

The amygdala modulates autonomic activity via two pathways: b y affecting t h e a c t i v i t y of t h e h y p o t h a l a m u s (see Fig. 4-5) a n d b y a f f e c t i n g t h e autonomic centers in t h e brain s t e m (see Fig. 4-6). The amygdala is a nuclear complex located in t h e anteromedial part of t h e t e m p o r a l lobe. Its n u c l e i a r e g r o u p e d i n t o t h r e e d i v i s i o n s : t h e corticomedial, t h e basolateral, a n d t h e central divisions. Extensive i n t e r c o n n e c t i o n s exist b e t w e e n t h e divisions a n d with t h e a m y g d a l o i d complex of t h e opposite side. T h e corticomedial division is phylogenetically t h e oldest part of t h e amygdala. I t receives extensive input from t h e olfactory system, directly via t h e lateral olfactory stria a n d indirectly via t h e pyriform a n d entorhinal c o r t i c e s . It c o m m u n i c a t e s w i t h t h e h y p o t h a l a m u s v i a t h e v e n t r a l amygdalofugal (amygdalohypothalamic) tract (see Fig. 4-5). T h e b a s o l a t e r a l division is phylogenetically t h e n e w e s t p a r t of t h e amygdala. The basolateral division has extensive reciprocal connections with neocortical sensory association areas, mainly in t h e temporal a n d parietal lobes (see Fig. 4-5). The central division forms t h e main efferent pathways from t h e amygdala to t h e hypothalamus a n d t h e autonomic centers in t h e brain s t e m , such as t h e midbrain periaqueductal gray region, t h e dorsal vagal nucleus, a n d t h e respiratory a n d cardiovascular centers. Efferent axons reach t h e hypothalamus via t h e ventral amygdalofugal tract o r t h e stria terminalis (see Figs. 4-5 a n d 4-6). Once in t h e forebrain or diencephalon, many of t h e s e axons d e s c e n d through t h e brain s t e m in t h e medial forebrain b u n d l e or t h e dorsal longitudinal fasciculus.


Regulation of autonomic function b y t h e amygdala differs from that of t h e hypothalamus. The hypothalamus responds in a reflex manner to physiologic c h a n g e s in t h e b o d y o n a m o m e n t - t o - m o m e n t b a s i s . In c o n t r a s t , t h e amygdala alters autonomic function based on learning a n d past experience. An individual c a n , for e x a m p l e , b e c o m e fearful of u n d e r g r o u n d parking garages as a result of being assaulted in o n e . Following such a n experience, t h e s i g h t , s m e l l , o r e v e n t h o u g h t of a n u n d e r g r o u n d g a r a g e can elicit autonomic changes such as a dry mouth a n d increases in heart rate, sweating, a n d breathing. These autonomic changes are not in response to changes in t h e physiologic state, but a r e learned responses to past experience.

Figure 4-5 Ventral (inferior)view of the left hemisphere showing the amygdaloid nuclear complex and the major connections that are involved in autonomic visceromotor function ( 1 ) ventral amygdalofugal (amygdalohypothalamic)tract to hypothalamus, ( 2 ) stria terminalis tract to hypothalamus, ( 3 ) reciprocal pathways between the basolateral amygdala and the sensorimotor association areas; and (4)to brain stem centers

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Autonomic Integrating Components Figure 4-6 Limbic pathways.

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HYPOTHALAMUS T h e hypothalamus plays a critical role in the survival of the individual and of the species through its control of homeostasis, and of motivated and emotional aspects of behavior, including feeding, drinking, and reproduction. T h e hypothalamus regulates homeostasis on the physiologic level through its control of the autonomic nervous system and on the cellular level through its control of the endocrine system. It regulates reproduction through its control of both gonadal hormone production and the behavioral components of mating and parenting. T h e hypothalamus is composed of paired nuclei and fiber bundles through which it communicates widely with other areas of the central nervous system. T h e nuclei are groups of cells that are poorly defined anatomically. T h e hypothalamus communicates with the pituitary gland through the infundibular stalk (Figure 4-7). T h e hypothalamus can b e divided on each s i d e into three zones: periventricular, medial, and lateral. The periventricular zone is a thin layer bordering the third ventricle. T h e medial and lateral zones are divided by a paramedian p l a n e , w h i c h includes columns of t h e fornix and t h e mammillothalamic tract (see Fig. 4-7). In general, the periventricular zone is primarily involved in visceromotor control and in endocrine functions, such as control of the anterior pituitary gland and the synthesis of oxytocin and vasopressin. The medial zone is an association area: it integrates widespread inputs from the limbic system and visceral sensory information from the brain stem and acts to produce affective behavior. T h e lateral zone is the rostral-most part of the reticular formation. It is concerned mainly with behavioral arousal. Within these zones several nuclei have been named and described in a variety of animals and are likely present in humans as well. Most of the nuclei are paired. Some nuclei within the periventricular zone are so close to the midline that they have fused into a single structure (see Fig. 4-7). with the exception of the supraoptic, suprachiasmatic, and paraventricular nuclei and the subfornical organ, a specific function cannot b e assigned to each named nucleus. Furthermore, very little is known with certainty about the anatomic organization of neural pathways that mediate integration of autonomic, neuroendocrine, and behavioral activities associated with homeostasis. What follows is a summary of the generally accepted functions of the different areas of the hypothalamus. Functions of the Hypothalamus

Temperature Control Thermoregulation is accomplished by both visceral and behavioral responses (see Case Study 7: Michael’s Last Run for a description of visceral responses to temperature change).Thermoreceptors are scattered in the skin, and throughout the central nervous system. The anteromedial hypothalamus, most likely the medial preoptic area, plays a critical role in the integration of appropriate


autonomic, somatic, and behavioral responses to temperature change. When the temperature rises, physiologic changes that reduce body heat (peripheral vasodilation, sweating, reduced metabolic activity) are elicited. When the temperature drops, physiologic changes that produce and conserve body heat (peripheral vasoconstriction, piloerection, shivering) occur. T h e balance of these two activities maintains a fairly constant body temperature. The neural pathways that carry out these responses are not yet understood.

Eating T h e hypothalamus and interconnected limbic structures play an important role in eating behavior. T h e mechanism(s) of this control is (are) currently unknown; however, the paraventricular nucleus of t h e hypothalamus is known to be a key player. Experimental manipulation of the paraventricular nucleus can alter food intake. T h i s alteration is m e d i a t e d partly by hypothalamic influences on the dorsal vagal nucleus that controls insulin release and on the sympathetic control of adipose tissue metabolism. Reproductive Behavior Reproductive behavior is a complex phenomenon that involves widespread areas of the nervous system including the cerebral cortex, limbic system, hypothalamus, and spinal cord. See Case Study 5:Clem’s Em6arrassing Pro6lem, for a description of brain stem and spinal cord structures involved in sexual response. The hypothalamus plays two important roles in reproduction: it controls reproductive hormone secretion, and it mediates sexual and parenting behaviors. T h e neural circuits that mediate sexual behavior and reproductive physiology are anatomically differentiated in the central nervous system of the male and female. A group of neurons near the center of the medial preoptic area is several times larger in the male than it is in the female. Several lines of experimental evidence in animals suggest that this area represents the final common pathway for masculine sexual behavior. This area is activated by input from widespread areas in the brain and, in males, is sensitive to levels of circulating androgens. T h e medial preoptic area in females is involved with parenting behaviors. Feminine sexual behavior is likely mediated by neurons in the ventromedial nucleus of the hypothalamus. Oxytocin, a p e p t i d e s y n t h e s i z e d by neuroendocrine cells i n t h e paraventricular and supraoptic nuclei, is present in efferent pathways from t h e h y p o t h a l a m u s t o s p i n a l a n d brain s t e m c e n t e r s involved a s a neurotransmitter in autonomic function, including sexual behavior. T h e hormone oxytocin also has reproductive functions. It enhances uterine smooth muscle contractility during labor and activates myoepithelial cells in mammary glands to aid in milk secretion during breast feeding.

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*Nuclei that occupy more than one zone

Figure 4-7 Hypothalamic zones and nuclei shown (A) in coronal view and ( B ) in longitudinal view. The plane of section in A is indicated by the vertical line in B.


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Cardiovascular Control and Fluid Balance The total volume of circulating blood, blood pressure, and fluid balance are intimately l i n k e d . It is not surprising, t h e r e f o r e , t h a t p a r t s of t h e hypothalamus control both autonomic cardiovascular functions and fluid balance. T h e paraventricular nucleus, which bridges periventricular and medial zones of the anterior hypothalamus, is composed of two distinct cell groups: magnocellular neurons and parvocellular neurons. T h e magnocellular n e u r o n s a r e n e u r o e n d o c r i n e in n a t u r e . T h e y synthesize a hormone, vasopressin, which is transported to the posterior lobe of the pituitary gland by axoplasmic transport and released into the circulating blood. Vasopressin acts to promote the resorption of water in the kidneys, thereby retaining fluid within the body. Another hypothalamic area, the supraoptic nucleus, is also composed of magnocellular cells that function with the paraventricular magnocellular neurons in vasopressin secretion. A population of parvocellular neurons (dorsal a n d lateral t o t h e magnocellular group of the paraventricular nucleus) functions as upper motor neurons of the autonomic nervous system. parvocellular neurons receive visceral sensory information from cardiovascular areas in the brain stem and project to brain stem and spinal cord autonomic cell groups, including preganglionic neurons. T h e y act to adjust the rate and strength of ventricular contractility in the heart and the peripheral resistance of blood vessels to maintain blood pressure. An increase in the activity of the magnocellular neurons is elicited by an increase in plasma osmolality, a decrease in plasma volume, information from sensory receptors in the mouth, and higher order cognitive factors such as the thought or sight of cool water. An increase in plasma osmolality is detected by osmoreceptive neurons scattered in the hypothalamus. Osmoreceptors signal the paraventricular and supraoptic nuclei to increase vasopressin synthesis and secretion by, as yet, unknown pathways. A decrease in plasma volume is signaled via neuronal pathways from baroreceptors in the large blood vessels and, via humoral pathways, by the release of angiotensin 11 into the circulation. Sensory signals from the baroreceptors are relayed to the supraoptic and paraventricular nuclei via relays in the nucleus of the tractus solitarius and cardiovascular areas of the brain stem. Angiotensin 11 circulating in the blood is detected by cells in the subfornical organ of the hypothalamus (see Fig. 4-7). The subfornical organ projects to the supraoptic and paraventricular nuclei. For more information on the subfornical organ, see Circumventricular Organs, on the following page. Both of these pathways elicit vasopressin release by magnocellular neurons in t h e supraoptic and paraventricular nuclei and activation of parvocellular neurons in the paraventricular nucleus.


Deferzsive Behavior T h e caudal, medial regions of the hypothalamus organize the autonomic c o m p o n e n t s of defensive behavior. T h e s e are pupillary dilation, piloerection, sweating, and increases in cardiac and respiratory rates. These effects are produced by augmentation of sympathetic activity and secretion of adrenaline from the adrenal medulla (see Case Study I: “Fight or Flight”Anxiety: Margaret arzd Matthew for details of defensive behavior). Diurrzal Rhythm The suprachiasmatic nucleus acts as the biological clock. It receives direct neuronal input from the retinae via the underlying optic chiasma. T h e mechanism(s) b y which the suprachiasmatic nucleus controls the circadian changes in t h e body are not yet understood. Examples of autonomic circadian changes are 24-hour, rhythmic temperature fluctuations, changes in glandular secretion, and the sleep-wake cycle. Circumven tricu la r 0rgans

Circumventricular organs provide a direct route from the blood to the central autonomic neurons. Some chemoreceptive neurons within the central nervous system are stimulated by molecules circulating in the blood. Although some of the molecules that stimulate central receptors are able to cross capillary walls, most are excluded by the blood-brain barrier and gain access to the brain only by passing through special areas where the barrier is absent. Because these special areas tend to cluster around the ventricles, they are called circumventricular organs. T h e circumventricular organs function as part of a humoral feedback system involved in a variety of autonomic functions including cardiovascular control, food intake, and fluid homeostasis. T h e circumventricular organs thought to b e involved i n autonomic function are the subfornical organ and the organum vasculosum of the lamina terminalis, both of which function in fluid balance. T h e area postrema functions a s an emetic center (see Case Study 3: Victoria and the Vicious Hot Dog: Emesis).

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RETICULAR CENTERS IN THE BRAIN STEM T h e r e t i c u l a r f o r m a t i o n is t h e rostral e x t e n s i o n of t h e s p i n a l c o r d interneuronal network. It e x t e n d s from t h e spinal cord through t h e brain s t e m a n d , according to s o m e , b e c o m e s t h e lateral zone of t h e hypothalamus. T h e reticular formation is a network ( r e t e m e a n i n g network) of loosely associated cells that are difficult t o identify anatomically. Reticular c e n t e r s involved in autonomic function receive w i d e s p r e a d input from t h e cerebrum a n d t h e nucleus of t h e tractus solitarius (see Chapter 3: Autonomic Sensory Components for a description of t h e nucleus of t h e tractus solitarius). Reticular centers project widely t o each other, to higher centers, a n d to autonomic preganglionic motor neurons. The reticular centers in t h e b r a i n s t e m t h a t a r e t h o u g h t to p l a y a r o l e in a u t o n o m i c f u n c t i o n a r e described below a n d in Figure 4-8. Midbrain Periaqueductal Gray

In t h e midbrain, t h e gray matter surrounding t h e aqueduct in t h e midbrain is t h o u g h t to p l a y a role in organizing t h e visceromotor c o m p o n e n t s of defensive a n d reproductive behavior. It has reciprocal connections with t h e prefrontal a n d insular cortices, t h e anterior hypothalamus, a n d t h e amygdala. I t receives sensory input from t h e spinal cord a n d trigeminal nucleus a n d projects caudally to t h e ventrolateral a n d ventromedial medulla. Cardiovascular Centers

Two centers in t h e brain stem play a major role in modifying activities of t h e

heart a n d blood vessels: a cardiovascular excitatory center exerts its effects via sympathetic pathways a n d a cardiovascular inhibitory center exerts its effects via parasympathetic pathways, specifically t h e vagus nerve (CN X). T h e s e c e n t e r s receive signals from t h e periphery, mainly from baro- a n d chemoreceptors, and from higher centers in t h e brain that d e m a n d changes in cardiovascular function in relation to i n t e n d e d activity a n d e m o t i o n a l expression. In addition, t h e cardiovascular centers maintain a close relationship with t h e activity of t h e respiratory system. The balance in activities of these two centers maintains cardiovascular homeostasis a n d adjusts t h e activity of t h e cardiovascular system to m e e t t h e changing n e e d s of t h e body. The cardiovascular excitatory center consists of a loose network of cells in t h e reticular formation of t h e rostral ventrolateral medulla. Many of t h e s e cells h a v e p a c e m a k e r p r o p e r t i e s through which t h e y provide a constant, rhythmic excitatory d r i v e to s y m p a t h e t i c preganglionic n e u r o n s in t h e intermediolateral cell column of t h e spinal cord. The rate of discharge of t h e s e cells is increased o r d e c r e a s e d b y signals from several structures, notably t h e nucleus of t h e tractus solitarius a n d t h e hypothalamus. The cardiovascular inhibitory (depressor) center consists of preganglionic parasympathetic cells located in t h e ventrolateral a s p e c t of t h e nucleus a m b i g u u s . It is d e s c r i b e d with Preganglionic Autonomic Motor Neurons in this chapter.


Specialist Information Interruption of the excitatory pathway from the brain stem to the spinal cord is responsible for the profound drop in blood pressure known as spinal shock that follows spinal cord injury.

Figure 4-8 Reticular centers in the brain stem that are thought to play a role in autonomic function. The approximate sites of these centers are indicated in the illustration; however, these areas are diffuse, and their borders are not known with certainty (respiratory centers are not shown). ( A ) ,dorsal view; (B), midsagittal view.

Sensory Nucleus 1 . The nucleus solitarius is included in this illustration a s a landmark Reticular NucleVCenters 2. Locus ceruleus 3. Cardiovascular excitatory center 4. Area postrema 5. Pontine micturition center

6. Pontine bladder storage center 7. Parabrachial nuclei 8. Midbrain periaqueductal grey

Parasympathetic Preganglionic Motor Neurons 9. The ventrolateral aspect of t h e nucleus ambiguus forms the cardiovascular inhibitory center

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Respiratory Centers

Poorly defined groups of cells, primarily in t h e medulla, b u t also in t h e p o n s , constitute t h e respiratory center. Within t h e m e d u l l a , cells in t h e dorsal region close to t h e nucleus solitarius function during inspiration, whereas cells situated more ventrally, medial to t h e nucleus ambiguus, are thought to function during expiration. T h e respiratory neurons a r e driven primarily b y local CO, levels, a n d b y sensory i n p u t from t h e peripherychiefly blood oxygen-and b y pulmonary stretch receptors, b y signals from local neurons, primarily t h e cardiovascular centers, a n d b y a multitude of inputs from higher centers, chiefly t h e hypothalamus, limbic s y s t e m , a n d c e r e b r a l cortex. Respiratory n e u r o n s d r i v e t h e r e s p i r a t o r y m u s c l e s b y projecting t o t h e phrenic nucleus in t h e cervical spinal cord (that innervates t h e diaphragm) a n d t h e respiratory motor neurons of t h e thoracic a n d lumbar cord that innervate t h e intercostal a n d abdominal muscles (see also Case Study 8: Patty’s Puffer). Micturition Centers

The b l a d d e r a n d its associated pelvic floor muscles have two functions, to s t o r e urine a n d to e x p e l it. Storage is accomplished b y relaxation of t h e d e t r u s o r m u s c l e a n d c o n t r a c t i o n of t h e u r e t h r a l s p h i n c t e r s , w h e r e a s e x p u l s i o n is a c c o m p l i s h e d b y c o n t r a c t i o n of t h e d e t r u s o r m u s c l e a n d relaxation of t h e urethral sphincters. See Case Study 4: Ro&ert and his KnockedOut Bladder, for a description of t h e neuronal control of bladder function. Sensory input from t h e expanding bladder initiates t h e expulsion reflex through connections in t h e sacral spinal cord. In a d d i t i o n , however, two centers in t h e p o n s modify this reflex through descending pathways. Cells in t h e dorsolateral rostra1 p o n s inhibit b l a d d e r activity a n d stimulate sphincter contraction. Cells in a more medial position in t h e p o n s have t h e opposite effect, i.e., t h e y stimulate b l a d d e r activity a n d inhibit s p h i n c t e r activity. These two centers constitute t h e pontine micturition center. Their activity is driven b y sensory input from t h e bladder itself a n d by signals from higher centers. In particular, t h e paracentral lobules a r e thought t o exert voluntary c o n t r o l o v e r m i c t u r i t i o n t h r o u g h t h e i r c o n n e c t i o n s with t h e p o n t i n e micturition centers (see Case Study 4: Robert and his Knocked-Out Bladder).


Specialist Information Two additional reticular nuclei within the brain stem, the parabrachial nucleus and the locus ceruleus, are widely interconnected with autonomic neuronal centers and are therefore thought to play roles in autonomic function; however, their specific roles are, as yet, not well understood. Parabrachial Nucleus The parabrachial nucleus is a reticular nucleus situated in the midbrain and rostral pons. It can be divided into three regions: the medial parabrachial nucleus, which receives gustatory information from the gustatory nucleus (rostral nucleus solitarius); the lateral parabrachial area, which receives general visceral information from the caudal parts of the nucleus solitarius; and the ventral parabrachial nucleus (KollikerFuse nucleus), which receives respiratory information from the nucleus solitarius. The medial and lateral parabrachial nuclei project to higher areas of the brain including the thalamus, hypothalamus and cerebral cortex. In contrast, the ventral parabrachial nucleus is part of a network in the lower brain stem that controls respiration. Locus Ceruleus Locus Ceruleus is included here as part of the autonomic nervous system because one of its principal sources of afferent information is from the cardiovascular excitatory center. Stimulation of locus ceruleus in rats produces a decrease in blood pressure and heart rate. Locus ceruleus is a small, elongated nucleus in the lateral part of the rostral pons and midbrain. The cells that constitute this nucleus secrete noradrenaline as their major neurotransmitter. In addition, they synthesize melanin whose presence gives the nucleus its bluish color (cerulean meaning deep blue, like a clear sky). Locus ceruleus has widespread projections to all areas of the cerebrum, brain stem, medulla and spinal cord. Because of such widespread connections, locus ceruleus has been implicated in almost every known brain function. TABLE 4-1 Preganglionic Neuron Projections to Postganglionic Neurons

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PREGANGLIONIC AUTONOMIC MOTOR NEURONS Preganglionic autonomic motor neurons are located in t h e brain s t e m a n d t h e spinal cord nuclei within t h e central nervous system. These neurons are described in detail in Chapter 5: A u t o ~ o m i cMotor CovMpouetzts a n d in chart form in T a b l e 4-1. In g e n e r a l , p r e g a n g l i o n i c a u t o n o m i c m o t o r n e u r o n s a r e s e g m e n t a l l y o r g a n i z e d in a r o s t r o c a u d a l d i r e c t i o n . In t e r m s of t h e i r morphology, conduction velocity, transmitter synthesis, a n d release, they are a h e t e r o g e n e o u s group. All preganglionic autonomic n e u r o n s synthesize acetylcholine as their major transmitter. Subsets of neurons express at least o n e additional putative neurotransmitter, such as substance P, neurotensin, somatostatin, enkephalin, GABA, or serotonin. Presumably this diversity has c o n s i d e r a b l e functional significance. T h e functional differences b e t w e e n s y m p a t h e t i c a n d p a r a s y m p a t h e t i c preganglionic m o t o r n e u r o n s a r e well understood, b u t functional differences among neurons within each division remain to be established. Preganglionic autonomic motor neurons function t o integrate autonomic reflexes in specific, large, areas of t h e body. Afferent signals a r e received a n d integrated from several sources, including direct visceral afferent input at t h e brain s t e m a n d spinal cord levels, input from t h e reticular centers described a b o v e , a n d from t h e descending pathways from t h e hypothalamus, limbic s y s t e m , a n d cerebral cortex. Preganglionic motor axons l e a v e t h e central n e r v o u s s y s t e m , b r a n c h w i d e l y , a n d t e r m i n a t e o n l a r g e n u m b e r s of postganglionic neurons a n d interneurons within specific autonomic ganglia.

POSTGANGLIONIC AUTONOMIC MOTOR NEURONS Postganglionic autonomic motor neurons a r e located in t h e autonomic ganglia. T h e distribution a n d connections of t h e ganglia a r e d e s c r i b e d in detail in Chapter 5: A u t o ~ o m i cMotor CovMponeMts. Postganglionic cells receive input from large numbers of preganglionic neurons, from sensory neurons in t h e target organ, a n d from interneurons within t h e s a m e ganglion (Figure 4-9). Interneurons a r e thought to comprise t h e small, dopaminergic intensely fluorescent cells (SIF cells). When stimulated, t h e s e cells exert a n inhibitory influence on t h e postganglionic cells. Specialist Information The word “ganglion” comes from the Greek word meaning a “knot.” A ganglion is a collection of nerve cell bodies located outside the central nervous system, afferent and efferent axons, glial supporting cells, and connective tissue (see Fig. 4-9).


Figure 4-9 A paravertebral ganglion and its connection with the spinal cord In the sympathetic autonomic nervous system: 1 . The intermediolateral cell column is composed of preganglionic motor neurons (red);

Preganglionic motor neurons receive impulses from higher centers, from the periphery of the body and from interneurons within the spinal cord grey matter (black); 2. Ventral roots contain somatic and preganglionic motor axons (somatic not shown); 3 . Dorsal roots contain somatic and visceral sensory axons (green) (somatic not shown);

4. White ramus communicans contains preganglionic motor axons and visceral sensory axons;

5 . The grey ramus communicans contains only postganglionic motor axons (orange); 6. A paravertebral ganglion includes the following:

- axons and axon terminals of preganglionic motor neurons, - postganglionic motor neuron cell bodies, - interneurons, and - collateral branches from sensory neurons; 7. The sympathetic chain that joins adjacent ganglia contains only preganglionic motor axons.

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LOCAL CIRCUITS Sensory afferents that drive reflex adjustments of visceral behavior act within t h e walls of t h e viscera. In t h e i n t e s t i n e s , for e x a m p l e , relatively complex local circuits, including sensory neurons, interneurons, a n d b o t h excitatory a n d inhibitory m o t o r n e u r o n s , organize peristaltic m o v e m e n t a l o n g t h e i n t e s t i n e s (Figure 4-10). See Cuse S t u d y 2: Megan’s Colon for a description of t h e neural circuits involved in peristalsis. Still other circuits organize secretion a n d absorption within t h e mucosal lining of t h e gut.

Figure 4-10 The neurons in the gut form local circuits that organize peristalsis Expansion of the gut wall by a bolus is detected by sensory afferent arms of command neurons ( 1 ) The efferent arms of command neurons signal inhibitory ( 2 ) and excitatory ( 5 ) interneurons, which in turn signal inhibitory and excitatory motor neuron (3G4 and 6G7) to cause contraction of the gut wall proximal to the bolus and relaxation of the gut wall distal to the bolus.

Autonomic Motor Components

V AUTONOMIC MOTOR COMPONENTS Characteristics of Autonomic Motor Function The underlying principles of autonomic motor function follow: 1 . Most organs a r e innervated b y two kinds of autonomic nerves:

sympathetic, a n d parasympathetic. In m o s t c a s e s , s y m p a t h e t i c a n d p a r a s y m p a t h e t i c s t i m u l a t i o n a r e antagonistic (e.g., sympathetic stimulation to t h e heart increases t h e heart rate, whereas parasympathetic stimulation decreases it). In contrast, s y m p a t h e t i c a n d parasympathetic n e r v e s t h a t s u p p l y t h e exocrine glands act in a synergistic fashion. Both kinds of nerves increase s e c r e t i o n , t h e p a r a s y m p a t h e t i c to a m u c h g r e a t e r e x t e n t t h a n t h e sympathetic. In addition, t h e sympathetic nerves increase blood flow to t h e exocrine glands, thereby providing fluid, ions, a n d proteins for secretion. T h e structural innervation of t h e organ systems is shown in Figure 5-1. The effects of sympathetic a n d parasympathetic stimulation o n t h e activities of t h e organs is summarized in Table 5-1. 2. Autonomic efferent (motor) pathways consist of two-neuron chains:

t h e preganglionic neurons a n d t h e postganglionic neurons. This two-neuron arrangement has several advantages: A single preganglionic neuron s y n a p s e s o n large n u m b e r s of

postganglionic neurons, thereby allowing for a small n u m b e r of central neurons t o influence large areas of t h e body. This is t h e principle of divergence of stimuli (Figure 5-2). Since sensory (afferent) axons course through t h e ganglia, a certain amount of sensory-motor integration takes place at t h e ganglionic level, thereby giving t h e autonomic nervous system a d e g r e e of autonomy from t h e central nervous system. A single preganglionic neuron can synapse on both excitatory a n d

inhibitory postganglionic neurons, thereby allowing for excitation a n d inhibition of various target cells, which produces a high d e g r e e of functional coordination.


3 . Blood vessels have either dual or single innervation.

Some vascular smooth muscle, predominantly in vessels in the pelvic area a n d head, is dually innervated: sympathetic nerves cause vasoconstriction and parasympathetic nerves cause vasodilation. However, vascular smooth muscle that is not located in t h e h e a d or pelvis is innervated only b y sympathetic nerves. In these vessels, vasoconstriction is caused by sympathetic stimulation, whereas vasodilation is caused by a decrease in sympathetic stimulation. In addition, regional vasomotion is affected by a large number of locally-produced factors (see Chapter 6: Autonomic Neurotransmitters, Receptors, and Effectors). 4. Sweat glands a n d arrectores pilorum muscles are innervated only b y

sympathetic nerves. Changes in sweating a n d hair erection a r e c a u s e d b y a n increase o r a decrease in sympathetic stimulation. 5. Effects of t h e motor division of t h e autonomic nervous system are exerted

b y changing t h e activity of autonomic effector cells. Autonomic effector cells include s m o o t h muscle cells, cardiac muscle cells, secretory cells a n d microvascular endothelium. Effector cells have their own intrinsic activity, which is m o d i f i e d , b u t n o t c a u s e d , b y a u t o n o m i c n e r v e s . T h e effect a n a u t o n o m i c n e r v e h a s o n its t a r g e t e f f e c t o r c e l l s d e p e n d s o n t h e t y p e ( s ) of neurotransmitters r e l e a s e d b y t h e axon, t h e t y p e (s) of receptors t h e effector cell expresses a n d t h e intracellular signalling mechanism that t h e receptors are linked to. The effector cells a n d how they a r e innervated are discussed in Chapter 6: Autonomic Neurotransmitters, Receptors, and Effectors.

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Overview of Autonomic Motor Nerves to t h e Organs T h e following important concepts are illustrated in Fig. 5-1 0

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Sympathetic preganglionic neurons are located in the intermediolateral cell column of TI to L2(A). Parasympathetic preganglionic neurons are located in the brain stem and in the intermediolateral cell column of S2 to S4(B). All of the visceral organs within the body are innervated by both sympathetic and parasympathetic nerves. The state of action of the organs is the result of the intrinsic activity of the organ and the balance of sympathetic versus parasympathetic stimulation.

Body wall and limb autonomic effectors, in contrast, receive their autonomic innervation from only sympathetic postganglionic neurons. Changes in the activity of these effectors are caused by an increase or a decrease in sympathetic stimulation. Sympathetic postganglionic neurons that supply the head and thoracic viscera are located in the cervical and upper thoracic ganglia of t h e sympathetic chain. Sympathetic postganglionic axons to the head reach their target structures by hitchhiking along the carotid arteries and their branches. Sympathetic preganglionic axons, which innervate preaortic ganglia, pass through the sympathetic chain, without synapsing, to form splanchnic nerves (A9, A l O , A1 1 ) . Sympathetic postganglionic neurons that supply the abdominal and pelvic viscera are located in preaortic ganglia and pelvic plexuses. Preganglionic sympathetic axons are short and postganglionic sympathetic axons are long. Preganglionic parasympathetic axons are long, and postganglionic parasympathetic axons are short. The sympathetic chain is longer than t h e spinal cord; therefore, most of the chain ganglia are not anatomically adjacent to the spinal segment from which they receive their innervation. The adrenal medulla is the only gland innervated by a preganglionic sympathetic axon (T8-L 1 -L2). Autonomic nerves to the organs and visceral structures in the body wall (vascular smooth muscle, microvascular endothelium, sweat glands, arrectores pilorum muscles) arise from both left and right sides of the central nervous system. In Fig. 5-1, they are shown as arising from one side only. Both of these groups of nerves are bilateral. Although they are actually highly branched, terminal segments of postganglionic neurons are shown as ending in a single, varicosed axon.


Figure 5-1 Overview of autonomic motor innervation to t h e organ systems

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NA: Noradrenaline - the different responses of effector cells to norepinephrine (NE) depend on the balance between (Y and p receptors and their respective subtypes (see Chapter 6). Note: the terms noradrenaline (NA) and norepinephrine (NE) are used interchangeably; ACh: Acetylcholine.


Figure 5-2 Preganglionic axons project to a large number of postganglionic axons. This "divergence of stimuli" allows only a few neurons in the spinal cord to have widespread influence in the body.

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Sympathetic Division: Thoracolumbar Outflow Cell Bodies of Preganglionic Sympathetic Neurons

Most preganglionic sympathetic neurons reside in t h e lateral horn of t h e spinal cord (see Figures 5-2 a n d 5-3). More precisely, t h e y r e s i d e in t h e intermediolateral cell column a n d closely surrounding regions in spinal s e g m e n t s T 1 to L 2 . Preganglionic s y m p a t h e t i c n e u r o n s a r e o r g a n i z e d somatotopically, t h a t is, t h o s e in t h e rostral s e g m e n t s (rostral m e a n i n g towards t h e n o s e ) of t h e intermediolateral column s u p p l y t h e h e a d a n d neck, a n d t h o s e in progressively m o r e caudal s e g m e n t s (caudal meaning towards t h e tail) s u p p l y t h e heart, lungs, a b d o m i n a l viscera, a n d pelvic viscera in that order. Preganglionic neurons s e c r e t e acetylcholine as their primary neurotransmitter. Preganglionic axons leave t h e spinal cord with t h e ventral roots of t h e s a m e spinal cord segment, join t h e mixed spinal nerves, a n d then leave t h e nerves as branches to t h e sympathetic ganglia. Since more than half of these axons are myelinated, the bundles they form appear white. The branches to the ganglia are therefore called the white rami communicantes.

Preganglionic axons d e s t i n e d for ganglia a b o v e T1 o r b e l o w L2 m u s t travel cranially or caudally within t h e sympathetic chain to reach their target ganglia (Figure 5-4). Preganglionic axons branch extensively before t h e y reach their target postganglionic neurons. In humans, t h e ratio of pre- to postganglionic neurons is more than 1 to 100. Preganglionic axons terminate in synaptic boutons that form synapses with t h e body a n d dendrites of t h e postganglionic neurons.


Figure 5-3 Sympathetic preganglionic neurons are located in the lateral horn (intermediolateral cell column) of the spinal cord ( A ) Sympathetic postganglionic neurons are located in the paravertebral ganglia ( B ) and in the preaortic ganglia ( C ) T h e adrenal medulla is a specialized sympathetic ganglion (D)

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Axons of Preganglionic Sympathetic Neurons

Axons of preganglionic sympathetic neurons project t o sympathetic ganglia. They take one of several possible routes (see Fig. 5-4). They may: 1 . Terminate within the first paravertebral ganglion they encounter; 2. Traverse the paravertebral ganglion to synapse in a preaortic ganglion; 3. Ascend or descend within the sympathetic chain to terminate in more

cranial or caudal paravertebral ganglia; or 4. Ascend or descend within the sympathetic chain and then traverse the paravertebral ganglion to terminate in a preaortic ganglion. The ascending a n d d e s c e n d i n g axons link t h e paravertebral ganglia together to form the sympathetic chain (also known as the sympathetic trunk). It is important to note that only 13 or 14 ganglia receive direct branches (white rami) from t h e spinal nerves. The remaining ganglia receive their preganglionic axons via ascending or descending axons in t h e sympathetic chain.


Figure 5-4 Variable routes taken by sympathetic preganglionic and postganglionic axons through the paravertebral and preaortic ganglia. (See text on pg. 80 for explanation of numbering.)

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Cell Bodies and Axons of Postganglionic Sympathetic Neurons

Postganglionic a n d e n t e r i c s y m p a t h e t i c n e u r o n s , which form t h e sympathetic ganglia, reside entirely outside the central nervous system. The cell bodies of t h e s e neurons are collected in groups (ganglia) of varying sizes. Their axons are unmyelinated, a n d their axon terminals are highly branched. They do not form true synapses with their target structures. Their axon terminals do n o t e n d a s b o u t o n s , b u t a s a s e r i e s of varicosities ( e x p a n s i o n s ) thought t o act a s s i t e s of neurotransmitter r e l e a s e . ( S e e Chapter VI for a more detailed description of postganglionic axon terminals.) Sympathetic ganglia form two groups: I . Ganglia located beside t h e vertebral bodies are the paravertebral ganglia. 2. Ganglia located in front of the aorta and clustered around the major

arteries are preaortic ganglia (also called prevertebral ganglia). A specialized subgroup of postganglionic neurons forms the adrenal medulla.

Paravertebral Ganglia During development, pairs of paravertebral ganglia form beside each of the 31 spinal cord segments; however, the cervical paravertebral ganglia subsequently fuse to form 2 to 3 large pairs of ganglia. In addition, the lumbosacral ganglia fuse irregularly, and the most caudal pair of paravertebral ganglia fuse in the midline t o form t h e ganglion impar (impar meaning u n p a i r e d ) . Adults, therefore, have only 22 to 23 pairs of autonomic paravertebral ganglia. k o n s of pre- and postganglionic sympathetic neurons leaving t h e ganglia form two sets of branches: the medial, mostly preganglionic, branches that innervate t h e viscera (via preaortic ganglia), and t h e lateral postganglionic branches that rejoin the spinal nerves and travel with them to the body wall where they innervate peripheral blood vessels, sweat glands, and arrectores pilorum muscles (see Fig. 5-4). The lateral branches consist almost exclusively of postganglionic axons. The axons are unmyelinated and, therefore, appear grey. Accordingly, they are called the grey rami communicantes.

Early in development, t h e spinal nerves and ganglia form beside their spinal cord segment. However, a s t h e fetus grows, t h e vertebral column grows longer than the spinal cord so that, by birth, the more caudal spinal nerves exit from the vertebral canal at sites far caudal to t h e location of their spinal cord segment. The autonomic ganglia associated with t h e s e spinal nerves, therefore, are also located caudal to t h e anatomic level of their spinal segments (see Fig. 5-1, and Figures 5-5 and 5-6).


Figure 5-5 Anatomic relationship between sympathetic cord segments, sympathetic ganglia, and sympathetic nerves Note the following: ( 1 ) the obliquity of the spinal cord nerve roots and the position of the ganglia relative to their spinal segments; ( 2 ) medial branches from the ganglia innervate the viscera (2A) and lateral branches innervate the body wall ( 2 B ) , ( 3 ) the cervical spinal nerves (C8 shown) include postsynaptic sympathetic axons from the grey rami communicantes.

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The sympathetic paravertebral ganglia form three groups: 1 . Cervical ganglia,

2. Thoracic and upper two, or three, lumbar ganglia, and 3. Lower lumbar and all of the sacral ganglia.

1. Cervical ganglia receive their autonomic

innervation from neurons in the intermediolateral cell column in the upper few thoracic spinal cord segments Cervical ganglia have no white rami communicantes, but they contribute (postganglionic) grey rami communicantes to the cervical spinal neves Their medial branches are also composed of postganglionic axons (not shown)

2. Thoracic and the upper 2 (or 3) lumbar ganglia receive their innervation from neurons in the intermediolateral cell column in the spinal cord segments associated with the same spinal nerves. These ganglia have both white and grey rami communicantes Their medial branches to the abdominal and pelvic viscera are composed of preganglionic axons

3. Lower lumbar and all the sacral ganglia receive their innervation from neurons in the intermediolateral cell column in the lower thoracic and upper 2 or 3 lumbar spinal cord

segments.These ganglia have no white rami communicantes, but they contribute grey communicantes to the lumbosacral spinal nerves. Their medial branches to the pelvic viscera are composed of preganglionic axons. They are called the sacral splanchnic nerves.

Figure 5-6 The sympathetic paravertebral ganglia (shown on one side only)


I . Cervical Ganglia (Figure 5-7) The superior cervical ganglion is the largest of the three cervical ganglia. It is located adjacent to the vertebral bodies of C2 and C3. It supplies the heart and structures in the head and neck. The postganglionic axons reach their target structures in t h e head by hitchhiking on the carotid arteries.

The middle cervical ganglion is t h e smallest of the three. I t is located adjacent to t h e vertebral body of C6. It supplies the heart and structures in t h e neck.

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The inferior cervical ganglion may be fused with t h e first thoracic ganglion to form t h e large stellate (star-shaped)ganglion. It is located adjacent to t h e vertebral b o d y of C7. It supplies t h e heart, lower neck, arm, a n d posterior cranial arteries. The cervical ganglia differ from t h e remaining ganglia in that 95 percent of their medial branches a r e composed of postganglionic axons. 2. Thoracic Ganglia a n d the Rostra1 Two (or Three) Lumbar Ganglia (Figures 5-8, 5-9, a n d 5-10) 0 Thoracic ganglia are 1 1 in number ( t h e first o n e is often fused with t h e

inferior cervical ganglion). 0

0

0

0

0

0

0

0

0

0

All thoracic ganglia s e n d grey rami communicantes to t h e adjacent b o d y wall, including t h e arm (T24T5).They supply blood vessels, sweat glands, a n d arrectores pilorum muscles.

Ganglia T2 to T5 supply postganglionic axons to t h e heart a n d lungs Preganglionic axons passing through ganglia T5 to T9 form t h e greater splanchnic nerve, which e n d s in t h e coeliac ganglion which, in turn, supplies t h e stomach a n d proximal parts of t h e gut. Preganglionic axons passing through ganglia T8 to L2 supply t h e adrenal medulla. Preganglionic axons passing through ganglia T9 a n d T 10, a n d occasionally TI I , form t h e lesser splanchnic nerve, which e n d s in t h e superior mesenteric ganglion, which, in turn, supplies t h e middle part of t h e gut. In a b o u t half of t h e population, preganglionic axons passing through ganglion TI 2 form t h e lowest (least)splanchnic nerve that e n d s in t h e aorticorenal ganglion, which, in turn, supplies t h e kidney. The first a n d second (and sometimes t h e third) lumbar ganglia receive white rami communicantes from t h e spinal cord. All of t h e lumbar ganglia have grey rami communicantes that rejoin t h e appropriate spinal nerves to supply t h e abdominal wall a n d lower limbs.

Usually four lumbar splanchnic nerves pass from t h e ganglia to join t h e abdominal plexuses. Fibers of t h e lower lumbar splanchnic nerves hitchhike along t h e iliac arteries a n d their branches to supply t h e vessels of t h e pelvis.


Figure 5-8 Typical thoracic ganglia showing grey and white rami communicantes and their relationship to spinal nerves.

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Figure 5-9 Thoracic and upper lumbar sympathetic ganglia and spinal cord showing the thoracolumbar intermediolateral cell column and the anatomic relationship of the ganglia t o their spinal segments.


Figure 5-10 Lower thoracic and upper lumbar sympathetic ganglia, showing their continuity with the lower lumbar and sacral sympathetic ganglia.

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3. Caudal Lumbar Ganglia plus the Pelvic Ganglia (see Figures 5-10 and 5-1 1 ) The pelvic sympathetic chains have four or five sacral ganglia on each side of the sacrum.

The two chains usually fuse in the midline, anterior to the coccyx, to form the ganglion impar. The pelvic ganglia form grey rami communicantes, whose lateral (postganglionic) branches supply the pelvic wall and lower limb. Their medial (preganglionic) branches contribute to the superior and inferior hypogastric plexuses (the inferior hypogastric plexus is also called t h e pelvic plexus),which innervate the distal part of the colon and t h e pelvic viscera.


Figure 5-1 I Lower lumbar and sacral sympathetic ganglia showing their anatomic relationship to the sacrum and to the superior and inferior hypogastric pelvic plexuses. Medial branches which supply the viscera are shown on the left side of the illustration and lateral branches which supply the body wall are shown on the right side of the illustration.

Note: The nomenclature surrounding the autonomic nerves in the pelvis can be confusing. The sympathetic nerves from the sacral sympathetic ganglia (medial branches) are called the sacral splanchnic nerves. The parasympathetic nerves in the pelvis (shown in Figure 5-18) are called the pelvic splanchnic nerves. An easy way to remember this is S = Sympathetic and Sacral and P = Parasympathetic and Pelvic.

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Preaortic (Prevertebral) Ganglia and Plexuses (Figure 5- 1 2) The preaortic ganglia are extensively intermingled with afferent (sensory) and efferent (motor) axons. They are even less well defined anatomically than the paravertebral ganglia. They receive their preganglionic axons from the intermediolateral cell column of the spinal cord. These axons leave the spinal cord a s part of the ventral root, join t h e white rami communicantes, p a s s through t h e paravertebral ganglia without synapsing, a n d form t h e splanchnic nerves (see Fig. 5-8). Cell bodies of the postganglionic neurons form the preaortic ganglia. Four ganglia, the coeliac, the superior mesenteric, the renal, and t h e inferior mesenteric, are fairly consistent anatomically and are therefore easy to recognize. The superior mesenteric, t h e renal, and t h e inferior mesenteric ganglia constitute the aorticorenal ganglion, which has become dissociated from the coeliac ganglion. The preaortic plexuses ( t h e singular form is plexus) comprise inter4 c o n n e c t i n g n e t w o r k s f o r m e d b y t h e p r e a o r t i c ganglia t o g e t h e r with sympathetic, parasympathetic, and sensory axons. In general the plexuses cluster around t h e origin of major blood vessels a n d are n a m e d for t h e vessel with which they are associated. The postganglionic axons hitchhike along t h e vessels to reach their target structures. Two plexuses are not n a m e d for their associated blood vessels: t h e superior and inferior hypogastric pelvic plexuses. The superior hypogastric plexus lies inferior to the origins of the common iliac arteries, and t h e inferior pelvic hypogastric plexuses are deep within t h e pelvis and are associated with pelvic nerves. Superior and inferior hypogastric plexuses are connected to each other by hypogastric nerves.


Figure 5-1 2 Preaortic ganglia and their plexuses (simplified)

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The Adrenal Medulla is a Modified Sympathetic Ganglion (Figure 5-1 3) Like t h e other autonomic ganglia, t h e chromaffin cells that form t h e adrenal medulla originate in t h e neural crest. They a r e innervated b y preganglionic sympathetic neurons (T8 to L l ) . However, two major differences b e t w e e n chromaffin cells a n d o t h e r postganglionic n e u r o n s in sympathetic ganglia should be noted: I . Unlike other sympathetic postganglionic neurons, chromaffin cells do not have axons. They release their neurotransmitters into t h e blood through fenestrations (holes) in t h e walls of nearby capillaries. The circulatory system carries t h e transmitters to distant sites in t h e body, giving t h e chromaffin cells a n extremely widespread influence. 2. Chromaffin cells synthesize mainly adrenaline as their neurotransmitter, along with a small amount of noradrenaline. This is in contrast to sympathetic postganglionic cells that synthesize mainly noradrenaline.

Normally chromaffin cells r e l e a s e very little neurotransmitter into t h e blood, b u t in conditions of stress a n d fear, stimulation from t h e preganglionic

Figure 5-13 T h e adrenal medulla: sympathetic preganglionic nerves release acetylcholine ( 1 ) to stimulate the chromaffin cells in the adrenal medulla to secrete adrenaline and some noradrenaline ( 2 ) into the blood stream ( 3 ) .


s y m p a t h e t i c n e r v e s c a u s e s a m a s s i v e o u t p o u r i n g of a d r e n a l i n e which supports a n d augments sympathetic effects in t h e b o d y (see Case Study 1: “Fight or Flight”-Anxiety: Margaret and Matthew).

Parasympathetic Division: Craniosacral Outflow Cell Bodies of Preganglionic Parasympathetic Neurons are Located in the Brain S t e m a n d in the Sacral Spinal Cord (Figure 5-14)

Preganglionic parasympathetic neurons form four n a m e d nuclei in t h e brain s t e m a n d also t h e intermediolateral cell column in t h e sacral spinal cord. Within t h e brain s t e m t h e parasympathetic nuclei are as follows: Edinger-Westphal Nucleus (Figures 5-1 5 a n d 5-1 6) The Edinger-Westphal nucleus is located in t h e midbrain at t h e level of t h e superior colliculus just a b o v e t h e main oculomotor complex. Its role is t o control t h e size of t h e pupil. It plays a pivotal role in t h e pupillary light reflex a n d also during accommodation. Superior and Inferior Salivatory Nuclei (see Fig. 5-1 6) The salivatory nuclei are two small groups of cells in t h e brain s t e m located at a b o u t t h e junction of t h e p o n s a n d medulla. T h e rostra1 nucleus (i.e.t h e superior salivatory nucleus) s e n d s secretomotor (activating) signals to t h e lacrimal gland ( b e c a u s e of this, it is sometimes referred t o as t h e lacrimal nucleus). In addition, it s e n d s secretomotor signals to t h e submandibular and sublingual salivary glands a n d t h e glands of t h e nasal a n d oral mucosa. The inferior salivatory nucleus is located just caudal t o t h e superior salivatory nucleus. The inferior salivatory nucleus drives t h e parotid salivary gland. Dorsal Vagal Nucleus (see Fig. 5-1 6 a n d Figure 5-1 7) The dorsal vagal nucleus occupies part of t h e floor of t h e fourth ventricle, where it forms t h e vagal trigone. It extends into t h e medulla a n d spinal cord as far a s C1. This large nucleus plays an important role in gut motility a n d secretion/absorption. It is probably t h e only source of vagal axons to t h e abdominal viscera.

Nucleus AmGiguus (see Fig. 5- 16) T h e preganglionic p a r a s y m p a t h e t i c n e u r o n a l cell bodies t h a t form t h e nucleus ambiguus are located in t h e brain s t e m ventral to, a n d approximately c o e x t e n s i v e with, t h e dorsal vagal n u c l e u s . T h e s e n e u r o n s a r e l o o s e l y a s s o c i a t e d , a n d t h e n u c l e u s t h a t t h e y form is n o t e a s i l y i d e n t i f i e d a n a t o m i c a l l y ( h e n c e its n a m e ) . T h e n u c l e u s a m b i g u u s c o n s i s t s of two divisions: a dorsal division that supplies motor innervation to t h e soft palate, pharynx, esophagus, a n d larynx a n d a ventrolateral division that innervates t h e h e a r t . Strictly s p e a k i n g , o n l y t h e v e n t r o l a t e r a l division of n u c l e u s ambiguus can be considered to be a parasympathetic nucleus. Intermediolaterd Cell Colum~(see Fig. 5-1 4 and Figure 5-1 8) Within t h e sacral spinal cord t h e preganglionic parasympathetic neurons are located in t h e intermediolateral cell columnin spinal s e g m e n t s S2 t o S4.

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Figure 5-14 Cell bodies of parasympathetic preganglionic neurons reside in the brain stem ( A ) ,and in the lateral horn (intermediolateral cell column) of spinal cord segments S2-S4 ( B ) . Cell bodies of parasympathetic postganglionic neurons reside in small ganglia close to ( C ) , or within the walls of the target organs. In the gut, preganglionic parasympathetic neurons synapse with enteric neurons ( D ) . Some texts define a subset of enteric neurons as postganglionic parasympathetic neurons.


Their function is to supply parasympathetic innervation to t h e lower bowel a n d pelvic organs. Axons of Parasympathetic Preganglionic Neurons Project to the Parasympathetic Ganglia

Cranial Ganglia Axons of the EdingerWestphal nucleus form the parasympathetic component of the oculomotor nerve (CN 111). They travel with this nerve to the apex of the orbit, where they terminate in the ciliary ganglion (seeFig. 5- 1 5). T h e ciliary ganglion is c o m p o s e d of cell bodies of p o s t g a n g l i o n i c

parasympathetic neurons. Axons of t h e ciliary neurons form several small bundles that e n t e r t h e e y e via t h e short ciliary nerves a n d terminate on t h e ciliary m u s c l e , w h e r e t h e y a c t to c h a n g e t h e s h a p e of t h e l e n s d u r i n g accommodation, a n d o n t h e pupillary constrictor muscle, where they act t o constrict t h e pupil during accommodation a n d in response to light.

Figure 5-1 5 Signals from the Edinger-Westphal nucleus in the midbrain stimulate the parasympathetic postganglionic neurons in the ciliary ganglion to activate their target structures, the ciliary and the pupillary constrictor muscles.

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k o n s of the superior salivatory nucleus travel with branches of cranial nerve VII (facial nerve) to their target ganglia, the pterygopalatine and submandibular ganglia. The pterygopalatine ganglion is located within t h e pterygopalatine fossa, where it is attached to t h e maxillary nerve (CN V2). It is composed of cell bodies of postganglionic parasympathetic neurons. Axons from t h e pterygopalatine ganglion enter the orbit and terminate on t h e lacrimal gland where they act to stimulate tear formation (see Figs. 5-1 5 and 5-1 6). The submandibular ganglion is located in the floor of the mouth suspended from t h e lingual nerve ( a branch of t h e mandibular nerve, CN V3). Axons of submandibular neurons travel to the submandibular and sublingual glands where they act to stimulate secretion of saliva (see Fig. 5-1 5). Axons of t h e inferior salivatory nucleus travel with t h e glossopharyngeal nerve (CN IX) to the otic ganglion. The otic ganglion is located just below the foramen ovale of the skull, where it is attached t o a branch of t h e mandibular nerve (CN V3). Axons from t h e otic ganglion travel via the auriculotemporal nerve to enter t h e parotid gland, where they act to increase secretion of saliva (see Fig. 5-16).


99

Figure 5-1 6 Cell bodies of parasympathetic postganglionic neurons form the cranial parasympathetic ganglia: ( 1 ) the ciliary ganglion; ( 2 ) the pterygopalatine ganglion; ( 3 ) the otic ganglion; and ( 4 ) the submandibular ganglion.

100 Autonomic Nerves

Thoracic and AGdorninal Garzglia (see Fig. 5-1 7) Axons of the dorsal vagal and ventrolateral division of the nucleus ambiguus travel with cranial nerve X (vagus nerve). They a n d t h e enteric neurons terminate in numerous small ganglia within t h e walls of t h e thoracic and abdominal viscera, their target organs. They receive their preganglionic axons from t h e dorsal vagal nucleus and t h e ventrolateral division of nucleus a m b i g u u s , whose axons form t h e autonomic motor component of t h e vagus nerve (CN X). The vagus nerve supplies all of t h e thoracic organs and t h e gut and its associated structures (e.g., liver and pancreas) a s far distally a s the splenic (left colic) flexure, a s well a s t h e kidneys. Postganglionic parasympathetic axons are short and confined t o small areas of the target organs. They act to modulate t h e activities of cardiac and smooth muscle and to stimulate secretion of visceral glands.

Autonomic Motor Components 101

Figure 5-1 7 Thoracic and abdominal parasympathetic ganglia are located within the walls of their target structures. The vagus nerve ( C N X ) is the major parasympathetic preganglionic nerve supplying the thoracic and abdominal viscera. This figure also shows the enteric neurons.


Pelvic Gmglia (see Fig. 5-1 8) Pelvic parasympathetic ganglia are scattered within t h e superior a n d inferior hypogastric plexuses (the inferior hypogastric plexus is also called t h e pelvic p l e x u s ) , a n d within t h e walls of t h e p e l v i c o r g a n s . T h e y r e c e i v e t h e i r preganglionic axons from t h e intermediolateral cell column of segments S2 to S4 of t h e spinal cord. Their postganglionic axons are of varying lengths. They act to modulate t h e activities of smooth muscle a n d to stimulate secretion of pelvic glands.

Figure 5-18 Parasympathetic ganglia in the pelvis showing their anatomic relationship to the sensory nerves, to the sacrum, and to sympathetic chain (see also note to Figure 5-1 1 ) .

Autonomic Motor Components I03

The Enteric Division Autonomic Neurons Within the Walls of the Gut

Autonomic neurons within t h e walls of t h e gut form a semi-independent network c a l l e d t h e e n t e r i c n e r v o u s s y s t e m . T h e r e a r e a l m o s t as m a n y neurons within t h e walls of t h e gut as t h e r e a r e in t h e spinal cord. T h e s e neurons are often referred to as a third division of t h e autonomic nervous system, t h e enteric nervous system, o r enteric division (enteron meaning gut). The enteric division functions reasonably well in t h e complete a b s e n c e of input from t h e sympathetic a n d parasympathetic divisions. Its role is t o control gut motility, secretion, a n d absorption. The enteric division includes motor neurons that coordinate activation of smooth muscle, sensory neurons t h a t signal chemical c h a n g e s , p a i n , a n d d i s t e n t i o n in t h e g u t , a n d interneurons that integrate intrinsic activity a n d that receive signals from t h e sympathetic a n d parasympathetic nerves. The effects of sympathetic a n d parasympathetic stimulation of t h e enteric division are antagonistic (Table 5-2). TABLE 5-2 Sympathetic and Parasympathetic Stimulation of Enteric Division

The enteric neurons form two anatomically distinct, b u t interconnected, plexuses. The myenteric plexus (of Auerbach) is located between t h e inner circular a n d o u t e r l o n g i t u d i n a l s m o o t h m u s c l e l a y e r s (Figure 5-1 9) . It f u n c t i o n s to c o o r d i n a t e p e r i s t a l s i s a l o n g t h e g u t a n d l i n k s with t h e submucosal plexus. The submucosal plexus (of Meissner) is located in t h e submucosal layer of t h e gut. It regulates ion a n d water transport across t h e gut epithelium, a n d links with t h e myenteric plexus.(See Case Study 2: Megads C o l o ~for a more detailed discussion of t h e enteric nervous system.)


Figure 5-1 9 The enteric nervous system showing the myenteric plexus (of Auerbach) between the inner circular and outer longitudinal muscle layers and the submucosal plexus (of Meissner) in the submucosal space of the gut. The insert shows a simplified version of sympathetic and parasympathetic nerves that affect an enteric neuron. Neurons in the enteric nervous system use a variety of neurotransmitters. Enteric neurotransmitters are discussed in Chapter VI.

Autonomic Neurotransmitters, Receptors, and Effectors

VI AUTONOMIC NEUROTRANSMITTERS, RECEPTORS, AND EFFECTORS NEUROEFFECTOR MECHANISMS The autonomic functions in t h e body a r e largely carried o u t by t h e c o m b i n e d activities of a u t o n o m i c effector cells: cardiac muscle cells; secretory cells in both endocrine and exocrine glands; smooth muscle cells; and the endothelial cells of the microvasculature. Many autonomic effectors have their own intrinsic activity that is modified, b u t in most c a s e s not caused, by autonomic nerves. For example, cardiac muscle cells contract independently, t h e autonomic nerves serving t o modify t h e timing and strength of their contraction.

SYNAPTIC STRUCTURE Autonomic nerves communicate with each other by means of specialized zones of contact called synapses. The two fundamental types of synapses are chemical synapses, in which t h e presynaptic cell s e c r e t e s o n e or more chemicals - called neurotransmitters - that diffuse across a space ( t h e synaptic cleft) to affect the postsynaptic cell (Figures 6-1, 6-2, and 6-3), and electrical synapses, in which signals pass directly from one cell to another through structures called gap junctions (see Fig. 6-1, and Figures 6-4 and 6-5). Chemical synapses are by far t h e most common type of synapse in the nervous s y s t e m ; electrical s y n a p s e s a r e relatively rare. However, g a p junctions a r e prominent b e t w e e n autonomic effector cells, where t h e y function to transmit electrical signals rapidly from cell to cell so that groups of cells can co-ordinate their actions.

Figure 6-1 Transmission of signals: ( A ) in chemical synapses by secretion of one or more chemicals (neurotransmitters)that diffuse across synaptic clefts, and ( B ) in electrical synapses, directly from cell to cell via gap junctions in one or both directions.

Autonomic ~eurotransmitters, Receptors, and Effectors 107

~ r a n s ~ i s s i oofn Signals Between Pre- and Postgang~ionicAutonomic Neurons (True Synapses)

Preganglionic autonomic axons form chemical synapses upon specific regions of their target postganglionic neurons within autonomic ganglia (see Figs. 6-3A and 6-3B). Axons terminate as expansions called terminal boutons. These boutons contain synaptic vesicles (membrane-bound sacs that contain n e u ro t ra n s m i t t e r a n d n e u rom o d u I ator m ol ecu 1 e s ) a n d n u m e ro u s ~itochondria.Transmitter release occurs at specialized (active) zones in the presynaptic membrane. Ultrastructurally, these active zones are characterized by fuzzy dark thickenings that probably represent attachment sites for cytoskeletal proteins and other proteins involved in vesicle attachment and secretion. T h e synaptic cleft is 20 to 40 n m i n width. Receptors for the neurotrans~ittersare clustered in the postsynaptic cell m e ~ b r a n eopposite the active zones in areas called postsynaptic specializations. Binding of released neurotransmitters to the receptors causes a change in the electrical properties of the postsynaptic membrane, thereby transmitting the signal.

I08 A u t o n o ~ i cNerves

Transmission of Signals Between Postgan~lionicAutonomic Neurons and Effector Cells (Neuroeffector Junctions)

Like pregang~ionicneurons, postganglionic neurons signal their effector cells by secreting chemicals; however, postganglionic axon terminals do not form true synapses. The terminal part of t h e axon (i.e.,t h e part of t h e axon that branches within t h e walls of t h e target organ) is composed of a series of irregular expansions called varicosities between which are located narrower regions called i n t e ~ a r i c o s esegments. Varicosities contain synaptic vesicles a n d m i t o c h o n d r i a . Varicosities p r o b a b l y r e p r e s e n t sites of t r a n s m i t t e r release; however, presynaptic active zones similar to those in true synapses a r e almost never s e e n . Varicosities measure 1 to 3 p m in diameter a n d u p to 4 p m in length. They are fusiform in shape. The terminal 3 to 4 varicosities in a n axon are Larger than t h e proximal o n e s , a n d t h e y stain more intensely for n e u rot ran sm itt er. T h e s i z e of t h e synaptic cleft varies widely. On average, t h e d i s t a n c e between a varicosity and t h e nearest effector cell is much larger than that in a true synapse. For example; in vascular smooth muscle, nearly 40 percent of the varicosities lie between 100 a n d 200 nm from t h e presumed target cells. In s o m e other tissues, however, the cleft can be as small a s 10 to 20 nm - comparable to that of a true synapse (see Fig. 6-2). T h e effector (postjunctional) cells do not display postsynaptic specializations, a n d evidence does not suggest that receptors a r e clustered at p a r t i c u l a r sites in t h e p o s t j u n c t i o n a l m e m b r a n e . B e c a u s e of t h e s e structural characteristics, autonomic neuroeffector junctions do not act over clearly defined regions in t h e postjunctional cells, b u t rather have a more w i d e s p r e a d influence, which may e n c o m p a s s several sites o n n u m e r o u s postjunctional cells. This kind of transmission is referred to as volume transmission.

Figure 6-2 Autonomic neuroeffector junctions in rat salivary gland showing the characteristic wide variation in the size of the synaptic cleft. In ( A ) the distance from the varicosity to the nearest effector cell is approximately 90 n m , whereas in ( B ) the distance is only 15 n m - less than the distance between preand postsynaptic membranes in many true synapses. TC = target cell; V = varicosity.

Autonomic Neurotransmitters, Receptors, and Effectors I09


Transmission of Signals Among Neuroeff ector Cells (Gap Junctions)

Viewed eu face, g a p junctions a p p e a r a s patches that contain a varying n u m b e r of g a p j u n c t i o n c h a n n e l s t h r o u g h which t h e e f f e c t o r c e l l s c o m m u n i c a t e (see Fig. 6-4A). Viewed in cross s e c t i o n with a n electron microscope, g a p junctions a p p e a r a s areas in which t h e adjacent membranes are separated by a very narrow space that measures approximately 3.5 nm, i.e.,about half t h e width of standard cell membranes (see Figs. 6-4B and 6-4). G a p junction c h a n n e l s a r e formed b y two hemicylinders, o n e in t h e presynaptic membrane a n d one in t h e postsynaptic membrane. These m e e t in t h e g a p b e t w e e n t h e t w o m e m b r a n e s a n d c o n n e c t to e s t a b l i s h a continuous channel about 1.5 nm in diameter. Each hemicylinder is called a c o n n e x o n a n d is c o m p o s e d of six i d e n t i c a l p r o t e i n s u b u n i t s c a l l e d connexins, which are arranged hexagonally around t h e central channel . The channels formed by t h e connexon are usually o p e n , but they can be closed by lowered intracellular p H o r e l e v a t e d cytoplasmic calcium. It h a s b e e n s u g g e s t e d t h a t t h e o p e n i n g a n d closing of t h e channel is c a u s e d by t h e rotation of t h e connexins with respect to each other a s illustrated in Fig. 6-4.

Figure 6-4 Gap junctions are shaped approximately like pancakes. ( A ) Gap junction seen e~ face in chicken pigmented epithelial cells (courtesy of Dr H Wolburg, lnstitut f u r Pathologie der Universitat Tubingen, Germany). ( B ) Cross-sectional view of a gap junction in rat intestinal smooth muscle.

Autonomic Neurotransmitters, Receptors, and Effectors 1 1 1

Figure 6-5 Part of a gap junction between in-gut smooth muscle showing both

efl

/ace and cross-sectional views

I12 Autonomic Nerves

NEUROTRANSMISSION The process of autonomic neurotransmission is highly complex. In this text, w e will describe currently accepted principles of autonomic neuroeffector mechanisms, and we will provide examples where appropriate. Comprehensive coverage of this topic is well beyond the scope of this book, but readers are directed to relevant publications listed in the bibliography. The effect that autonomic stimulation has on effector cells depends on three major factors: The combination of neurotransmitters and neuromodulators released by the nerve; T h e type of receptors expressed by the effector cell; and T h e intracellular mechanism(s) in the effector cell that is (are)coupled to the receptor. Autonomic Neurotransmitters

Classic Autonomic Neurotransmitters The “classic”autonomic neurotransmitters, acetylcholine and noradrenaline, have been recognized and studied for the better part of a century. Acetylcholine is the major neurotransmitter secreted by both sympathetic and parasympathetic preganglionic autonomic neurons; by parasympathetic postganglonic neurons; and by sympathetic postganglionic neurons, which innervate the sweat glands and some vascular smooth muscle. Noradrenaline (and in some cases its metabolite, adrenaline) is the major neurotransmitter secreted by the majority of postganglionic sympathetic nerves (Figures 6-6, 6-8, and 6-9). Until recently, it has been customary to use adrenergic n e r v e s and cholinergic nerves as synonyms for sympathetic and parasympathetic postganglionic n e r v e s , respectively. T h i s simple model is no longer appropriate. Intensive research during the last two decades shows that other chemicals act a s co-transmitters or, i n s o m e c a s e s , a s t h e major neurotransmitter in autonomic nerves. The use of adrenevgic ueurotransmissiou and cholinergic neurotrausmission t o r e f e r t o specific c o m p o n e n t s of neurotransmission is now considered more preferable. Receu tl y Discovered Ne u rotra ns mitters In addition to t h e classic neurotransmitters, many - possibly all autonomic nerves release one or more additional chemicals that include purines, amino acids, and/or neuropeptides. T h e s e recently discovered n e u rot ra n s m it t e rs act a s c o - tra n sm i t te rs, and/or ne u YO modu la t o rs. C o transmitters are substances that are co-localized in, and co-released from varicosities. They act on their own receptors in the postjunctional cells. Neuromodulators are substances that are also co-localized in, and coreleased from varicosities, however they have no direct action on the postjunctional cells. Rather, they act to affect the prejunctional release of,

Autonomic Neurotransmitters, Receptors, and Effectors 1 13

or t h e postjunctional r e s p o n s e t o , t h e neurotransmitters. E x a m p l e s of c o - t r a n s m i s s i o n a n d n e u r o m o d u l a t i o n c a n be s e e n in sympathetic activation of vasoconstriction in cutaneous blood vessels. These nerves release noradrenaline, ATP, a n d neuropeptide Y. ATP is responsible for t h e initial twitch responses of t h e smooth muscle, whereas noradrenaline p r o d u c e s t h e longer-lasting tonic contractions. N e u r o p e p t i d e Y acts as a neuromodulator by potentiating t h e effects of ATP a n d noradrenaline in t h e vascular smooth muscle cells. Neuropeptide Y also acts as a neuromodulator in t h e vas deferens, b u t there it acts prejunctionally to inhibit t h e release of ATP a n d noradrenaline from sympathetic nerves. In addition to their role as neurotransmitters t h e classic transmitters noradrenaline a n d acetylcholine act a s neuromodulators in that they act presynaptically to inhibit their own release (Fig. 6-6). In t h e c a s e of noradrenaline, t h e presynaptic action is mediated by a 2 -ad re n erg i c receptors .

Chemical Coding of Autonomic Neurons In different populations of autonomic neurons, n e u r o p e p t i d e s co-exist in specific combinations related to their peripheral projection a n d , presumably, to their function. This observation led to t h e concept of chemical coding of autonomic neurons, t h e central premise of which is that neurons that express t h e s a m e combinations of p e p t i d e s have common autonomic target tissues a n d f u n c t i o n s ( F i g u r e 6-7). In t h e g a s t r o i n t e s t i n a l t r a c t , for e x a m p l e ; e x c i t a t o r y m o t o r n e u r o n s t o a l l l a y e r s of i n t e s t i n a l m u s c l e s e c r e t e a c e t y l c h o l i n e a n d t a c h y k i n i n s ( s u b s t a n c e P) as t r a n s m i t t e r s , w h e r e a s inhibitory motor neurons t o t h e s a m e muscles all a p p e a r t o s e c r e t e nitric oxide, ATP, a n d probably vasoactive intestinal p o l y p e p t i d e (VIP) as their transmitters.

I I4 Autonomic Nerves Figure 6-7 Innervation of the gut showing the combination of neurotransmitters and cotransmitters that are thought to characterize enteric neurons. This summary is based on work in the guinea pig by Costa et al, 1986, 1996. Please note that the co-existing substances may vary in different species and different parts of the gastrointestinal tract. 1 . Sympathetic postganglionic axons

descending from preaortic plexuses innervate enteric neurons in the myenteric and submucosal plexuses, thereby causing inhibition of the enteric motor reflex pathways, vasoconstriction, and inhibition of mucosai secretion. 2. Sensory signals from the lumen and wall of

the gut are carried in the sensory arm of local sensory neurons. These neurons activate interneurons which, in turn, activate either orally excitatory or anally inhibitory enteric motor neurons, which causes polarized contraction or relaxation of the circular and longitudinal muscle layers for peristalsis. 3. Enterofugal neurons from the gut ascend to

preaortic ganglia where they act to modulate the activity of postganglionic sympathetic neurons in a reflex loop.

4.Sensory projection neurons, probably encoding pain, project from the gut to the central nervous system with collaterals in the prevertebral ganglia.

ACh CCK CGRP DYN ENK GAL GRP NA NO NPY SOM SP VIP

Acetylcholine C holecystokini n Calcitonin Gene-Related Peptide Dynorphin Enkephalin Galanin Gastrin- Related Peptide Noradrenaline (Norepinephrine) Nitric Oxide Neuropeptide Y Somatostatin Substance P Vasoactive Intestinal Polypeptide

Autonomic Neurotransmitters, Receptors, and Effectors I I5

Auto no mic Receptors

Receptors that transduce chemical signals between pre- and postganglionic autonomic neurons, and between postganglionic neurons and effector cells, fall into two categories: Directly-gated receptors, which predominate in the ganglia, and Second messenger-linked receptors, which predominate in autonomic neuroeffector junctions. Receptors O M P o s t g a q h i c Cells T h e predominant receptor t y p e in autonomic ganglia is t h e nicotinic acetylcholine receptor. T h e nicotinic receptor is directly-gated. In this type of receptor, the molecular complex that forms the receptor also forms an ion channel. Binding of the transmitter to the receptor changes the conductance

I16 Autonomic Nerves Figure 6-8 Major neurotransmitters and receptors in sympathetic preand postganglionic neurons and effectorcells.


Figure 6-9 Simple schematic showing the major adrenergic and cholinergic receptors expressed by postganglionic neurons and effector cells. Adrenergic Receptors. At least four types of adrenergic receptors are known to exist; they are denoted as c r l , a2, P I ,and 82. Each type has a different tissue distribution and allows noradrenaline and adrenaline to elicit different responses in the effectorcells by virtue of their linkage to different intracellular processes. The tissue distribution of, and cellular response to, the receptor types is shown in Table 6-1, pg. 133. Cholinergic Receptors. Two major categories of cholinergic receptors act in the autonomic nervous system: nicotinic receptors and muscarinic receptors. Nicotinic receptors are found primarily in autonomic ganglia, where they transduce signals between pre- and postganglionic neurons. Muscarinic receptors mediate all of the postganglionic actions of parasympathetic nerves. These receptors also mediate sympathetic innervation of the sweat glands.

of t h e ion channel which, in turn, changes t h e electrical properties of t h e postganglionic cell, t h e r e b y transducing t h e signal from t h e preganglionic neuron. The nicotinic acetylcholine receptor is an intrinsic membrane protein with five subunits. Two of t h e s u b u n i t s , t h e a s u b u n i t s , a r e identical. Each a subunit b i n d s o n e molecule of acetylcholine. When both a subunits have b o u n d acetylcholine, t h e conformation of t h e p r o t e i n c h a n g e s , t h e r e b y o p e n i n g t h e ion channel a n d allowing K' a n d Na' ions to flow across t h e m e m b r a n e according to their concentration gradients (Figure 6-1 OA). This produces a depolarization of t h e membrane, which can elicit t h e generation of action potentials that are propagated along t h e axon toward t h e target organ.

Receptors at EffectorCells In t h i s family of r e c e p t o r s , t h e s e c o n d m e s s e n g e r - l i n k e d r e c e p t o r s , recognition of t h e transmitter a n d activation of t h e effectors are carried out b y distinct a n d s e p a r a t e molecules (see Fig. 6-IOB). S e c o n d messengerlinked receptors include t h e muscarinic acetylcholine receptor a n d t h e aa n d fi-adrenergic receptors. Most of t h e peptides that are co-transmitters in autonomic nerves also act through second messenger systems.

Autonomic Neurotransmitters, Receptors, and Effectors 1 19

The receptor molecule is an intrinsic membrane protein. It is linked on its cytoplasmic side with a G protein, so called b e c a u s e it b i n d s a guanine nucleotide. G proteins are a complex of t h r e e subunits, a , p, a n d y . The many different t y p e s of G proteins have different effects within t h e cell. G proteins that have stimulatory effects within t h e cells a r e indicated as Gs; those that have inhibitory effects are indicated as Gi.

Figure 6-10 Autonomic receptors are of two types ( A ) Directly-gated receptors, e g the nicotinic acetylcholine receptor, or (B)Second messenger-linked receptors, e g , the muscarinic acetylcholine receptor

In t h e resting state, G proteins exist as heterotrimers b o u n d t o a receptor. T h e a s u b u n i t is also b o u n d t o g u a n o s i n e d i p h o s p h a t e (GDP). When a receptor is activated b y a transmitter, its conformation changes, causing t h e a subunit of t h e G protein to decrease its affinity for GDP, so that GDP comes off t h e active site. Because t h e concentration of guanosine t r i p h o s p h a t e (GTP) in cells is much higher than that of GDP, t h e GDP that is leaving is r e p l a c e d with GTP. O n c e t h e GTP is b o u n d , t h e a s u b u n i t a s s u m e s its activated conformation a n d dissociates both from t h e receptor a n d from t h e py dimer. Until recently it was thought that only t h e free a s u b u n i t h a d biologic activity; however it is now known t h a t b o t h t h e free a a n d P y subunits can activate specific effector mechanisms within t h e cell. The active s u b u n i t s c a n affect i o n c h a n n e l s d i r e c t l y or t h e y c a n m o d i f y e f f e c t o r molecules, thereby producing second messengers. Common second messengers include cyclic adenosine monophosphate (CAMP)(Figure 6-1 2A) or diacylglycerol (DAG) a n d inositol triphosphate (IP,) (see Fig. 6-19). The second messenger triggers a biochemical cascade in t h e cell that can have a v a r i e t y of c o n s e q u e n c e s , i n c l u d i n g o p e n i n g o r c l o s i n g i o n c h a n n e l s , liberating Ca" from intracellular stores, altering t h e properties of transmitter receptors, or regulating g e n e expression. T h e duration of b o t h a a n d P y s u b u n i t activation is limited b y t h e GTPase activity of t h e a subunit. Once GTP is cleaved to GDP, t h e a a n d Py subunits re-associate, b e c o m e inactive, a n d return to t h e receptor.


AUTONOMIC EFFECTOR CELLS Cardiac Muscle

Pacema lieY Ce Ils The heart has its own inherent activity which is initiated a n d co-ordinated by s p o n t a n e o u s l y firing p a c e m a k e r cells in t h e wall of t h e right atrium. T h e pacemakers form t h e sinoatrial (SA) n o d e , t h e atrioventricular (AV) n o d e , a n d t h e common atrioventricular b u n d l e (of His). The conducting system consists of t h e p a c e m a k e r s , t h e left a n d r i g h t b u n d l e b r a n c h e s , a n d t h e subendocardial plexus of Purkinje cells (see Case Study 7: Michael’s Last R U Mfor a description of t h e anatomy of t h e pacemakers a n d t h e conducting system of t h e h e a r t ) . P a c e m a k e r cells a r e s p e c i a l i z e d cardiac muscle cells, t h e contractile fibers of which a r e scarce or a b s e n t (Figure 6-1 1 ) . T h e s e cells depolarize slowly by m e a n s of a gradually decliMiMg outward flow of K+ ions

Autonomic Neurotransmitters, Receptors, and Effectors 121

and an increased inward flow of Cat* ions. W h e n they reach their threshold potential, these cells produce an action potential that is propagated along t h e conducting pathways to the cardiac myocytes, thereby causing the myocytes to contract. Following t h e action potential, t h e pacemakers repolarize by activating their membrane pumps. They then begin this slow depolarization again, which leads to another action potential. This repetitive generation of electrical activity makes the heart beat. T h e S A node has the fastest rate (70 per minute at rest). T h e S A node dominates t h e other pacemakers and is therefore referred to as the pacemaker. If the SA node slows dramatically, or fails, the AV node will begin to fire at its natural rate of 50 to 60 per minute. If the AV node also fails, the pacemakers in the bundle of His will drive the heart at a slower rate of 30 to 40 per minute, which may or may not b e sufficient to maintain cardiac output and blood pressure at levels compatible with life.


Sympathetic Stimulation Increases the Rate of Action Potential Generation in Pacemaker Cells

Sympathetic nerves increase the rate of generation of action potentials in pacemaker cells by increasing the Ca++conductance during depolarization. A s a result, the flow of Ca" ions into the cell increases, thereby increasing the rate of mem brane depolarization (see Fig. 6- 1 2A). Noradrenaline released from sympathetic varicosities binds with p ,-adrenergic receptors in the cardiac myocyte membrane. The bound receptor then binds a stimulatory G protein on its cytoplasmic side, thereby liberating the cy subunit which binds with adenylyl cyclase, thereby activating it. The activated adenylyl cyclase catalyzes the conversion of ATP to CAMP. Increased cytoplasmic levels of C A M P activate t h e cytoplasmic p r o t e i n kinase ( P K A ) which i n turn phosphorylates the L-type Ca" channel, making it more likely to open during membrane depolarization.

Figure 6-12 ( A ) Sympathetic stimulation increases entry of Cat+ ions across the membrane, which increases the rate at which action potentials are generated.

Autonomic Neurotransmitters, Receptors, and Effectors I23

Parasympathetic Stimulation Decreases the Rate of Action Potential Generation in Pacemaker Cells

P a r a s y m p a t h e t i c n e r v e s d e c r e a s e t h e r a t e of g e n e r a t i o n of a c t i o n potentials b y activating K' channels, which increases t h e outward flow of K' ions, thereby effectively hyperpolarizing t h e membrane, a n d slowing its rate of d e p o l a r i z a t i o n (see Fig. 6-1 2 B ) . Acetylcholine (ACh) r e l e a s e d from p a r a s y m p a t h e t i c varicosities b i n d s with M2 muscarinic r e c e p t o r s . T h e receptor binding activates a G protein, which liberates its & subunit t o bind with t h e K' channel, thereby increasing t h e flow of K'. Potassium diffuses out of t h e cell along its concentration gradient, leaving t h e inside of t h e cell more negative.

Figure 6-12 ( B ) Parasympathetic stimulation increases the flow of K+ out of the cell, hyperpolarizing the membrane and slowing the generation of action potentials.


Cardiac Myocytes Individual cardiac muscle cells a r e elongated, branching cells that contain o n e o r two central nuclei. Their contractile filaments a r e organized into typical sarcomeres (Fig. 6-12 a n d Figure 6-13). They have a sarcoplasmic reticulum that is not a s extensive as that in skeletal muscle, b u t that is much more ordered than in smooth muscle. Transverse tubules invaginate from t h e sarcolemma in t h e region of t h e Z bands. As is fitting for an active, aerobic tissue, cardiac muscle cells have an abundance of large mitochondria, where aerobic metabolism takes place. Cardiac muscle cells a r e connected t o each o t h e r b y specialized intercellular junctional complexes called intercalated disks. The intercalated disks include three types of junctions: d e s m o s o m e s , a d h e r e n s junctions, a n d g a p junctions. D e s m o s o m e s a n d a d h e r e n s junctions s e r v e a s attachment points for t h e contractile filaments, a n d attach t h e cardiac muscle cells t o each other a n d to t h e extracellular matrix. The g a p junctions allow for rapid transmission of electrical signals between cells (see Figs. 6-4B a n d 6-5 for g a p junction structure).


Contraction of cardiac myocytes occurs when action potentials generated b y p a c e m a k e r cells i n v a d e t h e myocyte m e m b r a n e . This results in t h e opening of voltage-gated L-type calcium channels. Calcium enters t h e cell a n d c a u s e s i n c r e a s e d r e l e a s e of calcium from i n t e r n a l s t o r e s in t h e sarcoplasmic reticulum and mitochondria. Actin a n d myosin, which form t h e sarcomeres, interact in t h e p r e s e n c e of increased free calcium to c a u s e contraction. Subsequently, p u m p s located in t h e sarcoplasmic reticulum, mitochondria1 membranes, and sarcolemma act to remove calcium from t h e cytoplasmic compartment, resulting in a drop in free calcium levels. The contractile filaments n o longer g e n e r a t e mechanical force, a n d t h e sarcomeres lengthen again, which allows the heart muscle to relax. Sympathetic stimulation increases t h e strength a n d speed of cardiac m y o c y t e c o n t r a c t i o n b y i n c r e a s i n g t h e inward flow of calcium. U n d e r n o n s t i m u l a t e d c o n d i t i o n s , a p p r o x i m a t e l y half of t h e a v a i l a b l e calcium c h a n n e l s a r e inactive a n d do n o t often open during m e m b r a n e depolarization. Noradrenaline binding with t h e &-adrenergic receptors in t h e cardiac myocyte m e m b r a n e results in phosphorylation of t h e calcium

Figure 6-13 The action of ( A ) sympathetic and ( B ) parasympathetic nerves on cardiac myocytes


c h a n n e l s via t h e p a t h w a y shown in Fig. 6-13A. Phosphorylation of t h e channels has three consequences: a higher proportion of t h e channels o p e n during depolarization; t h e frequency of opening increases; a n d t h e length of t i m e t h e c h a n n e l s stay o p e n increases. In a d d i t i o n , t h e diffusible G s is thought to couple directly with t h e L-type calcium channel, making it more likely to o p e n with m e m b r a n e d e p o l a r i z a t i o n . T h e s e effects c o m b i n e d p r o d u c e a n o v e r a l l i n c r e a s e in c a l c i u m e n t r y d u r i n g m e m b r a n e depolarization which, in turn, enhances t h e contraction in t h e myocytes. P a r a s y m p a t h e t i c n e r v e s exert t h e i r m a j o r c a r d i a c e f f e c t s o n t h e pacemaker cells a n d o n atrial myocytes. Very few parasympathetic nerves reach t h e ventricles. T h e effect of parasympathetic nerves o n p a c e m a k e r cells is described o n p a g e 123. In atrial myocytes they act to decrease t h e e f f e c t s of s y m p a t h e t i c s t i m u l a t i o n b y i n h i b i t i n g p r o d u c t i o n of CAMP. Acetylcholine b i n d s M2 muscarinic receptors in t h e myocyte m e m b r a n e ; t h e s e a r e coupled to a n inhibitory G protein (Gi). The liberated cy subunit inhibits adenylyl cyclase, thereby decreasing t h e production of CAMP, which ultimately counteracts t h e effect of sympathetic stimulation (see Fig. 6-1 3B). The ultrastructural appearance of cardiac muscle is shown in Figure 6-1 4.

Figure 6-14 Ultrastructural features of cardiac myocytes. (A) Longitudinal section through parts of two adjacent myocytes showing the arrangement of the sarcomeres; ( B ) cross section of a myocyte at higher power showing mitochondria and the contractile filaments. Myosin molecules, the large filaments, are surrounded by actin molecules, the smaller filaments.


Secretory Cells

Secretion in both exocrine and endocrine glands is affected by autonomic nerves; however, the roles of autonomic nerves in endocrine gland secretion are not, as yet, well understood. Exocrine glands are found on the surface of the body (sweat and lacrimal glands) and within all the hollow organs. These glands are composed of secretory units, ducts, and surrounding connective tissue. A secretory unit is a group of secretory epithelial cells that release their secretion into a lumen, and the duct is an epithelially-lined tube that conveys the secretions from one or more secretory units onto the surface of the skin or into the lumen of the organ. T h e connective tissue of a n exocrine gland includes myoepithelial cells (specialized smooth m u s c l e cells, whose contractions squeeze the glands and help to expel their contents). Glandular epithelium is composed of two kinds of secretory cells: mucous cells and serous cells. Mucous cells secrete mucus, a thick, glycoprotein that functions in lubrication and debris entrapmenthemoval. Serous cells secrete water containing ions and, in many cases, enzymes. Individual glands can be composed primarily of mucous cells (e.g.,mucous glands of the trachea), serous cells (e.g.,sweat glands), or a mixture of both types of cells (e.g., submandibular salivary glands) (Figure 6-1 5). At rest, glandular secretion occurs at a very low rate, but it increases by as much as 1,000 to 10,000 fold in response to autonomic stimulation. For example, lacrimal glands normally secrete just enough tears to replace the amount lost by evaporation from t h e surface of t h e eye. With strong parasympathetic stimulation tear formation increases from the basal level of 0.1 pL per minute to 3 to 4 mL per minute, i.e.,more than 10,000 fold.

Figure 6-15 T h e structure of a mixed salivary gland


Parasympathetic n e r v e s supply t h e most important secretomotor stimulation to the glands, and in some glands they also act to dilate the vascular supply, thus increasing blood flow to replenish the cells' water and ions during secretion. Sympathetic nerves play a minor role in glandular secretion. In t h e parotid gland, for example, sympathetic stimulation increases the amount of amylase secreted in the saliva. Glandular secretion is elicited by release of ACh from secretomotor postganglionic parasympathetic nerves. Acetycholine binds with muscarinic receptors on the basal surface of secretory cells. T h e glandular muscarinic receptors are coupled to C proteins that activate phospholipase C (PLC). T h e y release the diffusible second-messenger inositol triphosphate (IP3). IP binds with receptors on the endoplasmic reticulum, causing the release of C$+ from intracellular stores. Increased intracellular Ca" activates K' and C1channels in the luminal membrane, allowing efflux of these ions. Water follows down an osmotic gradient. At t h e s a m e time Ca" induces exocytosis of secretory granules that contain the secretion product of the cell (Figure 6-16).

Figure 6-16 The action of postganglionic parasympathetic nerves on exocrine gland cells

A u t o n om i c N e u rot ra n s m it t e r s , Receptors , a n d Effectors .I2 9

Smooth Muscle Cells

Smooth muscle cells are found in the walls of all the hollow viscera including the blood vessels, the iris and ciliary muscles of the eye, and in the s k i n as arrectores pilorum muscles. Smooth muscle cells are capable of partial contraction and can maintain tension almost indefinitely; therefore, t h e y have the contractile characteristics that make them ideal for regulating the luminal diameters of hollow organs and blood vessels. Individual smooth muscle cells (Figure 6-1 7) are long, ribbon-like cells, which are tapered at both ends. They have long central rod-shaped nuclei. T h e mitochondria, endoplasmic reticulum ( E R ) , and Golgi apparatus occupy the perinuclear region. Contractile and cytoskeletal filaments occupy the remaining cytoplasm. T h e surface membrane of the smooth muscle cell is highly ordered. Rows of caveolae, running longitudinally in the cell, alternate with rows of membrane-associated dense bodies. T h e caveolae are flaskshaped invaginations of the cell membrane (Figure 6-19). They are thought to b e t h e smooth muscle counterpart of T tubules. D e n s e b o d i e s are electron dense areas on the cell surface and within the cytoplasm. T h e s e serve as attachment points for intracellular contractile and cytoskeletal proteins. T h e membrane-associated dense bodies probably also function as anchor points to the surrounding extracellular matrix.

Figure 6-1 7 Ultrastructural features of smooth muscle cells in a rat aorta. ( A ] Low power view showing parts of four cells. The convoluted nucleus is typical of a contracted smooth muscle cell. Organelles occupy the central part of the cell The extracellular material, which consists mainly of collagen and elastin fibers, is secreted by the smooth muscle cells; (B)high power view of two adjacent cells. On the cell membrane alternating areas of caveolae and membrane-associated dense bands can be seen. Contractile filaments occupy much of the cytoplasm.


The three-dimensional arrangement of smooth muscle cells varies with site and function. In blood vessels and airways, in which diameters change, force is a p p l i e d circumferentially. Accordingly, smooth muscle cells a r e arranged in circular layers, their number varying with the size of the bronchus or vessel. In organs that display peristalsis, such a s the gut, oviduct, ureter, a n d v a s d e f e r e n s , force is a p p l i e d a l t e r n a t e l y i n circumferential a n d longitudinal directions (see Case Study 2: Megaits COIOM). Accordingly, smooth muscle cells are arranged in two main layers, an inner circular o n e and an outer longitudinal one. In t h e gut, especially, this arrangement is highly o r d e r e d (Figure 6-18). In t h e urinary a n d gall b l a d d e r s , whose overall dimensions change, force is applied from all directions towards the lumen of t h e organ. Accordingly, s m o o t h muscle cells a r e arranged much m o r e randomly and are interlaced.

Figure 6-18 Smooth muscle cells in the wall of a rat intestine are seen in cross section in the inner, circular layer and in longitudinal section in the outer, longitudinal layer.

Autonomic Neurotransmitters, Receptors, and Effectors 13 I

T h e contraction of s m o o t h muscle likely occurs d u e to t h e interaction between actin a n d myosin filaments a n d is triggered by a rise in intracellular Ca" concentration. The mechanisms by which smooth muscle cell activity is modulated to m e e t t h e diverse n e e d s of t h e b o d y are numerous a n d as yet o n l y i n c o m p l e t e l y u n d e r s t o o d . F u r t h e r m o r e , t h e a c t i o n s of t h e m a j o r transmitters, noradrenaline a n d acetylcholine, a r e modified b y cot r a n s m i t t e r s t h a t differ in different s i t e s . For e x a m p l e , sympathetically induced vasoconstriction can involve u p to three phases, each mediated by a different neurotransmitter. Since a comprehensive review of this rapidly evolving field is beyond t h e s c o p e of this text, we have chosen to describe two mechanisms: t h e intracellular events that follow binding of noradrenaline with a , adrenoceptors in vascular smooth muscle, causing contraction (Fig. 6-19) a n d t h e e v e n t s t h a t follow b i n d i n g of n o r a d r e n a l i n e w i t h p 2 adrenoceptors in pulmonary smooth muscle causing relaxation (Figure 6-20).

Figure 6-1 9 Sympathetic nerve stimulation causes vascular s m o o t h muscle contraction using IP, a s a second messenger


In vascular smooth muscle (see Fig. 6-19), noradrenaline released from sympathetic varicosities binds with the a ,-adrenergic receptors which are coupled to G proteins that activate phospholipase C, thereby releasing the diffusible second-messenger IP,. Inositol triphosphate binds with receptors on the endoplasmic reticulum, thereby causing the release of Ca" from intracellular stores. Increased free intracellular Ca" associates with the actin and myosin filaments to mediate smooth muscle contraction. In pulmonary smooth muscle (see Fig. 6-20), noradrenaline released from sympathetic varicosities (and inhaled p, agonists - see Case Study 8: Patty's Puffer) binds to p2 receptors on smooth muscle cells. T h e p2 receptors are coupled with the cAMP/PKA second-messenger system described on page 122. Increased levels of PKA are thought to phosphorylate a large K' channel, which allows efflux of K' from the cell, thereby hyperpolarizing its membrane, which, in turn, inhibits transmission of action potentials and entry of Ca" and allows the relaxation of the smooth muscle.

Fig. 6-20 Sympathetic nerve stimulation causes bronchiolar smooth muscle relaxation by increasing the outward flow of K', thereby hyperpolarizing the cell membranes and decreasing the chance that an action potential will be propagated.

Autonomic Neurotransmitters, Receptors, and Effectors 133 Table 6-1 Summary of Adrenergic and Cholinergic Receptor Types and Their Effects on Target Cells.

ACh = Acetylcholine; CAMP = Cyclic adenosine monophosphate; Gs = Stimulatory G protein; Gi = Inhibitory G-protein; IP, = lnositol triphosphate; [Ca++]i= Internal (cytoplasmic) calcium concentration; NO = Nitric oxide, also known as endothelialderived relaxing factor (EDRF).

Case Study I

“FIGHT OR FLIGHT”-ANXIETY: MARGARET AND MATTHEW CASE HISTORY: MARGARET During her first visit to a Caribbean country, Margaret MacKenzie, a 35year-old woman, d e c i d e d to try snorkeling over a local coral reef. Although s h e e n j o y e d t h e fascinating plants a n d fishes, s h e found t h e t a s t e of salt water unpleasant a n d was having trouble maintaining h e r orientation a n d position in t h e waves. Margaret lifted her h e a d u p a n d noticed that s h e was drifting further a n d further from shore. with a start s h e realized that t h e tide was going out. S h e could hear her breath whistling through h e r snorkel, a n d s h e noticed that her breathing rate was fairly fast a n d getting faster. Shortly thereafter s h e noticed that her heart h a d begun to pound. Margaret d e c i d e d to swim in to shore. Although not usually a strong swimmer, Margaret found u n e x p e c t e d r e s e r v e s of s t r e n g t h t h a t e n a b l e d h e r to swim a g a i n s t t h e outgoing tide. When s h e arrived on t h e beach s h e was pale, breathing hard, a n d her heart was racing. Over t h e next few moments her color, a n d her heart a n d respiratory rates began t o return to normal.

GUIDING QUESTIONS 1 . What is t h e “Fight or Flight” reaction? 2. What mechanisms caused Margaret’s circulatory changes? 3. How can Margaret’s increase in energy be explained? 4. What mechanisms caused Margaret’s respiratory changes?

Case Study 1

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“Fight or Flight”-Anxiety:

Margaret a n d M a t t h e w

CASE HISTORY MATTHEW Matthew was a first-year student in a medical illustration program. As part of his education, h e was required to attended an autopsy with his class. This was to b e his first experience viewing a dead human body, and h e was apprehensive about it for days in advance. A s h e was attempting to sketch the great vessels of the heart, h e noticed that his breathing rate was fast and getting faster. At the same time, h e noticed that his heart had begun to race, that h e was sweating despite the cool temperature, and that h e was feeling lightheaded and nauseous. His professor, noticing that Matthew was pale and his pupils were dilated, led him to a chair outside the autopsy room. She handed Matthew a paper bag and recommended that h e breathe into it for a few minutes. Soon Matthew’s lightheadedness and nausea began to subside and his respiratory and heart rates began to return to normal.

GUIDING QUESTIONS 1 . How does anxiety relate to the “Fight or Flight” reaction? 2. why was Matthew pale and sweating? 3 . Why did Matthew feel lightheaded? 4. How did breathing into a paper bag relieve Matthew’s symptoms?

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Figure CSI-I The "Fight or Flight" reaction.

C a s e S t u d y 1 - “Fight or Flight”-Anxiety:

M a r g a r e t a n d M a t t h e w 137

DISCUSSION: MARGARET 1 . What is the “Fight or Flight” reaction?

T h e “Fight or Flight” reaction is a physiologic response to a real or perceived threat to one’s safety. Depending on the nature of the threat, the person either mounts a defense (fight) or attempts to escape from the threat (flight).Both fight and flight require sudden, vigorous muscle action. The body prepares itself for action in the following ways (Figure CS 1-1 ): Phase One: The Sympathetic Cascade is Activated A. Perception of Fear in the Cerebral Cortex. Activating signals are sent via the hypothalamus to the sympathetic preganglionic neurons in the spinal cord which, in turn, activate:

Chromaffin cells in the adrenal medulla ( A l ) ; and Sympathetic postganglionic neurons throughout t h e body (A2). Phase Two: Massive Quantities of Sympathetic Neurotransmitters are Released B. Release of Neurotransmitters. T h e adrenal medulla releases mainly adrenaline into circulating blood ( B 1 ) ; and Sympathetic postganglionic nerve endings release mainly noradrenaline into the synaptic spaces around the effector cells (B2). Adrenaline has essentially the same effects in the body as noradrenaline, but its effects last about 10 times as long because it is not removed from the blood as quickly as is noradrenaline.

Phase Three : C irc u la ting and Locally - released N e u rot ra nsrn it te rs Cause the Following Body Changes C. Changes in Muscle Activity. Intense muscle activity requires energy and an increase in oxygen delivery and carbon dioxide removal. These requirements are met by: T h e breakdown of glycogen in the muscle to produce glucose ( C l ) ; and Dilation of the blood vessels in the muscle to promote delivery of oxygen and removal of carbon dioxide (C2).

Dilation of muscular vessels is mainly caused by local metabolites resulting from vigorous action.


D. Changes in Liver Activity. Glucose that provides extra energy for muscle action is also made available b y hepatocytes in t h e liver. Hepatocytes release their glucose into the circulation so that it can be carried to the contracting muscles (glycogenolysis).

E. Changes in Heart Activity. The rate and stroke volume of the heart increase to meet the demands of the muscles for increased blood supply (see Fig. CS1-1 and Figure CS1-2). Adrenaline and noradrenaline act on cardiac p , receptors to increase the rate of discharge of the sinoatrial (SA) node, to decrease the conduction time through the atrioventricular (AV) node, and to increase the excitability of the conducting bundles and cardiac muscle cells ( E 1 ) . In addition, the blood flow to the heart muscle itself is also increased by the vasodilatory action of adrenaline and noradrenaline on p2receptors on smooth muscle cells in the coronary vessels (E2). For more information on the innervation of the heart, see Case Study 7: Michael’s Last RUM. F. Changes in the Lungs. Increased oxygen concentration in the blood and removal of carbon dioxide are accomplished by increasing the respiratory rate and volume and by dilating the bronchi ( F l ) . Blood flow to the lungs is also increased b y the action of adrenaline and noradrenaline on p2receptors on smooth muscle cells in the pulmonary vessels (F2).

G. Other Changes. As part of the “Fight or Flight” reaction, the autonomic

nervous system also causes the following: Dilation of the pupils’ ( G l ) ; Erection of body hair’; Vasoconstriction in the skin and viscera, thereby making more blood available for the muscles (G2);and Sweating, which helps dissipate the heat produced by intense muscle activity. In Margaret’s case, the cool surrounding water would make sweating unnecessary, but see what happens to Matthew. 2. What mechanisms c a u s e d Margaret’s circulatory changes?

Fear of being washed out to sea was perceived in the frontal lobes of Margaret’s cerebrum and sent to widespread areas in her brain, including her hypothalamus. Signals coordinated i n h e r hypothalamus w e r e sent via sympathetic pathways to all of the sympathetically innervated structures in the body, including h e r adrenal medulla, which responded by secreting large amounts of adrenaline into her blood. Both direct sympathetic stimulation and circulating adrenaline acted on adrenergic receptors in her heart and blood vessels. I .?

Obviously t h e s e reactions do n o t h e l p h u m a n b e i n g s m o u n t a d e f e n s e o r escape from a threat. T h e y w e r e inherited from o u r p r i m a t e a n c e s t o r s in which t h e y functioned to m a k e t h e animals a p p e a r m o r e threatening, which, in turn, h e l p e d t h e m d e f e n d t h e m s e l v e s b y intimidating t h e i r p r e d a t o r s .

C a s e S t u d y 1 - “Fight o r Flight”-Anxiety:

Figure CSI-2 Sympathetic nerves to t h e h e a r t

Margaret a n d M a t t h e w I39


Signals bound for Margaret’s heart descended through her spinal cord to preganglionic sympathetic neurons in the intermediolateral cell column in spinal segments TI to T5. Signals passed via the preganglionic axons to the sympathetic chain w h e r e they synapsed in t h e cervical and upper five thoracic ganglia. From the ganglia, postganglionic sympathetic cardiac nerves carried signals to h e r heart to act on the sinoatrial node (pacemaker) and directly on the cardiac muscle cells. Neuronal and hormonal stimulation caused an increase in the rate and strength of Margaret’s heart beat (see Figs. CSI-1 and CS1-2). To support the increased workload of the cardiac muscle, the coronary vessels w e r e dilated by the vasodilatory action of adrenaline on p2receptors on vascular smooth muscle cells. Within Margaret’s skin and visceral vascular beds, neuronal and hormonal

Figure CSI-3 Constriction or dilation of vascular beds in various areas of the body is controlled by contraction or relaxation of vascular smooth muscle. Perfusion of capillary beds is controlled by the precapi I lary sphincters

Case Study 1

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“Fight o r Flight”-Anxiety:

M a r g a r e t and M a t t h e w 141

stimuli caused constriction of the precapillary arterioles (Figure C S 1-3), decreasing blood flow and increasing blood pressure, and of the large veins (capacitance vessels), causing an increase in venous return to the heart. At the same time, within h e r muscles, the accumulation of local metabolites and circulating adrenaline caused dilation of the blood vessels. As a result, blood flow to h e r muscles increased to enhance t h e delivery of oxygen and nutrients and the removal of waste products. Also the blood flow to h e r skin was reduced, giving h e r a pale appearance. Margaret’s vascular changes were coordinated with h e r physical activity by the cardiovascular center in h e r brain stem. T h e cardiovascular center receives signals from ( 1 ) the motor areas of Margaret’s brain that initiate voluntary movement, from the hypothalamus and ( 2 ) from receptors in the muscle that sense the degree of activity of the contracting muscles. T h e cardiovascular center uses this information to constantly modify the motor signals back to the vascular system. 3. How can Margaret’sincrease in energy be explained?

Margaret’s increased energy came from glucose - a fuel that can b e rapidly converted to energy by the cells. Muscle and liver cells store large amounts of glucose in the form of glycogen. In the muscle cells, circulating adrenaline encourages the breakdown of glycogen (glycogenolysis) to glucose-6-phosphate (Figure CS 1-4). Since glucose-6-phosphate cannot pass through cell membranes readily, it stays within the muscle cells, w h e r e it is metabolized to produce energy.


In the liver hepatocytes, circulating adrenaline and noradrenaline released from sympathetic nerves also encourage t h e breakdown of glycogen t o g l u c o s e - 6 - p h o s p h a t e . Liver cells a l s o contain t h e e n z y m e , glucose-6p h o s p h a t a s e , which removes t h e p h o s p h a t e from glucose-6-phosphate, producing glucose. Glucose is able to pass through cell membranes readily; therefore, it moves out of the liver into the circulating blood. It is carried to the muscle cells where it provides an additional source of energy (see Fig. CS1-4). 4. What mechanisms caused Margaret’s respiratory changes? (Figure CS 1-5)

The circulatory and respiratory systems work together; therefore, when Margaret’s hypothalamus s e n t stimulatory signals t o h e r cardiovascular centers, it also stimulated t h e respiratory centers in t h e brain stem. As a result, her lungs increased t h e exchange of respiratory gases between t h e air and her blood. Circulating adrenaline and sympathetic stimulation acted: On the pzreceptors in the bronchiolar smooth muscle cells, allowing them to relax and thereby allowing the bronchioles to dilate, which, in turn, allowed a greater volume of air to be moved in and out of the lungs (A). On the p2 receptors in the smooth muscle cells in the walls of the pulmonary blood vessels, allowing them to dilate and thereby to increase blood flow to the lungs (B). Activation from the respiratory center acted: To increase t h e rate and depth of diaphragmatic movements (via t h e phrenic nerves), thereby increasing the volume of the thoracic cavity, which, in turn, increased t h e volume of air that was moved in and out of the lungs ( C ) . To increase the rate of movement of external intercostal muscles (via intercostal spinal nerves) in concert with the diaphragm to further increase t h e volume of air that was moved in and out of t h e lungs (D).

Case Study 1

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“Fight or Flight”-Anxiety:

Margaret and M a t t h e w 143

Figure CSl-5 Sympathetic signals t o the lungs arise in the intermediolateral cell column of spinal cord segments T1-T6. Preganglionic axons synapse in the cervical or upper thoracic sympathetic ganglia. Postganglionic axons travel to the lungs via the pulmonary plexus. Signals from the respiratory centers in the brain stem travel caudally in the spinal cord t o the paired phrenic nuclei in spinal segments C3-C5 and t o the motor neurons that control the intercostal muscles in segments TI-T12.Axons from the phrenic nuclei form the phrenic nerves, which descend through the thorax on either side of the heart to innervate the diaphragm. Sympathetic pathways are shown on the left side of the illustration and the somatic pathways are shown on the right.


DISCUSSION: MATTHEW 1 . How does anxiety relate to the “Fight or Flight” reaction?

Many of the physiologic changes that took place in Margaret’s body were elicited by h e r “Fight or Flight” reaction. In Margaret’s case, h e r fear of washing out to sea was a realistic one, and h e r “Fight or Flight” reaction almost certainly saved h e r life. T h i s reaction can also b e elicited by perceived fear (anxiety),as is illustrated by Margaret’s brother, Matthew. A s a result of his fear, Matthew’s sympathetic nerves w e r e activated and his adrenal medulla secreted a surge of adrenaline, which caused the same physiologic changes in his body as Margaret experienced in hers. 2. Why was Matthew pale and sweating?

Circulating adrenaline and sympathetic signals to Matthew’s skin caused vasoconstriction and activation of his sweat glands. T h e decrease in blood flow to his s k i n made him a p p e a r pale. T h e low blood flow and sweat production made his skin feel cold and clammy. This phenomenon is often referred to subjectively as a “cold sweat.” 3. Why did Matthew feel lightheaded?

Circulating adrenaline and sympathetic signals also caused an increase in Matthew’s breathing rate. Unlike Margaret, however, h e was not involved in strenuous physical activity that would have generated additional CO,; therefore, his increased breathing rate (hyperventilation) resulted in a drop of CO, in his blood. Low levels of CO, in the blood flowing to Matthew’s brain caused the blood vessels there to constrict, which effectively deprived his brain of some of the oxygen it needed, giving him a lightheaded feeling. Feelings of nausea generally accompany lightheadedness, but the mechanism that mediates this is unknown. 4. How did breathing into a paper bag relieve Matthew’ssymptoms?

Breathing into a paper bag forced Matthew to rebreathe his own expired air, which contained increasing amounts of CO,. Eventually the CO, in his blood built up to a level at which it acted as a vasodilator, relaxing the cranial blood vessels and allowing the delivery of adequate levels of oxygen to his brain (Figure CS 1-6).

Case Study 1

- "Fight

o r Flight"-Anxiety:

Margaret a n d M a t t h e w

Figure CSI-6 CO, changes in the blood during "Fight or Flight" and anxiety. The graphs above each figure represent changes in the blood concentration of CO, in mm Hg. ( A ) Normal breathing at rest. before she became alarmed, Margaret's body was producing physiologic amounts of carbon dioxide (CO,).The amount of expired CO, balanced its production, and Margaret's blood contained a constant CO,concentration. (B)Normal breathing during exercise: during Margaret's flight t o the beach, her vigorous muscle action produced increased CO, Consequently, h e r breathing rate increased so that more CO, would be expired, and she continued t o maintain a constant CO, concentration in her blood ( C ) Breathing plus anxiety ( n o exercise) during his anxiety attack Matthew began t o breathe rapidly and began to lose more CO, than his relatively inactive body was producing. Consequently, CO, levels in his blood began t o drop, thereby causing Matthew's blood vessels to constrict and blood flow to his brain to drop below the levels necessary for good neuronal function. Consequently, Matthew began to feel lightheaded. Eventually he would have lost consciousness ( D ) Restoring blood CO,: by breathing into a paper bag, Matthew was forced t o rebreathe some of his own expired air Because his body was producing some CO,,the concentration of CO, in the paper bag began to increase, and eventually Matthew was breathing enough CO, to bring his blood levels back up to physiologic levels. His vessels redilated, and blood flow t o the brain increased, restoring his neuronal function to normal.

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C a s e Study 2 MEGAN’S COLON CASE HISTORY A worried Mrs. Hirschsprung brought her 12-year-old daughter, Megan, to

h e r f a m i l y d o c t o r . M e g a n h a d a h i s t o r y of s e v e r e c o n s t i p a t i o n w i t h intermittent, explosive diarrhea a n d frequent bouts of colitis (inflammation of t h e colon). S h e had b e e n vomiting for t h e last 12 hours. What particularly worried Mrs. Hirschsprung was that Megan hadn’t had a bowel movement in more than 2 weeks. When t h e doctor examined Megan h e found that s h e was small for her a g e a n d that her a b d o m e n was quite prominent. H e could feel particularly active peristalsis in her large colon. T h e d o c t o r a r r a n g e d f o r r a d i o g r a p h s of M e g a n ’ s a b d o m e n a n d , subsequently, for a barium e n e m a . T h e radiographs showed that Megan’s rectum was narrow a n d empty, b u t that t h e sigmoid colon proximal to t h e rectum was massively d i s t e n d e d . To confirm his preliminary diagnosis t h e d o c t o r a r r a n g e d for b i o p s y s a m p l e s to be t a k e n from v a r i o u s a r e a s of Megan’s colon.

GUIDING QUESTIONS 1. Describe peristalsis, t h e mechanism by which t h e contents of t h e gut are

moved along. 2. What group of intrinsic nerves coordinates intestinal peristalsis? 3. What is t h e embryonic origin of t h e s e intrinsic nerve cells? 4. What extrinsic nerves also affect movement through t h e gut? 5. What did Megan’s biopsy show? 6. What caused t h e blockage in Megan’s gastrointestinal tract? 7. What is t h e n a m e of t h e condition shown in Megan’s radiograph?

Case Study 2 - Megan's Colon 147

CASE DISCUSSION 1. Describe peristalsis, the mechanism by which the contents of the gut

are moved along. T h e wall of t h e gastrointestinal tract i n c l u d e s two layers of s m o o t h muscle, an outer longitudinal layer, a n d an inner circular layer. When a bolus of food e n t e r s t h e gastrointestinal tract, t h e walls around it a r e stretched. This mechanical stretching s e t s u p a reflex in which t h e circular s m o o t h muscles just proximal t o t h e bolus contract a n d t h e longitudinal muscles relax, which p u s h e s t h e bolus further along. At t h e s a m e time, t h e circular muscles distal t o t h e b o l u s relax a n d t h e longitudinal muscles contract, making room for t h e bolus (Figure CS2-1). Movement is further facilitated by a l a y e r of lubricating m u c u s s e c r e t e d b y t h e m u c o u s g l a n d s in t h e g u t epithelium.

Figure CS2-I Schematic interpretation of the actions of the circular and longitudinal smooth muscle layers of the gastrointestinal tract during peristalsis.


2. What group of intrinsic nerves coordinates intestinal peristalsis?

P e r i s t a l s i s is c o o r d i n a t e d b y t h e e n t e r i c n e r v o u s s y s t e m , a highly specialized network of nerve cell bodies a n d their axons, which forms two n a m e d plexuses: t h e myenteric (Auerbach’s) plexus a n d t h e submucosal ( M e i s s n e r ’ s ) p l e x u s . T h e m y e n t e r i c plexus c o o r d i n a t e s gastrointestinal motility. It is located between t h e longitudinal a n d circular layers of smooth muscle in t h e wall of t h e gut. The submucosal plexus controls t h e secretory function of t h e m u c o s a . T h e s u b m u c o s a l p l e x u s is f o u n d b e t w e e n t h e innermost layer of smooth muscle a n d t h e mucosa. The enteric neurons that coordinate movement in t h e gut fall into three functional c l a s s e s : s e n s o r y n e u r o n s , i n t e r n e u r o n s , a n d m o t o r n e u r o n s . Stretching of t h e wall by a bolus is d e t e c t e d by sensory “command” neurons which project t o both excitatory a n d inhibitory interneurons, which, in turn, either excite or inhibit t h e motor neurons to t h e appropriate layer of smooth muscle (Figure CS2-2).

C a s e Study 2 - M e g a n ' s C o l o n

Figure CS2-2 Neurons in the myenteric plexus that affect peristalsis. The command neuron ( 1 ) located proximal to the bolus signals an inhibitory interneuron (2),which:

Inhibits inhibitory motor neurons ( 3 ) t o the circular muscle causing contraction, and Inhibits excitatory motor neurons ( 4 ) to longitudinal muscle causing relaxation. Distal to the bolus. the command neuron ( 1 I signals an excitatory interneuron (5),which: Excites inhibitory motor neurons ( 6 )to the circular muscle causing relaxation, and Excites excitatory motor neurons ( 7 )to longitudinal muscle thereby causing contraction.

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3. What is the embryonic origin of these intrinsic nerve cells?

The neurons that form t h e enteric nervous system are neural crest cells t h a t h a v e migrated from t h e d e v e l o p i n g neural t u b e into t h e gut during embryogenesis. T h e neural crest cells c o m e from two a r e a s of t h e neural t u b e . Those that colonize t h e esophagus, stomach, small intestine, a n d t h e ascending a n d transverse colons migrate from t h e future brain s t e m region (rhombencephalon) into t h e cranial parts of t h e gut, a n d from t h e r e t h e y migrate caudally within t h e gut wall. Those that colonize t h e descending a n d sigmoid parts of t h e colon a n d t h e rectum migrate from t h e sacral regions of t h e neural t u b e into t h e gut, a n d t h e n rostrally as far as t h e splenic flexure (Figure CS2-3). 4. What extrinsic nerves also affect movement through the gut?

Although t h e enteric nervous system functions in a highly i n d e p e n d e n t m a n n e r , its activities c a n be a l t e r e d b y s i g n a l s from s y m p a t h e t i c a n d parasympathetic nerves. Sympathetic signals from postganglionic neurons in t h e preaortic ganglia: Inhibit t h e enteric motor neurons, slowing peristalsis; Constrict t h e intestinal sphincters via direct innervation of sphincteric smooth muscle; Actively adjust t h e resistance of t h e gastrointestinal vasculature, which is part of their role in maintaining cardiovascular homeostasis; a n d Tonically inhibit secretomotor neurons in t h e submucosal ganglia. Below t h e diaphragm, efferent parasympathetic axons from t h e vagus nerve (CN X) to t h e gut a r e few in number, b u t t h e y have pronounced, wellknown effects in t h a t t h e y e n h a n c e gastric motility, relax t h e sphincters, a n d a r e secretornotor, mainly to t h e stomach. It h a s b e e n postulated that vagal efferents may act o n t h e command neurons (see Fig. CS2-2), t h e r e b y allowing for a widespread action of relatively few vagal axons. (Kirchgessner a n d Gershon, 1989.)

C a s e Study 2 - M e g a n ' s C o l o n

15 1

Region of Foregut

Superior, middle and inferior cervical ganglia

Aorta

Preaortic ganglion Region of midgut

Chromaffin cells of adrenal medulla Region of hindgut

Figure CS2-3 Axial origin and migration of neural crest cells to form the enteric ganglia. ( 1 ) Neural crest cells from the brain stem region form all of the enteric ganglia as far caudal a s the future transverse colon. ( 2 ) Neural crest cells from the sacral spinal cord form the caudal enteric ganglia.


5. What did Megan’s biopsy show?

W h e n a small sample of Megan’s rectal wall was examined under the microscope, nerve cell bodies of the myenteric and submucosal plexuses were very sparse or absent. During early development, the neural crest cells that should have colonized Megan’s rectum failed to do so. Whether this was the result of a defect in neural crest cell migration into the walls of the gut, or a failure of neural crest cells to survive once they arrived there, is not known. 6. What caused the blockage in Megan’s gastrointestinal tract?

Since there were few enteric neurons in Megan’s rectum, no coordinated peristalsis was present to carry feces through the denervated segment. Fecal matter accumulated proximal to the denervated area, expanding the normal parts of h e r colon. W h e n pressure proximal to the denervated segment was sufficiently high, feces were forced through the rectum explosively, resulting in overflow diarrhea. T h e chronic stasis of feces in the expanded colon allowed overgrowth of normal bacteria, resulting in Megan’s recurring colitis. Because of these chronic digestive problems, Megan’s nutritional status was not good, and she had not grown as much as she should have. 7. What is the name of the condition shown in Megan’s radiograph?

Figure CS2-4A shows the results of Megan’s barium enema. H e r narrow rectum and grossly expanded sigmoid colon can b e seen readily. For comparison, the results of a barium enema performed on a normal child of the same age are shown in Fig. CS2-4B. Since the colon proximal to the denervated segment is grossly expanded, this disease is called megacolon. It is also called aganglionic colon, since the enteric ganglia are sparse or absent in the affected segment, or Hirschsprung’s disease, after Harald Hirschsprung ( 1830- 19 16)’who first described the condition in 1886. Because Megan was born with this disease, it is said to b e congenital (present at birth). In more than 90 percent of cases of congenital megacolon, the denervated segment of gut is the rectum or lower sigmoid colon. Current treatment for this disease includes removal of the aganglionic segment of bowel and joining the normal bowel segments together.

Case Study 2 - Megan's Colon

Figure CS2-4 ( A ) A barium enema of Megan s colon Her rectum ( 1 ) IS small and narrow but her sigmoid colon ( 2 ) is grossly distended ComDlete filling of the sigmoid colon with the contrast agent is prevented by the accumulation of feces ( B ) a barium enema of a normal child approximately the same age as Megan showing normal dimensions of the rectum ( 1 ) and the sigmoid colon ( 2 ) (Radiographs courtesy of Dr David A Stringer B C Children s Hospital Vancouver B C )

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Case Study 3 VICTORIA AND THE VICIOUS HOT DOG: EMESIS CASE HISTORY Victoria, a 14-year-old high school student, purchased a hot d o g from an o u t d o o r food v e n d o r for lunch. L a t e r t h a t a f t e r n o o n s h e b e g a n to feel nauseous, a n d her skin was pale a n d d a m p . Her heart was beating rapidly a n d s h e felt dizzy a n d weak. Her mouth k e p t watering, a n d tears were causing her mascara to run. S h e rushed to t h e washroom a n d was sick t o her stomach.

GUIDING QUESTIONS 1 . Which motor nerves coordinate movement through t h e gut?

2. which gastrointestinal events take place during vomiting? 3. which brain s t e m center coordinates vomiting? 4. which somatic motor pathways are involved in t h e vomiting reflex? 5. Which autonomic motor pathways are involved in t h e vomiting reflex? 6. How do sensory signals that elicit vomiting reach t h e emetic center in

t h e brain s t e m ? 7 . How do toxins in t h e blood reach t h e emetic center in t h e brain s t e m ? 8. What are antiemetics a n d how do they work? 9. What explains Victoria’s pallor, clammy skin, rapid heart rate, a n d dizziness? 10. What causes Victoria’s excessive mouth-watering a n d tearing?

Case Study 3 - Victoria and the Vicious Hot Dog: Emesis 155

CASE DISCUSSION I . which motor nerves coordinate movement through the gut?

M o v e m e n t through t h e g u t r e q u i r e s a c o m p l e x interplay of somatic, e n teric, sympathetic, a n d parasympathetic nerves. M o v e m e n t at t h e oral a n d a n a l e n d s of t h e g u t is controlled b y t h e somatic nervous system. As food is chewed a n d swallowed, it is p u s h e d into t h e oropharynx b y t h e tongue. This movement is voluntary. Movement of t h e bolus into t h e pharynx stimulates t h e deglutition centers in t h e brain s t e m , eliciting complex involuntary activity of t h e pharyngeal muscles. Although t h e s e movements are involuntary, t h e signals to t h e muscles a r e carried b y somatic nerves. T h e respiratory passageways close, a n d breathing stops temporarily, so that food does not e n t e r t h e lungs. These movements propel food into t h e esophagus. O n c e t h e food e n t e r s t h e e s o p h a g u s , t h e e n t e r i c c o m p o n e n t of t h e autonomic nervous s y s t e m t a k e s o v e r a n d t h e bolus is m o v e d along b y peristalsis. Enteric receptors in t h e mucosa lining t h e gut a r e activated b y stretching of t h e luminal walls, hormones, a n d electrolytes. T h e s e sensory enteric neurons, acting via interneurons, activate motor neurons to t h e gut musculature, such that t h e gut wall proximal to t h e bolus contracts to push it along, a n d t h e gut wall distal t o t h e bolus relaxes to accommodate it (see Figure CS2-1 Case Study 2: Megau’s C O ~ ) . When t h e waste products resulting from digestion ( t h e fecal mass) reach t h e lower rectum, anorectal stretch receptors a r e activated. These, in turn, elicit relaxation of t h e internal anal sphincter via t h e autonomic nervous system a n d contraction of t h e diaphragm a n d abdominal wall musculature via t h e somatic nervous system. The resulting increase in intra-abdominal pressure causes initial movement of t h e fecal mass. At this point a powerful peristaltic contraction passes down t h e distal sigmoid colon a n d rectum, evacuating t h e m , a n d t h e striated muscles of t h e pelvic floor relax to allow passage of t h e fecal mass through t h e anus. It is a p p a r e n t that t h e central nervous system must have a defecation c e n t e r to coordinate this process a n d to allow for voluntary resistance t o t h e involuntary urge to defecate. However, t h e site a n d connections of such a center are currently unknown.


The rate of movement through t h e gut can be modified by t h e autonomic nerves. Parasympathetic signals to t h e stomach a n d u p p e r small intestine (Figure CS3-1) from preganglionic efferent neurons in t h e vagus nerve (CN X) accelerate gut motility a n d secretion. Sympathetic signals t o t h e s a m e area come from preganglionic neurons in thoracic spinal cord segments T6 to T 10, a n d from t h e r e t h e s e signals g o to postganglionic neurons in t h e coeliac ganglion. S y m p a t h e t i c signals act to inhibit t h e e n t e r i c m o t o r n e u r o n s , slowing peristalsis, a n d at t h e s a m e time, constrict t h e intestinal sphincters via direct innervation of sphincteric smooth muscle. In addition, sympathetic nerves actively adjust t h e resistance of t h e gastrointestinal vasculature a s part of their role in maintaining cardiovascular homeostasis. They tonically inhibit secretomotor neurons in t h e submucosal ganglia.

Case Study 3 - Victoria and the Vicious Hot Dog:Emesis 157

Figure CS3-1 The muscular walls of the gut are innervated by enteric neurons. Sympathetic and parasympathetic nerves act to inhibit or accelerate gut movement, respectively.


2. Which gastrointestinal events take place during vomiting?

Vomiting is a reflex action t h a t rapidly e m p t i e s t h e c o n t e n t s of t h e stomach a n d u p p e r intestines through t h e mouth. Vomiting begins with a p r o l o n g e d b u r s t of a u t o n o m i c activity in t h e i n t e s t i n e s , t h a t c a u s e s a retrograde peristalsis, which s w e e p s toward t h e bottom part of t h e stomach, filling it with intestinal contents. The pyloric sphincter at t h e lower e n d of t h e stomach closes a n d a series of retching movements begin. These consist of rhythmic contractions of t h e thoracic a n d abdominal muscles that increase intra-abdominal pressure. Very soon after, t h e cardiac (esophageal) sphincter at t h e u p p e r e n d of t h e s t o m a c h relaxes, a n d t h e retching m o v e m e n t s continue, t h e p r e s s u r e in t h e s t o m a c h i n c r e a s e s a n d forces its c o n t e n t s through t h e esophagus a n d out of t h e mouth (Figure CS3-2). 3. Which brain stem center coordinates vomiting?

Vomiting r e q u i r e s t h e c o o p e r a t i o n of b o t h t h e s o m a t i c a n d visceral musculature. T h e s e activities a r e c o o r d i n a t e d b y t h e e m e t i c (vomiting) center, a loosely-associated group of neurons located in t h e lateral reticular formation of t h e brain s t e m . 4. Which somatic motor pathways are involved in the vomiting reflex?

T h e e m e t i c c e n t e r signals m o t o r n e u r o n s in t h e s p i n a l cord via t h e r e t i c u l o s p i n a l t r a c t s to p r o d u c e t h e t y p i c a l b e n t - o v e r p o s t u r e t h a t a c c o m p a n i e s vomiting. This p o s t u r e allows for strong contraction of t h e thoracic a n d abdominal muscles, while minimizing strain o n other muscles. At t h e s a m e time, signals from t h e emetic center to t h e phrenic nucleus, a n d t o l o w e r m o t o r n e u r o n s in t h e s p i n a l c o r d , c a u s e s t r o n g , r h y t h m i c contractions of t h e diaphragm, intercostal muscles, a n d abdominal muscles (Figure CS3-3A). Still other signals are s e n t to t h e nucleus ambiguus to cause relaxation of pharyngeal muscles a n d closure of t h e glottis via t h e somatic motor component of t h e vagus nerve (CN X) a n d elevation of t h e soft palate ( t e n s o r veli p a l a t i n i m u s c l e ) via t h e s o m a t i c m o t o r c o m p o n e n t of t h e trigeminal nerve (CN V3) (see Fig. CS3-3B). The relaxed pharyngeal muscles allow for u n i m p e d e d passage of t h e vomitus out of t h e pharynx a n d mouth, a n d t h e closed glottis prevents vomitus from entering t h e trachea a n d lungs. Elevation of t h e soft palate helps to prevent vomitus from entering t h e nasal passages; however, in a particularly strong episode of vomiting, this barrier is ineffective.


Figure CS3-2 The vomiting process



5. Which autonomic motor pathways are involved in the vomiting reflex?

The giant, retrograde peristaltic contractions, in which the direction of peristalsis is reversed, occur when the emetic center signals the dorsal vagal nucleus to send parasympathetic impulses to the gut, which override the normal peristaltic pattern of activity in the enteric neurons. Once the reverse peristalsis fills the stomach antrum with intestinal contents, sensory signals from both chemoreceptors and mechanoreceptors in the antrum travel via vagal afferents to the nucleus of the tractus solitarius and from there to the emetic center. In turn, the emetic center signals the dorsal vagal nucleus, and efferent vagal signals cause contraction of the pyloric sphincter and relaxation of the esophageal sphincter via the enteric neurons (Figure CS3-4).


6. How do sensory signals that elicit vomiting reach the emetic center in the brain?

T h e m o s t likely c a u s e of Victoria’s v o m i t i n g w a s bacterial toxins in t h e hot dog. Direct irritation of h e r u p p e r gastrointestinal tract b y toxins stimulated chemoreceptors in t h e walls of her pharynx, esophagus, stomach, a n d intestines. Visceral sensory impulses from both chemoreceptors a n d stretch receptors traveled via t h e vagus nerve (CN X) to h e r brain s t e m , where t h e y s t i m u l a t e d t h e n u c l e u s of t h e tractus solitarius. T h e n u c l e u s of t h e t r a c t u s s o l i t a r i u s s e n t s i g n a l s to h e r e m e t i c c e n t e r which c o o r d i n a t e d t h e s o m a t i c a n d autonomic c o m p o n e n t s of h e r vomiting reflex (Figure cs3-5). 7. How do toxins in the blood reach the emetic center

in the brain stem?

B l o o d - b o r n e t o x i n s , a b s o r b e d from t h e g u t , a r e carried to all parts of t h e body including t h e brain. Most of t h e neurons in t h e brain are protected from circulating toxins by t h e blood-brain barrier; however, s o m e areas in t h e brain, including a small area in t h e brain s t e m , t h e a r e a p o s t r e m a o r chemoreceptive trigger z o n e , lack a blood-brain barrier. The capillaries in t h e s e areas have large p o r e s (called fenestrations) t h a t allow toxins t o diffuse out of t h e blood into t h e spaces surrounding t h e area postrema neurons. Within t h e area postrema, toxins stimulate chemoreceptive neurons, which, in turn, signal t h e e m e t i c c e n t e r in t h e lateral reticular formation t o coordinate vomiting (see Fig. CS3-5). 8. What are antiemetics and how do they work?

An antiemetic is a drug which p r e v e n t s vomiting. A n u m b e r of different antiemetic drugs a r e available that a c t o n d i f f e r e n t c o m p o n e n t s of t h e n e u r a l p a t h w a y i n v o l v e d in t h e e m e t i c reflex. D o p a m i n e b l o c k i n g a g e n t s , s u c h as m e t o c l o p r a m i d e , a n d d o m p e r i d o n e maleate inhibit area postrema neurons a n d act p e r i p h e r a l l y b y i n c r e a s i n g gastric motility, t h e r e b y m o v i n g t h e n o x i o u s a g e n t s o u t of t h e b o w e l . Antihistamines s u c h as d i m e n h y d r i n a t e a c t o n b o t h t h e a r e a p o s t r e m a a n d o n t h e e m e t i c c e n t e r . Their primary side-effect is drowsiness. Phenothiazines also act o n a r e a p o s t r e m a neurons. T h e s e drugs may also c a u s e m o v e m e n t disorders.

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9. What explains Victoria’s pallor, clammy skin, rapid heart rate, and

dizziness? In addition to coordinating her vomiting reflex, Victoria’s emetic center caused a generalized stimulation of h e r sympathetic nervous system. A s a result, h e r heart and breathing rates increased, and blood was shunted away from h e r skin, causing h e r to appear pale. Sympathetic activation also caused her sweat glands to be stimulated, making her skin damp (Figure CS3-6). Stimulation of Victoria’s breathing rate under relatively inactive physiologic conditions caused carbon dioxide levels in her blood to drop, which, in turn, caused vasoconstriction of the blood vessels that supply her brain. This gave rise to her sensation of light headedness and weakness (see also Fig. CS 1-6 Case Study I : “Fight or Flight” - Alzxiety: Margaret alzd Matthew).

Case Study 3 - Victoria and the Vicious Hot Dog:Emesis I65

10. What causes Victoria’s excessive mouthewatering and tearing?

In addition t o t h e parasympathetic stimulation of t h e enteric nervous s y s t e m via t h e v a g u s n e r v e ( C N X ) , t h e e m e t i c c e n t e r a l s o c a u s e s a generalized stimulation of other parasympathetic pathways, thereby causing secretomotor signals to travel to the salivary and lacrimal glands. Secretomotor signals to the lacrimal gland and to the submandibular and sublingual glands originate in t h e superior salivatory nucleus in t h e brain stem. Preganglionic axons leave t h e brain stem a s part of t h e facial nerve (CN VII)-the nervus intermedius portion. Within the facial canal they divide into two groups. One group joins the greater petrosal nerve and travels with it to the postganglionic neurons in the pterygopalatine ganglion. Postganglionic axons from the ganglion enter the orbit to supply the lacrimal glands, causing Victoria’s eyes to water. The second group travels with the chorda tympani nerve to join the lingual branch of the mandibular nerve and travels with it to t h e floor of t h e oral cavity where t h e axons terminate on postganglionic neurons of the submandibular ganglion. Postganglionic axons continue to the s u b m a n d i b u l a r a n d sublingual glands, where t h e y stimulate secretion, making Victoria’s mouth water (Figure CS3-7). S e c r e t o m o t o r signals t o t h e parotid gland originate in t h e inferior salivatory nucleus of t h e brain stem. Preganglionic axons leave t h e brain stem a s part of the glossopharyngeal nerve (CN IX) and branch from it a s the lesser petrosal nerve. The lesser petrosal nerve terminates on postganglionic neurons in t h e otic ganglion. Postganglionic axons join the auriculotemporal nerve and travel with it to the parotid gland, where they stimulate secretion.


Figure CS3-7 During vomiting, parasympathetic signals are sent to the gut ( 1 ) , a s well a s t o the sublingual ( 2 ) , submandibular ( 3 ) ,and parotid ( 4 ) salivary glands, and t o the lacrimal gland (5),t o cause secretion of saliva and tears.

Case Study 4 ROBERT AND HIS KNOCKED+OUTBLADDER CASE HISTORY While skiing the expert slopes at Whistler, Robert caught an edge, lost control, and collided with a tree. When h e was examined at the hospital, h e was found to have normal movement and reflexes of the upper limbs, but movement in his lower limbs was absent. The doctor ordered a radiograph and discovered that Robert had fractured and displaced his ninth thoracic vertebra and damaged his spinal cord. A s part of Robert’s immediate treatment, the doctor ordered insertion of a urinary tract catheter. Robert did not regain voluntary control of his lower limbs or conscious control of his bladder function. Note: Although damage to the spinal cord affects numerous sensory and motor functions, this case history focuses on bladder control.

GUIDING QUESTIONS 1 . What nerves control bladder function?

2. How is voluntary control over micturition exerted? 3 . What neural mechanisms are involved in bladder filling? 4. What neural mechanisms are involved in bladder emptying

(micturition)? 5. How does spinal cord transection affect the control of Robert’s bladder? 6. What is a “neurogenic”bladder?


CASE DISCUSSION I . What nerves control bladder function?

The bladder is essentially a sac with a thick muscular wall composed of smooth muscle called t h e detrusor muscle. The detrusor muscle is arranged in three layers; t h e outer and i n n e r layers are arranged longitudinally, a n d t h e m i d d l e layer is arranged in a circular pattern. T h e b l a d d e r o u t l e t is closed by two sphincter muscles - t h e internal urethral sphincter (smooth muscle), which is a thickening in t h e bladder wall around t h e entrance t o t h e urethra; and t h e external urethral sphincter (striated muscle), which is one of t h e muscles of t h e urogenital region. B l a d d e r filling a n d e m p t y i n g r e q u i r e t h e i n t e r p l a y of s y m p a t h e t i c , parasympathetic, a n d somatic activities that are coordinated by spinal cord centers a n d by brain stem a n d cerebral mechanisms. B l a d d e r s m o o t h m u s c l e is i n n e r v a t e d b y b o t h s y m p a t h e t i c a n d p a r a sympathetic autonomic motor nerves (Figure CS4-1): Sympathetic nerves originate in t h e intermediolateral cell column of spinal cord segments T11 t o L2. The preganglionic axons project to t h e inferior mesenteric ganglion a n d plexus surrounding t h e inferior mesenteric artery and possibly t o t h e lumbosacral sympathetic ganglia, (not shown),Postganglionic axons from t h e inferior mesenteric ganglion travel via t h e inferior hypogastric nerves to t h e bladder, where they inhibit smooth muscle contraction. In addition, s o m e of t h e s e axons innervate t h e parasympathetic ganglia, where they inhibit ganglionic transmission (Figure CS4-2). Parasympathetic preganglionic neurons are located in t h e intermediolateral cell column of spinal cord segments S2 t o S4. Their axons travel via t h e pelvic splanchnic nerves t o ganglion cells within t h e pelvic plexus and within t h e wall of t h e bladder. The postganglionic axons stimulate bladder smooth muscle contraction. Bladder urethral sphincters a r e innervated b y s y m p a t h e t i c a n d somatic motor nerves: The internal urethral sphincter (smooth muscle) is innervated by sympathetic axons from t h e inferior mesenteric ganglion. The external urethral sphincter (striated muscle) is innervated by somatic motor nerves that originate in t h e ventral horn of spinal segments S 2 to S4. k o n s of t h e s e neurons travel via t h e pudendal nerve t o t h e external urethra 1 sphincter.

Case Study 4 - Robert and his Knocked-Out Bladder I69

Figure CS4-I Motor nerves supplying the bladder Autonomic nerves are shown on the left side of the illustration and somatic nerves are shown on the right.


S e n s o r y a f f e r e n t s f r o m t h e b l a d d e r a r e p r e s e n t in s y m p a t h e t i c , parasympathetic, a n d somatic nerves (Figures CS4-3 a n d CS4-4): Sensory axons in t h e sympathetic nerves carry painful stimuli from t h e b l a d d e r to t h e spinal cord for transmission to t h e cerebral cortex, where they are consciously perceived. Sensory axons in parasympathetic nerves carry stimuli encoding t h e d e g r e e of stretch of t h e bladder wall to t h e spinal cord a n d brain s t e m , where they function in t h e reflex control of t h e bladder. Sensory axons in t h e p u d e n d a l nerve carry sensations of temperature, pain, a n d t h e passage of urine from t h e external urethral sphincter a n d urethra to t h e sacral spinal cord for transmission to t h e sensory cortex, where they are consciously perceived. The bladder does not have t h e autonomy of function that, for example, t h e e n t e r i c o r cardiovascular s y s t e m s have. In t h e brain s t e m , g r o u p s of loosely associated cells in t h e reticular formation of t h e p o n s constitute t h e pontine micturition a n d storage centers. In t h e hypothalamus, t h e anterior n u c l e u s a n d paraventricular nuclei function in micturition a n d s t o r a g e , respectively. Cortical n e u r o n s also function in t h e voluntary control of micturition by, as yet, unknown pathways. Note: T h e following pathways h a v e b e e n d e m o n s t r a t e d in m a m m a l s o t h e r t h a n humans. It is highly likely that they a r e t h e s a m e in humans; however, this is not known with certainty.

Case Study 4 - Robert and his Knocked-Out Bladder 17 I

Figure CS4-2 Sympathetic nerves inhibit transmission of excitatory signals in parasympathetic ganglia via presynaptic a2 receptors.

2. How is voluntary control over micturition exerted?

T h e following two p a g e s detail t h e p r o c e s s of b l a d d e r s t o r a g e a n d emptying in infants or anesthetized adults. As t h e infant matures or t h e adult regains consciousness, micturition is brought u n d e r voluntary control. T h e mechanism of voluntary control is still uncertain, b u t p r o b a b l y involves contraction of t h e e x t e r n a l urethral s p h i n c t e r . N e u r o n s in t h e a n t e r i o r hypothalamus excite t h e micturition center in t h e pons, initiating micturition. Neurons in t h e frontal cortex a n d t h e paracentral lobule inhibit t h e anterior h y p o t h a l a m i c a r e a , p r o m o t i n g c o n t i n e n c e . T h e p o s t e r i o r p a r t of t h e h y p o t h a l a m u s , a l o n g with t h e p o n t i n e s t o r a g e c e n t e r , also p r o m o t e s continence by exciting t h e external urethral sphincter.


3. What neural mechanisms a r e involved

in bladder filling? Bladder filling is coordinated by the pontine storage center - a group of reticular neurons in the lateral aspect of the rostra1 pons During bladder filling, the pressure in the bladder must be maintained at low levels to allow urine to flow into it from the kidneys where it is formed. As a result, the detrusor muscle must stretch passively. Like other muscles, the bladder has a tendency to contract in response to stretching of its fibers via a sensory-motor reflex loop that passes through the spinal cord This reflex loop must be inhibited to allow for passive stretching

A

SLjMzputktiC Motof N t ’ t 4 i o i ~(TI 1 - L 2 ) Sympathetic motor neurons are activated by signals from the pontine storage center and by sensory input from the bladder isall They act to A l Inhibit the contractility of bladder smooth muscle via p2receptors A2 Inhibit transmission of excitatory signals from pregangl i on ic parasympathetic neurons to postganglionic pa ra sy m pat het I c n e u ro n s v I a p re sy n a pt i c a2(Figure CS4-21 receptors and A ? Activate the internal urethral sphincter via a , receptors to promote urine retention

B. ParasyMzpatiietic Motor. Nrurons (S2-S4) Parasympathetic motor neurons are inhibited at two sites B1 Signals from the pontine storage center inhibit the transmission of signals from the sensory neurons to the preganglionic parasympathetic neurons in the spinal cord; and B2. Signals from the sympathetic neurons (see A2 above) inhibit transmission of signals from the preganglionic to the postgangl ionic parasympathetic neurons i n the parasympathetic ganglia

C Sonzatrc Motor. N P U ~ O MISZ-S4I S Somatic motor neurons to the external urethral sphincter are activated by pontine signals from the storage center and by sensory input from the expanding bladder wall Consequently the sphincter contracts to promote urine retention

Figure CS4-3 Neural mechanisms involved in bladder filling and storage

Case Study 4 - Robert and his Knocked-Out Bladder 173

4. What neural mechanisms are involved

in bladder emptying (micturition)? Bladder emptying is coordinated by the pontine micturition center - a group of reticular neurons in the medial aspect of the rostra1 pons As the bladder continues to f i l l , the sensory signals from the stretching walls increase their frequency of firing until a cri ti ca I press u re, the m i ct u r i t i on t h res h o Id is reached At this point the feeling of a full bladder is perceived consciously When micturition is initiated, the micturition center in the pons inhibits the storage center and acts to reverse the pattern of neural activity in the sympathetic. parasympathetic, and somatic nerves. "

"

A Sympathetic Motor Neurons ( T I 1-L2)

Sympathetic motor neurons are inhibited by the pontine micturition center. As a consequence A1 Sympathetic inhibition of the detrusor muscle I S removed, allowing contraction of the bladder wall: A2 Sympathetic inhibition of parasympathetic gang1ionic t ran sm issiori is removed, clearing the way for excitatory parasympathetic signals to reach the postganglionic neurons, and A3 Sympathetic activation of the internal urethral sphincter is decreased, thereby allowing the sphincter to relax and permitting the passage of urine. B Parasympathetic Motor Neurons (S2-S4)

Parasympathetic motor neurons are activated at two sites: BI The pontine micturition center and sensory signals from the bladder enhance activity of the preganglionic parasympathetic motor neurons in the spinal cord, B2 Loss of sympathetic inhibition (see A2 above1 allows enhanced transmission from pre- to postganglionic parasympathetic neurons in the parasympathetic ganglia via postsynaptic nicotinic receptors B?. Activated postganglionic parasympathetic neurons act on muscarinic receptors to elicit Contraction of the detrusor muscle and propel urine through the urethra.

C.Somatic Motor Neurons (S2-S41 Activating signals from somatic motor neurons to the external urethral sphincter are inhibited by the pontjne micturition center Consequently the external urethral sphincter relaxes to allow passage of urine, which elicits a secondary spinal reflex (not shown) causing contraction of the abdominal muscles and diaphragm, further increasing the pressure in the bladder and accelerating the flow of urine.

Figure CS4-4 Neural mechanisms involved in bladder emptying


5. How does spinal cord transection affect the control of Robert’s

bladder? (Figure CS4-5) The injury that Robert suffered interrupted t h e connections between t h e brain a n d t h e sympathetic, parasympathetic, a n d somatic spinal centers that control b l a d d e r function. without t h e facilitatory a n d inhibitory influences from t h e brain, R o b e r t h a d n o voluntary control o v e r micturition. Furthermore, t h e spinal centers acted in a n uncoordinated fashion. Bladder filling c a u s e d u n i n h i b i t e d reflex contraction of Robert’s b l a d d e r via t h e parasympathetic loop. At t h e s a m e time, t h e reciprocal relationship between b l a d d e r a n d sphincters was abolished (bladder-sphincter dyssynergia) such t h a t i n a p p r o p r i a t e contraction of t h e s p h i n c t e r i n t e r f e r e d with b l a d d e r e m p t y i n g . E m p t y i n g of R o b e r t ’ s b l a d d e r b e c a m e u n c o n t r o l l e d a n d haphazard, h e n c e his n e e d of a catheter. 6. What is a “neurogenic”bladder?

The word “neurogenic” m e a n s “caused by nerves.” Neurogenic bladder is t h e term given to any dysfunction of t h e urinary bladder caused b y a lesion of t h e central or peripheral nervous system. The reflex o r upper motor neuron t y p e of neurogenic b l a d d e r is caused b y cortical lesions or trauma to t h e central nervous system. The two t y p e s of reflex b l a d d e r , t h e u n i n h i b i t e d b l a d d e r a n d t h e a u t o m a t i c b l a d d e r , a r e determined b y t h e site of t h e lesion. 1. The uninhibited bladder results from lesions of t h e nervous system a b o v e

t h e level of t h e pons. If voluntary pathways to t h e pontine centers are interrupted, voluntary control over micturition is lost. However, since t h e pontine storage a n d micturition centers are still intact a n d in contact with t h e spinal centers t h e bladder e m p t i e s normally whenever it is full, just as it does in a n infant. 2. The automatic bladder or upper motor neuron type of neurogenic bladder

(which Robert has) is t h e result of lesions between the pontine storage a n d micturition centers and t h e lower spinal cord (Figure CS4-5). The stretch reflex, described above, is no longer inhibited b y t h e pontine storage center. The bladder walls contract in response to a minor amount of stretch, and no voluntary control over t h e external urethral sphincter is exerted. This results in frequent, involuntary voiding. However, t h e bladder is never emptied completely because, as soon as t h e stretch receptors are unloaded by bladder wall contraction, they stop driving t h e reflex, and contraction stops.

Case Study 4 - Robert and his Knocked-Out Bladder I75

Figure CS4-5 Reflex, or upper motor neuron type of neurogenic bladder.


T h e nonreflex or lower motor neuron type of neurogenic bladder is caused by lesions in the sacral cord, the cauda equina, or the peripheral nervous system (Figure CS4-6). Because the reflex loop is interrupted, the bladder does not respond to sensory signals generated b y stretching of the bladder wall. As a result, the bladder fills to capacity and urine leaves the bladder in an uncontrolled fashion. A nonreflex bladder, therefore, is characterized by urinary retention and overflow incontinence.

Figure CS4-6 Nonreflex, or lower motor neuron type of neurogenic bladder The reflex loop can be interrupted within the sacral spinal cord ( A ) ,nerve roots of the cauda equina ( B ) ,or somewhere along the course of the peripheral nerve (C). Without the sensory input to the spinal cord, a full bladder is not perceived consciously; the bladder does not contract and the external sphincter action is diminished.

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SpeciaIist Inf or mation This case history focussed on bladder function; however, Robert would have lost many other voluntary and involuntary functions following his injury. He would have lost voluntary control of his muscles and conscious appreciation of sensation at levels below his spinal lesion. Body temperature is controlled partly by sympathetic nerves to the blood vessels and sweat glands of the skin. Since coordination of Robert’s preganglionic sympathetic neuronal activity was also lost below the level of his injury, he developed difficulties in regulating his body temperature in response to environmental temperature changes, and became, to some degree, poikilothermic. In addition, he lost voluntary control over his reproductive organs; however, since the spinal centers that coordinate erection and ejaculation are still intact, it is still possible for Robert to become a father. For further information on the autonomic control of the reproductive organs, see Case Study 5: Glenn’s Embarrassing Problem.

Case Study 5

GLENN’S EMBARRASSING PROBLEM CASE HISTORY Glenn, a 39-year-old man, came to see his family doctor because of what h e described as a “very embarrassing personal problem.” Glenn’s problem was, that despite considerable interest o n his part, h e was frequently unable to have a n erection, a n d when h e was successful, t h e erection could not be maintained sufficiently to achieve ejaculation. Glenn’s p r o b l e m h a d b e g u n a c o u p l e of y e a r s ago a n d h a d b e c o m e progressively worse. In answer to t h e doctor’s questions, Glenn said that h e had not b e e n aware of having h a d any nocturnal erections or emissions. Prior to this time, Glenn had b e e n well. H e h a d n o history of endocrine diseases, although his father had recently died of complications from diabetes. Based on t h e s y m p t o m s which Glenn d e s c r i b e d , his doctor o r d e r e d blood t e s t s which confirmed t h e doctor’s suspicion that Glenn had d i a b e t e s mellitus.

GUIDING QUESTIONS I . What nerves control t h e functions of Glenn’s reproductive system? 2. What areas of t h e brain function in sexual response? 3. What is erectile tissue? 4. How a r e neural mechanisms involved in sexual response? 5.Why is Glenn failing to have an erection?

Case Study 5 - Glenn’s Embarrassing Problem 179

CASE DISCUSSION I . What nerves control the functions of Glenn’s reproductive system?

T h e male genitalia a r e as follows: t h e testes (singular form, testis), t h e organs that produce t h e spermatozoa (reproductive cells); t h e vasa deferentia (singular form, vas deferens), t h e t u b e s that deliver t h e s p e r m a t o z o a to t h e urethra; t h e accessory glands, t h e seminal vesicles, p r o s t a t e g l a n d , a n d b u l b o u r e t h r a l g l a n d s , which p r o d u c e n u t r i t i v e substances a n d activating factors for t h e spermatozoa; a n d t h e penis, t h e hydrostatic organ t h a t delivers s p e r m a t o z o a to t h e f e m a l e reproductive tract. T h e root of t h e p e n i s is c o m p o s e d of t h e urethra a n d erectile tissue surrounded b y t h e striated bulbospongiosus a n d ischiocavernosus muscles. T h e m a l e genitalia a r e i n n e r v a t e d b y b o t h t h e a u t o n o m i c a n d somatic divisions of t h e nervous system. Se ~ s o r yI M MewlztioM

The skin of t h e p e n i s h a s t h e highest density of sensory receptors in t h e body. Tactile sensations are carried primarily by t h e dorsal nerve of t h e penis to t h e sacral segments (S2-S4) of t h e spinal cord via t h e p u d e n d a l nerves. Within t h e spinal cord, t h e s e n s o r y n e u r o n s project to p a r a s y m p a t h e t i c preganglionic motor neurons within t h e s a m e spinal cord segments, a n d t o lumbar sympathetic preganglionic motor neurons. These two projections, in a d d i t i o n to visceral s e n s o r y afferents from t h e genitals, drive t h e reflex response d u e to tactile stimulation (Figure CS5-1). Impulses also travel cranially within t h e spinal cord to t h e higher cortical centers for conscious appreciation a n d interpretation of t h e sensations. The sensory pathway(s) b y which this sensory information reaches t h e brain is not known with certainty; however, since many of t h e impulses arising from t h e genitals a r e interpreted as pain, it is thought that sensory signals a r e carried t o t h e brain via t h e spinothalamic (pain a n d temperature) pathway.


Motor ImervatioM Motor nerves to t h e t e s t e s are thought t o be entirely of sympathetic (adrenergic) origin. These nerves function to move the spermatozoa along the epididymis into the vas deferens. The vas deferens, seminal vesicles and prostate gland are innervated by sympathetic motor nerves that activate smooth muscle a n d probably by parasympathetic nerves that drive secretion. T h e bulbourethral glands are innervated by parasympathetic motor n e r v e s that l i k e l y drive secretion. T h e penis is innervated by sympathetic, parasympathetic, and somatic motor nerves (Fig. CS5-1). Sympathetic Nerves. Preganglionic sympathetic neurons reside in the intermediolateral column of lower thoracic and upper lumbar spinal cord segments (TI 1 - L 2 ) . T h e y form two groups: I . Axons from neurons in lumbar segments travel to the pelvic plexus via the

inferior mesenteric plexus and hypogastric nerves. Within the pelvic plexus they synapse upon postganglionic sympathetic neurons whose axons project t o t h e internal genitals a n d p e n i s . Postganglionic sympathetic neurons are of two major types: Cholinergic sympathetic neurons that function as vasodilators to the erectile tissue of the penis (Fig. CS5-I), and Adrenergic sympathetic neurons that activate the smooth muscles of the epididymis, vas deferens, seminal vesicles, and prostate gland. 2. Axons of preganglionic sympathetic neurons in lower thoracic levels travel

caudally in the sympathetic chain to synapse upon postganglionic neurons in the sacral ganglia (S2-S4). Postganglionic axons join the pudendal nerve and travel with it to the penis. These axons function as vasoconstrictors to the erectile tissue during detumescence (loss of erection). These neurons are also adrenergic (Fig. CS5-1). Parasympathetic Nerves. Preganglionic parasympathetic neurons reside in the intermediolateral column of sacral spinal cord segments S2 to S4. Their axons leave the spinal cord with the motor roots of the spinal nerves, from which they branch to form the pelvic splanchnic nerves. T h e pelvic splanchnic nerves travel within the pelvis to the pelvic plexus, where they s y n a p s e upon postganglionic p a r a s y m p a t h e t i c n e u r o n s . Axons of postganglionic parasympathetic neurons innervate the erectile tissue of the penis ( t h e corpora cavernosa and t h e corpus spongiosum). T h e y a r e secretornotor to the bulbourethral glands and likely to the vas deferens, seminal vesicles, and prostate gland. Somatic Nerves. Somatic motor neurons in the ventral horns of spinal cord segments S2 to S4 project via t h e pudendal nerve t o t h e bulbospongiosus and ischiocavernosus muscles of the penis.

Case Study 5 - G l e n n ' s E m b a r r a s s i n g P r o b l e m 181

Figure CS5-1 Motor and sensory nerves involved in erection and detumescence


Figure CS5-2 Erectile tissue of the penis

Case Study 5 - Glenn’s Embarrassing Problem I83

2. What areas of the brain function in sexual response?

The integrating centers within t h e brain that function in t h e human sexual r e s p o n s e a r e n o t c o m p l e t e l y u n d e r s t o o d . However, s t u d i e s from o t h e r animals suggest that t h e medial preoptic-anterior hypothalamic a r e a a n d limbic pathways play a key role in erection a n d ejaculation. The thalamus a n d c e r e b r a l cortex also play a role in p e r c e p t i o n a n d interpretation of sensory input during sexual response. Pathways from t h e cerebral cortex a n d limbic areas likely converge o n t h e hypothalamus. Neural pathways from t h e hypothalamus travel through t h e ventrolateral areas of t h e brain s t e m to t h e lumbar ( L b L 2 ) a n d sacral (S2-S4) autonomic centers of t h e spinal cord. 3. What is erectile tissue?

Erectile tissue is a sponge-like arrangement of irregular vascular spaces surrounded b y connective tissue (Figure CS5-2). In t h e penis, erectile tissue forms t h r e e cylindrical bodies, t h e two corpora cavernosa a n d t h e corpus spongiosum, which a r e surrounded b y strong fibrous s h e a t h s , t h e tunicae a l b u g i n e a e (singular form, tunica a l b u g i n e a ) . Within e r e c t i l e t i s s u e , t h e vascular s p a c e s a r e s e p a r a t e d from o n e another b y partitions (trabeculae). Trabeculae a r e c o m p o s e d of fibroelastic tissue with numerous b u n d l e s of smooth muscle. The deep arteries of t h e corpora cavernosa a n d t h e paired urethral arteries t h a t s u p p l y t h e c o r p u s spongiosum e n t e r t h e cylinders centrally. From t h e deep arteries numerous helicene (coiled) arteries supply t h e vascular s p a c e s within t h e erectile tissue. The veins that drain erectile t i s s u e pass c e n t r i f u g a l l y o u t t h r o u g h t h e t h i c k t u n i c a a n d j o i n t h e circumferential veins (see Fig. CS5-2). When t h e erectile tissue is in t h e non-erect state, blood flow through t h e vascular s p a c e s is slight (see Fig. CS5-2A). However, during times of sexual excitement, t h e rate of blood flow to erectile tissue increases dramatically, causing t h e vascular spaces to engorge a n d t h e erectile tissue t o expand (see Fig. CS5-2B). T h e thick tunica limits e x p a n s i o n , t h e r e b y resulting in a n increase of internal p r e s s u r e a n d c o n s e q u e n t turgidity (stiffness) of t h e erectile body. The increased pressure also s e r v e s to compress t h e veins, slowing v e n o u s r e t u r n , further c o n t r i b u t i n g to t h e e n g o r g e m e n t of t h e vascular spaces.


4. How are neural mechanisms involved in sexual response?

Sexual response is driven by complex sensory and psychogenic stimuli. Direct mechanical stimuli to the penis and surrounding area can produce a complete sexual response via spinal cord reflexes. Psychogenic stimuli from t h e cerebrum can enhance or inhibit t h e sexual response to sensory stimulation and can, in addition, elicit a complete sexual response, even in patients with damage to their sacral spinal cords. Sexual response has four stages. A. Evectiorz-Elzgorgemeflt

of the Pem's

Increased blood flow through erectile tissue is mainly caused by relaxation of the smooth muscle in the walls of the arteries and in the trabeculae. Erection is driven by cholinergic n e r v e s t h a t a r e of both s y m p a t h e t i c a n d parasympathetic origin (see Fig. CS5-2B). cholinergic nerves to the erectile tissue release, in addition to acetylcholine (ACh), co-transmitters including VIP (vasoactive intestinal polypeptide), NPY (neuropeptide Y ) , and nitric oxide (also known as EDRF, or endothelial-derived relaxation factor because it is also released by endothelial cells). Recent evidence suggests that nitric oxide is likely the most effective vasodilator in this vascular bed; however, the cellular mechanisms by which these and other neurotransmitters effect smooth muscle relaxation is not well understood. Once erection is established, the somatic axons of the pudendal nerve stimulate the ischiocavernosus and bulbospongiosus striated muscles to contract, further increasing the pressure in the erectile bodies. This in turn increases the stiffness of the penis. Immediately following ejaculation, t h e activity of t h e cholinergic vasodilatory neurons decreases and adrenergic sympathetic axons in the pudendal nerve become active. Arterial smooth muscle contraction driven by t h e vasoconstrictor neurons decrease t h e arterial flow to the penis, thereby decreasing the pressure within the erectile tissue (Fig. CS5-2). A s the pressure drops, the efferent veins are no longer compressed and venous drainage further decreases the pressure in the erectile tissue. T h e penis gradually becomes flaccid again.

Case Study 5 - Glenn’s Embarrassing Problem 185

B. Secretiou-Release

of Glandular Fluids from the Secretory Epithelia

Cholinergic axons of postganglionic parasympathetic neurons in the pelvic plexus elicit secretion from t h e e p i t h e l i u m of the seminal vesicles, t h e prostate gland, a n d t h e bulbourethral glands (Figure CS5-3A). The fluid that is secreted from t h e glands includes nutritive and activating factors for t h e spermatozoa. These secretions plus t h e spermatozoa constitute t h e seminal fluid, or s e m e n . T h e autonomic a n d somatic nerves involved in t h e four stages of t h e sexual response are summarized in Table CS5-1. Table CS5-1 Autonomic and Somatic Nerves Involved in the Four Stages of Sexual Response

Sym = Sympathetic nerves; Para = Parasympathetic nerves.

C. Emission-Movement

of the Ejaculate into the Prostatic Part of the Urethra

Emission is mediated by adrenergic postganglionic, sympathetic neurons in t h e pelvic plexus. Peristaltic contractions in t h e walls of t h e epididymis and vas deferens propel the spermatozoa from t h e testis t o t h e prostatic part of t h e urethra, a n d s m o o t h muscle cells of t h e prostate gland a n d seminal vesicles contract delivering their fluids into t h e prostatic urethra. At t h e s a m e t i m e , t h e s m o o t h m u s c l e s of t h e internal urethral s p h i n c t e r contract to prevent retrograde ejaculation of s e m e n into t h e bladder (Table CS5-1 and Figure CS5-3B).

C a s e Study 5 - Glenn’s Embarrassing Problem I87

D. Ejaculation-Release

of the Ejaculate from the Penile Urethra

Muscles surrounding t h e proximal urethra are innervated by somatic motor neurons carried in t h e pudendal nerve. Ejaculation is t h e result of rhythmic contractions of perineal floor muscles, mainly t h e bulbospongiosus muscle that encircles t h e proximal part, o r bulb, of t h e corpus spongiosum, which propel t h e ejaculate along t h e urethra (Figure CS5-3C). T h e afferent s e n s o r y information carried from t h e contraction of t h e s t r i a t e d p e r i n e a l m u s c l e s a n d t h e s m o o t h m u s c l e of t h e v a s d e f e r e n s , prostate gland, a n d seminal vesicles, as well as t h e pressure changes in t h e urethra is thought to trigger t h e sensations of orgasm. 5. Why is Glenn failing to have an erection?

Glenn is suffering from a n autonomic neuropathy, which h a s occurred secondary to diabetes mellitus. Impotence in diabetes mellitus is common a n d is f r e q u e n t l y t h e first p r e s e n t i n g m a n i f e s t a t i o n of a n a u t o n o m i c n e u r o p a t h y . It m a y initially m a n i f e s t as i n c o m p l e t e e r e c t i o n , b u t m a y p r o g r e s s to c o m p l e t e i m p o t e n c e . A n o t h e r m a n i f e s t a t i o n is a b s e n c e of nocturnal erection and/or emission o n several consecutive nights. Diabetes mellitus is a disease characterized b y e l e v a t e d blood glucose l e v e l s . T h e m e t a b o l i c d i s t u r b a n c e is t h e r e s u l t of i n a d e q u a t e insulin levels, which p r e v e n t s t h e m o v e m e n t of glucose from t h e blood to t h e


cells, where glucose is metabolized. T h e persistent hyperglycemia results in i n c r e a s e d formation of s o r b i t a l a n d f r u c t o s e i n S c h w a n n c e l l s t h a t surround t h e nerves. It is thought t h a t this accumulation of sugars may d i s r u p t t h e structure a n d function of t h e Schwann cells a n d d a m a g e t h e a x o n s . T h e e a r l i e s t h i s t o l o g i c s i g n of n e u r o p a t h o l o g i c d a m a g e is degeneration of t h e Schwann cells, which, at a later s t a g e , is followed by irreversible axonal d a m a g e . T h e n e r v e s m o s t v u l n e r a b l e to diabetes m e l l i t u s are t h e s m a l l myelinated a n d unmyelinated nerves. In t h e autonomic nervous s y s t e m , postganglionic axons a r e almost exclusively nonmyelinated a n d are, therefore, highly susceptible to d a m a g e from high blood glucose levels. Note: For current information on autonomic innervation of t h e male reproductive system in a variety of species see W. G. Dail, 1993.

Case Study 6

FRED’S FACE IS CHANGING CASE HISTORY Fred had just celebrated his fortieth birthday and, after a good look in the mirror, h e decided to give himself a complete overhaul. After years of smoking, h e quit “cold turkey.” Determined not to gain weight subsequent to the loss of his smoking habit, Fred started a vigorous work-out program. H e had just completed a strenuous session and decided that before showering, h e would get rid of his accumulation of whiskers. As h e got ready to slather on the shaving cream, h e looked in the mirror and noticed that, while h e was sweating profusely, the right side of his face and his right arm were dry and much redder than on the left. This prompted him to take a closer look at his face. His right eyelid drooped slightly. Because of the signs h e observed, and h i s radical life-style change, Fred decided to visit his family doctor. The doctor confirmed all the signs described by Fred and then proceeded to examine him very thoroughly. She found one other problem that Fred had missed, but no other abnormalities. As part of h e r examination she dropped a dilute solution of cocaine (4-10%) into both of Fred’s eyes. Subsequently, she dropped hydroxyamphetamine (1%) into both eyes. Fred’s response to these drugs prompted h e r to order a full chest radiograph.

GUIDING QUESTIONS 1 . What do Fred’s signs and symptoms have in common? 2. What other change related to the initial symptoms did the doctor find

which Fred had not noticed? 3. What is the name given to this collection of signs and symptoms? 4. What are the possible sites of a lesion that could result in this collection of

signs and symptoms? 5. What effects do cocaine and hydroxyamphetamine have on the function of

autonomic nerves? 6. How did the use of these drugs help the doctor to diagnose and localize

Fred’s lesion? 7. Sweat production was also decreased in Fred’s right arm. What did this tell

the doctor? 8. Why did the doctor order a chest radiograph? 9. Fred’s radiograph is shown in Fig. CS6-8. What explains his signs and

symptoms?


CASE DISCUSSION 1 . What do Fred’s signs and symptoms have in common?

All of the changes Fred noticed, illustrated in Figures CS6-1 and CS6-2,

are related to the sympathetic nervous system. Lack of sweating (anhidrosis) is due to loss of sympathetic stimulation of the sweat glands. The redness is due to loss of sympathetic vasoconstriction of blood vessels, which allows increased blood flow. T h e droopy eyelid (ptosis) is caused b y loss of sympathetic stimulation of the superior tarsal muscle, a small band of smooth muscle which helps levator palpebrae superioris elevate the eyelid (Fig. CS6-I). Ptosis that results from a loss of sympathetic stimulation results in a 30 percent closure of the eye in contrast to a full ptosis (eye closure) due to loss of the oculomotor nerve (CN 111) to levator palpebrae superioris (Fig. CS6-2).

Since all of these signs and symptoms occurred on the same side of the body, they could all be due to interruption of the ipsilateral sympathetic pathway.

Figure CS6-I Sagittal view of the upper eyelid showing the superior tarsal muscle in the deep lamella of the levator palpebrae superioris muscle aponeurosis.

Case Study 6 - Fred's Face is Changing 19 1

Figure CS6-2 Typical appearance of a Horner's Syndrome patient. On the affected side, the eyelid droops slightly, the pupil is constricted, and the skin is warm, dry, and red.


2. What other change related to the initial symptoms did the doctor find which Fred had not noticed?

Because his right eyelid drooped and partially covered his pupil, Fred did not notice that h i s right pupil was smaller than h i s left pupil. This condition is called miosis and is commonly associated with the other signs seen on Fred’s face. T h e size of the pupil is determined by the balance of tension generated by the dilator pupillae muscle and the constrictor pupillae muscle (Figure CS6-3). T h e dilator pupillae muscle is innervated by sympathetic fibers that enter the orbit via the nasociliary, long ciliary, and sometimes, short ciliary nerves. When this innervation is interrupted, the pupillae constrictor muscle, which is innervated by the parasympathetic nerves from the ciliary ganglion via the short ciliary nerves, has no antagonist to balance its action and it constricts the pupil. 3. What is the name given to this collection of signs and symptoms?

Collectively these signs are called “Horner’sSyndrome.’’They indicate a lesion to the sympathetic nervous system on the same side of the body as the signs appear: Anhidrosis (lack of sweating) Ptosis (droopy eyelid) Redness Warm skin

Case Study 6 - Fred’s Face is Changing 193

Figure CS6-3 Cut-away view of the iris to show the innervation of constrictor and dilator pupillae muscles


4. What are the possible sites of a lesion that could result in this collection

of signs and symptoms?

Activation of t h e sympathetic pathways to targets in t h e h e a d begins in t h e hypothalamus a n d in autonomic networks in t h e brain stem. Activating signals d e s c e n d through t h e spinal cord t o t h e preganglionic sympathetic n e u r o n s in t h e intermediolateral cell column of spinal s e g m e n t s Tl-T3. Axons of t h e s e preganglionic neurons leave t h e spinal cord via t h e ventral roots a n d white rami communicantes. They e n t e r t h e sympathetic chain a n d travel upwards into t h e neck t o reach t h e cervical sympathetic ganglia where t h e y t e r m i n a t e b y s y n a p s i n g o n p o s t g a n g l i o n i c n e u r o n s . Axons of t h e postganglionic neurons in t h e middle a n d inferior/stellate ganglia rejoin t h e cervical nerves as gray rami communicantes to reach their target structures. k o n s of postganglionic neurons in t h e superior cervical ganglion accompany t h e b r a n c h e s of t h e carotid a r t e r i e s i n t o t h e h e a d to reach t h e i r t a r g e t structures (Figure CS6-4). A lesion that could cause Fred’s signs a n d symptoms could arise almost anywhere along this pathway, for example (see Fig. CS6-4): Pvegaugliouic Sites

In t h e brain s t e m where t h e descending axons from t h e hypothalamus could be interrupted a n d where t h e autonomic centers controlling vasomotor activity are (A); In t h e cervical spinal cord a b o v e TI (B); In t h e anterior roots of spinal nerves T1 to T3 (C); a n d Anywhere along t h e cervical sympathetic chain (D). Postgauglion ic Sites Anywhere along t h e path of t h e postganglionic axons ( E ) . Specialist Informat ion

Lesions within the cerebral hemisphere that could affect autonomic function include massive cerebral infarction, a pontine tumor, infarct in the lateral medulla, or herniation of the temporal lobe. Within the cervical cord, syringomyelia (a degenerative process in the center of the spinal cord) or cord tumors could affect descending autonomic signals. At the level of the T I ventral root, a bronchial neoplasm in the apex of the lung, apical tuberculosis, a cervical rib, or brachial plexus trauma could interrupt the transmission of autonomic impulses to the sympathetic chain. The sympathetic chain in the neck could be damaged during thyroid or laryngeal surgery, by carotid artery occlusion, or neoplastic infiltration. In addition, interruption of sympathetic outflow to the head could be caused by migrainous neuralgia, which is wholly transient, or may be due to a congenital insufficiency to autonomic nerves.

Case Study 6 - Fred’s Face is Changing I95

Figure CS6-4 Pathway of autonomic drive to the cervical sympathetic chain and dilator pupillae muscle. Lesions at various sites ( A - E ) along the pathway give rise to different patterns of autonomic sympathetic dysfunction. The parasympathetic pathway to the constrictor pupillae muscle is also shown.


5. What effects do cocaine and hydroxyamphetamine have on the function of autonomic nerves?

Both cocaine and hydroxyamphetamine are drugs that mimic the action of the sympathetic nerves. Under normal circumstances, w h e n noradrenaline is released from sympathetic varicosities, it first acts on target cells by binding to adrenergic receptors. T h e action of noradrenaline is normally terminated by its removal from the synaptic cleft (space) by a sodium dependent amine transporter in the nerve terminals. (Figure CS6-5B). Cocaine inhibits re-uptake of noradrenaline into the varicosities thereby maintaining the extracellular concentration of noradrenaline prolonging its action. Administration of hydroxyamphetamine causes t h e release of noradrenaline from t h e presynaptic terminals. Both drugs, therefore, increase the amount of neurotransmitter in the synaptic space, thereby enhancing and prolonging its action (see Fig. CS6-5C). 6. How did the use of these drugs help the doctor diagnose and localize Fred’s lesion?

’

A dilute solution of either drug can be dropped into the eye where it

diffuses through the cornea and can act on the pupillary nerves. Since the cornea is transparent, the effect of the drugs can be readily observed (see Fig. CS6-5A). Cocaine will dilate a normal pupil but not a Horner’s pupil. When the doctor applied cocaine to Fred’s eyes, his left pupil dilated briskly, telling h e r that the sympathetic innervation to the dilator pupillae was intact on that side. In his right eye, however, cocaine had no effect. This told the doctor that the sympathetic nerves to the right dilator pupillae muscle were not able to release neurotransmitter. Therefore, the postganglionic axon was either damaged, or was not being stimulated to release transmitter by its preganglionic axon (see Fig. CS6-5D).

Figure CS6-5A Drugs dropped onto the cornea diffuse through it and gain access t o the iridial nerves

Case Study 6 - Fred’s Face is Changing 197

Figure CS6-5D Lack of transmitter release caused by either lack of stimulation of, or damage to, the postganglionic sympathetic neuron results in pupillary constriction due to the unopposed action of parasympathetic stimulation Hydroxyamphetamine induces release of neurotransmitter from an intact axon ( A ) ,but not from a damaged axon ( B )


To determine whether t h e lesion affected Fred’s postganglionic neurons, t h e doctor subsequently applied hydroxyamphetamine. Both of Fred’s pupils dilated briskly. This told t h e doctor that t h e postganglionic neurons supplying both of Fred’s e y e s were intact, since they contained transmitter that could be r e l e a s e d b y h y d r o x y a m p h e t a m i n e . T h e interruption in t h e s y m p a t h e t i c pathway t o Fred’s right e y e , was therefore localized e i t h e r in t h e central nervous system or somewhere along t h e path of t h e preganglionic neuron. 7. Sweat production was also decreased in Fred’s right arm. What did this

tell the doctor? S y m p a t h e t i c n e r v e s s u p p l y s u d o m o t o r drive to s w e a t g l a n d s (Figure CS6-6). The superior cervical ganglion s u p p l i e s sympathetic nerves to t h e h e a d a n d neck, whereas t h e m i d d l e a n d inferior cervical gangliahtellate ganglia s u p p l y sympathetic nerves to t h e u p p e r limb. Lesions within t h e hemisphere, brain s t e m , a n d u p p e r spinal cord (Figure CS6-7A) affect t h e sympathetic drive to all sympathetic ganglia, a n d therefore affect sweating (in a d d i t i o n to o t h e r a u t o n o m i c functions) o v e r t h e e n t i r e b o d y , e i t h e r i psi 1ate ra 11y or bilaterally. Lesions affecting t h e u p p e r thoracic roots (Figure CS6-7B) affect t h e s y m p a t h e t i c d r i v e to all t h r e e c e r v i c a l g a n g l i a , a n d t h e r e f o r e affect autonomic function in t h e ipsilateral arm a n d face. Lesions of t h e neck proximal to t h e superior cervical ganglion (Figure CS6-7C) cause decreased sweating over only t h e ipsilateral side of t h e h e a d a n d neck. Lesions distal to t h e superior cervical ganglion (Figure CS6-7D) would likely only affect a few b u n d l e s of sympathetic nerves a n d therefore would be unlikely to have a noticeable affect on sweating.

Figure CS6-6 The red skin on the right side of Fred’s face contrasts with the paler, normal skin, creating a harlequin appearance. Lack of sympathetic stimulation decreases sweating, and allows vasodilation, resulting in warm, red skin ( A ) . Piloerection does not occur. Sympathetic stimulation to the skin results in sweating, vasoconstriction and piloerection ( B ) .

Case Study 6 - Fred’s Face is Changing I99

Figure CS6-7 The superior cervical ganglion supplies the head and neck whereas the middle and inferior/stellate ganglia supply the upper limb.


8. Why did the doctor order a chest radiograph?

Knowing t h a t F r e d ’ s l e s i o n w a s n o t localized a l o n g t h e p a t h of t h e postganglionic neuron, a n d that t h e sweating pattern a n d t h e a b s e n c e of other neurological deficits m a d e it unlikely that t h e central nervous system was affected, t h e doctor suspected that t h e lesion lay somewhere along t h e cervical sympathetic chain, a n d ordered a chest radiograph. Since Fred had b e e n a heavy smoker s h e wanted to investigate t h e possible p r e s e n c e of carcinoma of t h e lung. Tumors of t h e lung a p e x can put pressure o n , a n d i n v a d e , t h e s y m p a t h e t i c trunk a t t h e level of t h e stellate and/or inferior cervical sympathetic ganglion. 9. Fred’s radiograph is shown in Figure CS6-8. What explains his signs and symptoms? A lesion at t h e apex of Fred’s right lung was s e e n on t h e radiograph. A biopsy showed that it was a squamous cell carcinoma of t h e lung (Pancoast tumor). From t h e position of t h e tumor, it was clear that it was damaging t h e preganglionic a x o n s in t h e cervical s y m p a t h e t i c chain a n d t h e inferior cervical/stellate ganglion.

Figure CS6-8 A radiogoraph of Fred’s chest showing the location of his tumor in the apex of his right lung The overlay shows the position of the cervical ganglia in relation to the tumor. (Courtesy of Dorothy Cancer Agency, Vancouver, B.C) Harrison, B.C.

Case Study 7

MICHAEL'S LAST RUN CASE HISTORY While holidaying in Greece, Michael n e e d e d to cash a traveler's check. It was very hot in t h e bank. As h e stood in line, h e began to feel uncomfortably hot, sweaty, a n d a bit nauseous. Shortly thereafter, Michael felt distinctly l i g h t h e a d e d , a n d fell to t h e floor, u n c o n s c i o u s . W h e n h e r e g a i n e d consciousness a few moments later, h e was very pale. When Michael returned to his villa h e took a good look at himself in t h e mirror. H e was 55 years old, too heavy, a n d out of s h a p e . Michael had b e e n a long distance runner in his youth so h e d e c i d e d to g e t back into running a n d s h a p e up. ~ n m i n d f u lof t h e heat, h e started running on a n isolated beach. H e forgot to take a bottle of water with him. Michael was soon out of breath a n d flushed, but h e p u s h e d himself t o k e e p going, e v e n when h e b e c a m e very uncomfortable. After running for a n hour or so, Michael collapsed. Two hours later s o m e beachcombers found him unconscious, lying in t h e s u n . His skin was p a l e , dry, a n d h o t to t h e touch. By t h e time they were able to get Michael to t h e hospital his b o d y t e m p e r a t u r e was 44" C ( 1 11.2" F) a n d h e was d e e p l y c o m a t o s e . D e s p i t e heroic a t t e m p t s t o lower his b o d y temperature, Michael suffered a cardiac arrest a n d died.

GUIDING QUESTIONS 1 . What causes fainting? 2. What mechanisms maintain blood pressure? 3. What sensory signals modulate t h e actions of Michael's cardiovascular

system? 4. w h a t central nervous system centers integrate t h e sensory a n d motor activities of Michael's cardiovascular system? 5. What intrinsic motor nerves controlkoordinate Michael's heart action? 6. What extrinsic, autonomic motor nerves modulate Michael's heart action? 7. What ~ e c h a n i s m control s vasodilation a n d vasoconstriction of Michael's blood vessels? 8. How does t h e b o d y maintain a constant temperature? 9. What is heat stroke? 10. Why did Michael recover so readily after fainting in t h e bank but not after collapsing o n t h e beach?


CASE DISCUSSION I . What causes fainting?

Fainting or “syncope’’is a transient loss of consciousness d u e to inadequate blood flow to the brain. The brain derives almost all of its energy from the oxidative metabolism of glucose and therefore is highly dependent on a steady supply of oxygen-rich blood. Although the brain constitutes only 5 percent of the body mass, it demands 15 percent of the total cardiac output, and uses 20 percent of the available oxygen. Blood flow to the brain is, under most circumstances, maintained at a constant rate despite wide variations i n systemic blood pressure through a process called autoregulation. However, when the systemic blood pressure falls below a critical level, autoregulation fails and consciousness is lost. In Michael’s case, there were two factors at work that led to low systemic blood pressure: the warm temperature caused vasodilation in his cutaneous vessels as part of the heat-dissipating process, and the prolonged standing in line without using his leg muscles caused pooling of blood in his lower limbs. A s a result, the blood was not returned to the heart in sufficient quantities to maintain adequate flow to his brain (Figure CS7-1). 2. What mechanisms maintain blood pressure?

Systemic blood pressure is determined by: A) the cardiac output and B) the total resistance of the vasculature. The total resistance of the vasculature is determined by tonic sympathetic drive to the visceral and somatic vascular smooth muscle. 3. What sensory signals modulate the actions of Michael’s cardiovascular system?

Sensory signals that modulate the activities of the cardiovascular system arise from a variety of sources: A. When Michael formed the intention to start running, sensory signals were

sent from his cerebral cortex to the cardiovascular centers in his medulla to cause an increase in heart rate and blood pressure and vasodilation in his skeletal muscles in anticipation of the need for increased blood supply to his muscles (Figure CS7-4). B. Oxygen receptors in Michael’s carotid body monitored the oxygen levels

in his blood and sent a train of signals to the cardiovascular and respiratory centers in his medulla to increase or decrease cardiorespiratory action as needed to maintain adequate blood oxygenation (Figure CS7-2).

Case Study 7 - Michael’s Last Run 203

C. Baroreceptors in Michael’scarotid sinus, aorta, and atria ~ o n i t o r e dthe pressure of blood leaving and returning to his heart and sent signals to the ~ardiovascu~ar centers in his medulla to increase or decrease the strength and rate of his heart beat, and the peripheral vascular resistance to alter blood pressure as needed. This baroreceptor reflex is the most important

mechanism for controlling blood pressure on a moment-by-moment basis (Figure (37-3).

Figure CS7-1 Changes in blood distrib~tionwhen Michael fainted at the bank.

204 A u t o n o ~ i cNerves

€ 3r~ ~ r e ~ Reflex e~~~r

Sensory signals encoding baroreception (pressure) travel to the medulla with the glossopharyngeal (CN IX) and vagus (CN X) nerves. The baroreceptors send a constant train of signals to the medulla where they terminate in the nucleus of the tractus solitarius which, in turn, sends a train of signals to the cardiovascular centers of the brain stem, W h e n t h e arterial pressure increases, t h e rate of discharge in t h e baroreceptors increases. T h i s process stimulates t h e cardiovascular inhibitory center (see Fig. CS7-4) which, in turn, slows the heart and, at the same time, inhibits the cardiovascular excitatory center causing general vasodilation. T h e effects of these actions are a decrease in cardiac output and a decrease in the return of blood to the heart which together cause a decrease in arterial pressure. Conversely, when the pressure in the arteries falls, the frequency of the signals from the baroreceptors also falls and has the opposite effect on the heart and blood vessels so that the blood pressure rises. This negative feedback loop acts to maintain a constant blood pressure in the large arteries.

Specialist Information Baroreceptors are very sensitive to rapid changes in blood pressure but tend to adapt to longer term changes in blood pressure (i.e., those that last more that a few days). This means that the baroreceptor system is unimportant for long-term regulation of blood pressure even though it is an extremely important mechanism for preventing the rapid changes in arterial pressure that occur over minutes or hours. Prolonged regulation of arterial pressure requires other control systems, mainly those concerned with regulating body fluid balance.

Case Study 7 - Michael's Last Run 205

Figure CS7-3 Sensory signals to the cardiovascular centers in the brain stem that modulate cardiovascular activity The baroreceptor reflex is shown on the right side of the illustration and the sympathetic outflow to the heart i s shown on the left side of the illustration.


4. What central nervous system centers integrate the sensory and motor

activities of Michael’s cardiovascular system?

Three major areas in the medulla are known to have a profound effect on cardiovascular function: the nucleus of the tractus solitarius that integrates b o t h sensory stimuli, a n d motor stimuli t o cardiovascular targets; t h e cardiovascular excitatory and inhibitory centers (Fig. CS7-4). The nucleus of the tractus solitarius is a long thin group of cells in the dorsolateral part of the brain stem in which primary sensory information from t h e baroreceptors is integrated with signals from t h e hypothalamus a n d cortical c e n t e r s . T h e n u c l e u s of t h e tractus solitarius p r o j e c t s t o t h e cardiovascular excitatory a n d cardiovascular inhibitory c e n t e r s of t h e reticular formation. The cardiovascular excitatory center consists of a loose network of cells in t h e reticular formation of t h e rostra1 ventrolateral medulla. Many of t h e s e cells have pacemaker properties and they provide a phasic excitatory drive to sympathetic preganglionic neurons in the intermediolateral cell column of t h e spinal cord through the reticulospinal pathways (Fig. CS7-4). The rate of discharge of t h e vasomotor excitatory cells is increased or decreased by signals from a variety of sources, notably the nucleus of the tractus solitarius and t h e hypothalamus.

Figure CS7-4 Cross section of the brain stem showing the major centers controlling blood pressure

Case Study 7 - Michael’s Last Run 207

T h e c a r d i o v a s c u l a r i n h i b i t o r y c e n t e r c o n s i s t s of p r e g a n g l i o n i c parasympathetic cells located in t h e ventral part of t h e nucleus ambiguus. h o n s of cardiovascular inhibitory neurons leave t h e brain s t e m a s part of t h e vagus nerve (CN X). Signals from t h e frontal cortex a n d limbic system also converge o n t h e hypothalamus a n d t h e vasomotor centers in t h e medulla. Both peripheral a n d central signals are integrated b y t h e cardiovascular centers, which then construct appropriate motor responses a n d relay them t o t h e heart through t h e motor neurons of t h e autonomic nervous system. 5. What intrinsic motor nerves controkoordinate Michael’s heart action?

The heart has its own intrinsic system for coordinating t h e contraction of its muscle fibers. This system consists of groups of specialized noncontractile cardiac muscle cells: t h e sinoatrial n o d e , t h e atrioventricular n o d e , a n d t h e b u n d l e of H i s . T h e s e s p e c i a l i z e d c a r d i a c m u s c l e c e l l s g e n e r a t e a spontaneous, rhythmic pattern of electrical activity, as well as a network of conducting cells that carry t h e impulses to t h e cardiac muscle, causing it to contract a t a rate d e t e r m i n e d b y t h e activity of t h e sinoatrial n o d e . T h e sinuatrial n o d e is t h e dominant n o d e , a n d as such, it is called the pacemaker of t h e heart (Figures CS7- 5 a n d CS7-6). S e e Chapter VI, Figure 6-1 1 , for a description of t h e cellular structure of pacemaker cells. The sinoatrial (SA) n o d e is located in t h e wall of t h e right atrium at t h e superior e n d of t h e crista terminalis at t h e junction of t h e anterolateral aspect of t h e superior vena cava a n d t h e right atrial a p p e n d a g e . It has a flattened elipsoid s h a p e about 10 to 20 mm long, 3 mm wide, a n d about 1 m m thick. The SA n o d e initiates an impulse that is carried along t h e walls of t h e right atrium to converge on t h e atrioventricular (AV) n o d e . The AV n o d e is located in t h e interatrial s e p t u m anterior to t h e coronary sinus orifice. It is oval, about 7 to 8 mm long, 3 mm thick, a n d 1 m m in width. The anteroinferior e n d of t h e AV n o d e continues as t h e common atrioventricular bundle (of His) b y which impulses are conducted to t h e ventricles. The bundle of His divides into right a n d left b r a n c h e s t h a t lie u n d e r t h e e n d o c a r d i u m of t h e interventricular s e p t u m . T h e right branch i n n e r v a t e s t h e m u s c l e of t h e interventricular s e p t u m , t h e anterior papillary muscle, a n d t h e wall of t h e right ventricle. The left branch supplies t h e interventricular s e p t u m , papillary muscles, a n d t h e wall of t h e left ventricle. The right branch remains a discrete bundle whereas t h e left branch breaks u p into many fine bundles.


6. What extrinsic, autonomic motor nerves modulate Michael’s heart action?

Autonomic nerves act on the pacemakers and on the cardiac muscle itself to modify the intrinsic heart activity in response to the changing metabolic needs of the body. Paras y m pa t he tic 1n nerva t ion Routine cardiac function is mostly u n d e r parasympathetic control. The p a r a s y m p a t h e t i c preganglionic n e r v e cell b o d i e s a r e l o c a t e d i n t h e cardiovascular inhibitory center in the medulla. Their axons come together with other axons of t h e vagus nerve at t h e lateral surface of t h e medulla where they emerge a s a series of rootlets which converge into a single nerve, the vagus nerve ( C N X). The vagus nerve exits the skull through t h e jugular foramen and descends through the neck within the carotid sheath to enter the thorax (see Fig. CS7-5). The autonomic n e r v e s around t h e heart form superficial a n d deep plexuses. The superficial cardiac plexus lies below t h e aortic arch a n d anterior to the right pulmonary artery. It is formed by t h e cardiac branch of t h e left superior cervical sympathetic ganglion and t h e lower of t h e two cervical cardiac branches of the left vagus nerve. The d e e p cardiac plexus is anterior t o t h e tracheal bifurcation, a b o v e t h e point of division of t h e pulmonary trunk, and posterior to the aortic arch. It is formed by the cardiac branches of the cervical and upper thoracic sympathetic ganglia and of the vagus and recurrent laryngeal nerves. From the root of the neck downward, the nerves take different paths to reach t h e d e e p a n d superficial cardiac plexuses. On t h e right, t h e vagus nerve descends posterior to the root of the lung where it breaks up into a posterior plexus and is joined by fibers from the left vagus nerve. After giving off a cervical cardiac branch to the superficial cardiac plexus where a small parasympathetic ganglion is usually found, t h e left vagus nerve descends posterior to the root of the left lung and with all other cervical and thoracic cardiac branches, joins the d e e p cardiac plexus. From the superficial and deep cardiac plexuses, the vagus nerve breaks up into many branches that join plexuses around the coronary arteries. As well, the superficial cardiac plexus is in communication with the deep cardiac plexus. From the right half of the d e e p cardiac plexus, branches go to the right atrium and to t h e right and left coronary plexuses. From the left half of t h e deep cardiac plexus, branches go to the left atrium and the left coronary plexus. Cardiac preganglionic parasympathetic axons act on parasympathetic ganglia located in the atrial and interatrial walls of the heart near t h e SA and AV nodes. Parasympathetic postganglionic fibers release acetylcholine that binds with muscarinic receptors to slow the rate of depolarization of the pacemaker cells and therefore decrease heart rate, atrial contractility, and atrioventricular conduction. See Chapter 6: Autonomic Neurotransmitters, Receptors, and Effectors,Figure 6-12B, for details of t h e cellular events that follow muscarinic binding by acetylcholine in cardiac tissue.

C a s e Study 7 - Michael's Last R u n 209

Figure CS7-5 Parasympathetic pathways from the brain stem to the heart


S y m pat he tic I n ne ma tio n

S y m p a t h e t i c n e r v e s p l a y a m a j o r role in regulating blood p r e s s u r e b y controlling t h e resistance of t h e arteries a n d t h e capacity of t h e veins. During cardiac function at rest, they play only a minor role in controlling t h e strength a n d rate of t h e heart beat. During physiologic stress (e.g., running), however, increased sympathetic activity, combined with d e c r e a s e d parasympathetic activity increases t h e rate a n d force of contraction of t h e heart, leading t o a n increase in cardiac output. The preganglionic sympathetic neurons that supply t h e heart a r e located in t h e intermediolateral cell column of t h e spinal cord from thoracic level TI t o T5 (Fig. CS7-6). The preganglionic fibers exit from t h e spinal cord in t h e ventral roots to join t h e mixed spinal nerves from which they branch as white rami communicantes to reach t h e sympathetic ganglia where many of them synapse with postganglionic sympathetic neurons. S o m e fibers ascend in t h e sympathetic chain t o t h e inferior, middle, or superior cervical ganglion where they synapse. Three pairs of sympathetic cardiac nerves emerge from t h e s e ganglia to supply t h e heart. They form part of t h e mixed cardiac plexuses in which they mingle with each other a n d with t h e rest of t h e sympathetic fibers coming from TI to T5 a s well as with parasympathetic motor (efferent) fibers a n d sensory (afferent) fibers. Sympathetic preganglionic axons that did not s y n a p s e in t h e s y m p a t h e t i c chain, s y n a p s e in small s y m p a t h e t i c ganglia within t h e cardiac plexuses. From t h e plexuses, postganglionic sympathetic nerves pass t o t h e heart t o act on t h e sinoatrial n o d e a n d on myocytes. The adrenergic receptors on cardiac cells are predominantly j3, receptors. Adrenergic stimulation causes a n increase in heart rate, atrial contractility, atrioventricular conduction, a n d ventricular contractility. In contrast, t h e a d r e n e r g i c r e c e p t o r s o n coronary blood v e s s e l s a r e p r e d o m i n a n t l y P2 receptors, which, when activated, cause relaxation of vascular smooth muscle a n d , t h e r e f o r e , dilation of t h e arteries. S y m p a t h e t i c stimulation c a u s e s increased heart rate, impulse conduction, a n d force of contraction a n d , at t h e s a m e time, increased blood flow through t h e coronary vessels to support t h e higher activity of t h e heart. See Chapter 6: Autonomic Neurotransmitters, Receptors, a n d Effectors, Figures 6-12 a n d 6-13, for d e t a i l s of t h e cellular e v e n t s that follow b i n d i n g of t h e p , - a d r e n e r g i c r e c e p t o r s b y n o r a d r e n a l i n e a n d adrenaline in cardiac tissue.

Case Study 7 - Michael’s Last Run 21 1

2 12 Autonomic Nerves

7. What mechanisms control vasodilation and vasoconstriction of Michael’s

blood vessels?

Blood vessels are not simple conduits like plumbing pipes, but are highly active structures whose diameters can be altered on a second-by-second basis. Smooth muscle cells, which form part of the walls of all blood vessels except capillaries, contract and relax, directing blood flow throughout the body as circumstances demand, increasing perfusion of some capillary beds and decreasing perfusion in others. In addition, the overall tone of the vasculature plays an important role in maintaining blood pressure, by creating resistance to blood flow. Control of blood flow is exerted mainly by the small muscular arteries and large arterioles, and, appropriately, these vessels have the most densely innervated walls. Precapillary sphincters control flow through small, local vascular beds. Their innervation is also dense (Figure CS7-8). At any one time, about 64 percent of circulating blood is in the veins. The contraction of venous smooth muscle cells moves blood out of the venous reservoir, thereby increasing the return of blood to the heart. Vessel diameter is controlled by: Autonomic nerves, Vasomotion, Myogenic autoregulation, Local factors, and Ci rcu la t i ng factors. Autonomic Nerves Sympathetic Pathways. T h e sympathetic division of the autonomic nervous system has a profound affect on vascular diameter. Blood vessels throughout the body are tonically innervated by sympathetic nerves in a segmental fashion (Figure CS7-7). In most vascular beds, an increase causes vasoconstriction, while a decrease in the rate of sympathetic signals causes vasorelaxation. However, in some regions of the body sympathetic signals are vasodilatory, for example, in the coronary and external genital vascular beds. In the coronary vessels sympathetic nerves elicit vasodilation by acting on P,-adrenergic receptors. In the vessels of skeletal muscles and the external genitals, sympathetic n e r v e s cause vasodilation by secreting acetylcholine, which, in turn, causes the synthesis of nitric oxide, a strong vasodilator (see Case Study 5: Clem’s Embarrassing Problem, Figure CS5-2). Parasympathetic Pathways. Parasympathetic nerves originate in the parasympathetic ganglia in the head and pelvis and are vasodilatory in function. T h e y act to balance vasoconstriction in the head and cause vasodilation in the external genitals during erection.

Case Study 7 - Michael’s Last Run 2 I 3


Vasomotion Vasomotion is the spontaneous, pacemaker-driven opening and closing of precapillary sphincters (see Fig. CS7-8). Myogenic Autoregulation Vascular smooth muscle constricts in a reflex manner in response to stretching of the vessel walls.

Local Factors T i s s u e metabolic factors act on vascular smooth m u s c l e to adjust the perfusion of local vascular beds within an organ to ensure that blood flow is adequate to meet local metabolic needs. Local factors include tissue oxygen and carbon dioxide, and endothelial factors, such as endothelin, a potent vasoconstrictor or nitric oxide, a vasodilator. In organs that require a constant blood supply such as the brain, lungs, and kidney, local metabolites are a major regulatory factor.

Figure CS7-8 Constriction or dilation of vascular beds in various areas of the body is controlled by contraction or relaxation of vascular smooth muscle. Perfusion of local capillary beds is controlled by the precapillary sphincters.

Case Study 7 - Michael's Last R u n 2 I5

Circtt la t i M ~Factors

Circulating factors t h a t affect v e s s e l d i a m e t e r i n c l u d e a d r e n a l i n e a n d noradrenaline, vasopressin, a n d angiotensin tI. These cause general vasoconstriction a n d a n increase in blood pressure. Circulating inflammatory mediators such as histamine a n d bradykinin cause vasodilation a n d a d r o p in blood pressure, 8. How does the body maintain a constant temperature?

Human beings a r e homeofherms, i.e., we maintain our b o d y temperature within very narrow limits around 37" C (98.6"F). This core temperature, o r "set point," varies somewhat with t h e time of d a y a n d t h e state of t h e organism. T h e b o d y is constantly producing h e a t through m e t a b o l i c activities a n d physical exercise. A t r e s t , with n o external work b e i n g d o n e , m e t a b o l i c energy a p p e a r s a s h e a t a n d amounts to 1 kcal p e r kg of b o d y weight p e r hour. w i t h s t r e n u o u s exercise m o r e t h a n three-quarters of t h e metabolic work a p p e a r s as heat; t h e other o n e quarter is u s e d to move t h e body. Body t e m p e r a t u r e is s e n s e d b y thermosensitive receptors in t h e skin, within t h e organs, a n d ~ i t h i nt h e anterior h y p o t h a ~ a m u s ,spinal cord, a n d brain s t e m . An increase in t h e core t e m p e r a t u r e elicits a h e a t dissipating r e s p o n s e a n d a d e c r e a s e in c o r e t e m p e r a t u r e elicits a h e a t conserving r e s p o n s e . T h e neural organization of t h e thermoregulatory c o n n e c t i o n s within t h e brain a n d spinal cord are not well understood. W h e n t h e c o r e t e m p e r a t u r e b e g i n s to d r o p ~ e ~ ot hwe set p o i n t , t h e sympathetic nerves respond in two ways: b y decreasing h e a t loss a n d b y increasing heat production.

Decreased Heat Loss T h e a m o u n t of blood c i r c u l a t i n g t h r o u g h t h e s k i n , e s p e c i a l l y of t h e extremities, is d e c r e a s e d to minimize h e a t loss. D e c r e a s e in c u t a n e o u s blood flow is caused by sympathetic vasoconstriction. Local vasoconstrictive mechanisms in t h e skin also act to d e c r e a s e blood flow through e x p o s e d areas in a more localized fashion. tn addition, t h e sympathetic fibers to t h e a r r e c t o r e s pilorum m u s c l e s a r e a c t i v a t e d to r a i s e t h e b o d y hairs in a n a t t e m p t to create a more effective insulating layer. In human beings b o d y hair is not thick enough to form a significant insulating layer so this response is n o t effective. However, it still occurs b e c a u s e w e h a v e i n h e r i t e d t h i s mechanism from our hairy mammalian predecessors. T h e "goose b u m p s " that a p p e a r o n t h e skin during a s u d d e n chill a r e d u e to t h e slight puckering of t h e skin by t h e contracting arrectores pilorum muscles. Increased Heat ProducfioM Heat p r o d u c t i o n is i n c r e a s e d , initially, b y i n c r e a s i n g m u s c l e t e n s i o n . S u b s e q u e n t ~ yif, t h e temperature of t h e surface skin decreases below 23" C (74" F), shivering begins a n d produces additional heat t o maintain t h e b o d y temperature. The activation of shivering is controlled b y t h e hypothalamus. Shivering, a rhythmic contraction of t h e somatic muscles, is mediated b y t h e somatic motor system.


Specialist Information During a fever, pyrogens from bacteria in the body increase the set point to a higher level, allowing a concomitant increase in body temperature. Fever increases the metabolic rate by about 13 percent for each centigrade degree above normal. The increased metabolic rate requires an increased food intake, hence the saying “feed a fever.”

W h e n the core temperature rises above the set point, as in Michael’s case, sympathetic nerves respond by increasing heat loss in two ways: 1. Convective transfer of heat to the surface of the body is increased by

vasodilation of the cutaneous circulation and a concomitant vasoconstriction in body organ circulation. The sympathetic axons to the cutaneous vascular smooth muscle decrease their firing rate, allowing relaxation of the smooth muscle and an increase in the volume of the vascular bed. (There may also be a group of sympathetic cholinergic vasodilator neurons that act to dilate the vascular bed in the skin of the proximal limbs.) The amount of blood circulating through the skin may approach 12 percent of the cardiac output, approximately a 10-fold increase over resting levels. 2. Sweat glands are activated releasing moisture onto the skin surface.

Evaporation of this moisture cools the skin (Figure CS7-9). Blood circulating through the cooling skin is also cooled. Sweat glands are activated by choli n e rgic su d om otor (sweat- prod u ci ng ) pos tgangli on i c sympathetic axons. There are approximately 2.5 million sweat glands in the skin of an average adult male, and fewer in the skin of females. The rate of sweating can exceed 1.5 liters per hour, representing an evaporative heat loss of 900 kcal per hour.

Figure CS7-9 (A) Sympathetic signals to the sweat glands cause sweating via a cholinergic mechanism. ( B ) The train of sympathetic signals to the vascular smooth muscle in the skin decreases, allowing vascular dilation

Case Study 7 - Michael's Last Run 21 7

9.What is heat stroke?

Heat stroke is loss of consciousness caused b y insufficient blood flow to t h e brain s e c o n d a r y to t h e b o d y ' s efforts to d i s s i p a t e h e a t , In t h e h e a t dissipating process, cutaneous vasodilation shifts a significant proportion of t h e blood volume to t h e skin a n d away from t h e vital organs (see Fig. CS7-1). To a d e g r e e , this is compensated for b y a shift in water from t h e tissues into t h e blood. However, water loss d u e t o sweating further decreases t h e blood volume a n d venous return to t h e heart drops. This is especially p r o b l e ~ a t i c during t i m e s of strenuous activity b e c a u s e muscle activity produces more h e a t a n d shifts m o r e of t h e blood away from t h e internal organs into t h e muscles. Taking a "siesta" during t h e hottest part of t h e d a y is a behavioral adaptation t o avoid t h e risk of heat stroke. When t h e venous return to t h e heart reaches critically low levels, blood flow to t h e brain can b e c o m e inadequate for normal function. At this point h e a t s y n c o p e (fainting) occurs (Figure CS7-10). In serious h e a t stroke t h e core t e m p e r a t u r e can reach 43 t o 44" C ( 1 10" F). Such high t e m p e r a t u r e s increase t h e leakage of ions from neurons, decreasing their ability to conduct a n action potential, a n d can eventually d e n a t u r e enzymes a n d lead to d e a t h of t h e brain cells a n d eventually of t h e patient. Heat stroke is considered t o be a medical emergency. H e a t stroke is m o r e common in tropical climates b u t it does occur in t e m p e r a t e zones, especially during a prolonged h e a t wave. I t can also be brought o n b y strenuous physical activity u n d e r conditions of high ambient t e m p e r a t u r e s a n d humidity. To maintain a n a d e q u a t e blood volume it is important to replace t h e fluid lost b y sweating during strenuous activity. This is why t h e r e a r e frequent water stations on t h e route of marathon runs.

2 I8 Autonomic Nerves

10. Why did Michael recover so readily after fainting in the bank but not

after collapsing on the beach? In t h e b a n k , Michael’s total blood v o l u m e w a s n o r m a l . H e f a i n t e d because his blood was pooled in his skin a n d lower limbs a n d therefore was n o t available in sufficient q u a n t i t y for circulation t o t h e brain. When h e fainted two events occurred. When h e fell to t h e floor, gravity was acting to encourage blood return t o his heart, a n d stimulation of t h e s y m p a t h e t i c nerves constricted his skin vasculature, shifting additional blood back toward his heart. A d e q u a t e blood flow to his brain was restored a n d h e regained consciousness. On t h e beach, Michael h a d b e e n running in t h e hot sun for a prolonged period of time. His poor physical condition resulted in inefficient muscle action which led t o excess h e a t production, a n d his extra weight m a d e it more difficult for him t o dissipate h e a t effectively. He h a d b e e n sweating copious quantities of fluid a n d not replacing it b y drinking water, therefore, his total blood volume was dangerously low. In addition, blood h a d b e e n s h u n t e d to h i s s k i n a n d s k e l e t a l m u s c l e s b y t h e d e m a n d s of t h e r m o r e g u l a t i o n a n d running. W h e n blood flow t o h i s b r a i n b e c a m e i n a d e q u a t e , h e c o l l a p s e d . At t h i s p o i n t , h i s s y m p a t h e t i c n e r v e s a c t e d strongly to stop his sweating a n d constrict his skin vascular bed to conserve fluid a n d restore circulation to his vital organs. As a result, thermoregulation c e a s e d a n d his b o d y temperature began to rise. Michael’s skin b e c a m e pale ( d u e t o vasoconstriction), hot ( d u e to increasing body temperature), a n d dry ( d u e to cessation of sweating). Despite t h e shift of blood to his vital organs, circulation to Michael’s brain d i d not reach a d e q u a t e levels for recovery. As h e lay in t h e hot sun, his b o d y temperature eventually rose to lethal levels a n d his excitable tissues (neurons, cardiac muscle) began to depolarize a n d eventually c e a s e d t o function. Specialist Information When blood flow to the vasomotor center in the brain stem becomes low enough to cause nutritional deficiency, increases in levels of C02 and other metabolites stimulate the neurons in the vasomotor center. This results in an immediate, strong sympathetic stimulation that raises the blood pressure and increases blood flow through the brain stem to restore nutritional status. This is called the Central Nervous System Ischemic Effect and is one of the most powerful activators of the sympathetic vasoconstrictor system. The ischemic effect occurs when the blood pressure falls far below normal (to about 40 mm Hg) and so is not one of the mechanisms for regulating normal arterial pressure. It operates as an emergency arterial pressure control system when blood flow to the brain decreases dangerously close to the lethal level. It is sometimes called the “last ditch stand” pressure control mechanism.

Case Study 8

PATTY’SPUFFER CASE HISTORY Patty was invited by her friend Marilyn t o form a fourth for bridge. A few minutes after s h e e n t e r e d Marilyn’s apartment, Patty began to wheeze a n d experience shortness of breath. When s h e looked around, s h e saw that her bridge partner was smoking. Patty, who suffered from asthma, realized that t h e smoke was causing her t o have breathing difficulties. S h e immediately inhaled a c o u p l e of puffs from t h e anti-asthma inhaler that s h e always carried with her. It acted quickly t o r e v e r s e t h e a t t a c k , a n d s h e b e g a n to b r e a t h e m o r e easily. Marilyn c o m m e n t e d t h a t s h e too suffered from a s t h m a , b u t t h a t h e r a s t h m a was caused b y a n allergy to cats.

GUIDING QUESTIONS 1. What is asthma? 2. How a r e bronchiolar d i a m e t e r a n d m u c u s s e c r e t i o n controlled u n d e r

normal conditions? 3 . What triggers a n asthma attack? 4. What causes airway obstruction during a n asthma attack?

5. How did t h e drugs in t h e puffer relieve Patty’s symptoms?


CASE DISCUSSION I.What is asthma?

Asthma is a chronic disease characterized b y paroxysmal obstruction of t h e bronchial airways. Patients with a s t h m a may complain of wheezing, c o u g h , o r s h o r t n e s s of b r e a t h . T h e word asthma c o m e s from t h e G r e e k , asthmatos, m e a n i n g s h o r t n e s s of b r e a t h . Doctors call it SOB! Breathing b e c o m e s difficult d u e t o narrowing of t h e airway, which is t h e c o m b i n e d result of e d e m a t o u s mucosal m e m b r a n e s a n d constriction of t h e s m o o t h muscle of t h e bronchiolar walls. Asthma sufferers exhibit a familiar wheezing sound a n d have problems breathing, especially when expiring air. They also s e e m to have unusually irritable a n d sensitive airways (“twitchy” breathing t u b e s ) , which undergo greater than normal changes in airway calibre. An inherited predisposition to asthma accounts for a significant proportion of all asthma cases. 2. How are bronchiolar diameter and mucus secretion controlled under

normal conditions? (Figures CS8-1 and CS8-4A) T h e smooth muscles a n d glands of t h e bronchial t r e e of t h e lungs are s u p p l i e d b y b o t h parasympathetic a n d s y m p a t h e t i c autonomic neurons. Under normal conditions, t h e nerves act together t o maintain appropriate dilation of t h e airway a n d secretion of its glands in changing respiratory states. For example, during heavy breathing in exercise, bronchioles dilate to facilitate t h e m o v e m e n t of air in a n d o u t of t h e lungs, a n d glandular secretion increases to counteract t h e drying effect of rapid air movement. Bronchiolar diameter a n d mucus secretion a r e controlled b y t h e following autonomic nerves: Visceral Sensory Fi6evs Visceral sensory fibers from t h e walls of t h e airway travel to t h e brain s t e m with t h e vagus nerve (CN X). Their nerve cell bodies reside in t h e inferior vagal ganglion, a n d their central axons project to t h e nucleus of t h e tractus solitarius (NTS) in t h e medulla. Neurons of t h e NTS project within t h e brain s t e m to v a r i o u s r e g i o n s , i n c l u d i n g t h e d o r s a l v a g a l n u c l e u s a n d t h e respiratory centers. Respiratory n e u r o n s also receive i n p u t s from higher centers in t h e hypothalamus a n d cerebral cortex. They drive t h e autonomic (preganglionic sympathetic a n d parasympathetic) neurons that control t h e smooth muscle a n d glands of t h e lungs. Sy m pat he tic Pregang lion ic Neurons

Sympathetic preganglionic neurons are located in t h e intermediolateral cell column of t h e spinal cord. Their axons leave t h e spinal cord at t h e T1 to T6 l e v e l s t o s y n a p s e in t h e i r r e s p e c t i v e s y m p a t h e t i c ganglia. S o m e axons ascend to t h e inferior cervical ganglion. Sympathetic postganglionic axons leave t h e sympathetic ganglia via medial branches a n d mingle with vagal a x o n s to form t h e p u l m o n a r y p l e x u s e s . S y m p a t h e t i c n e u r o t r a n s m i t t e r s s t i m u l a t e P,-adrenergic r e c e p t o r s , which in turn, c a u s e relaxation of t h e

Case Study 8 - Patty's Puffer 22 1

Figure CS8-I Autonomic control of bronchiolar diameter and mucus secretion


bronchiolar smooth muscle cells, thereby allowing t h e bronchi to dilate. The role of t h e sympathetic nerves in driving secretion of t h e mucous glands is minor. See Fig. 6-20 in Chapter 6: A u t o m m i c Neurotrmsmitters, Receptors, a ~ Effectors d for a description of t h e cellular e v e n t s that follow binding of B,-adrenergic receptors in pulmonary smooth muscle. Pa ras y m pa t he tic Prega M g lio M ic N e u YOMs P a r a s y m p a t h e t i c preganglionic n e u r o n s a r e l o c a t e d in t h e d o r s a l vagal nucleus. Their axons travel as part of t h e vagus nerve (CN X) to t h e pulmonary plexuses, where they synapse o n postganglionic neurons. The postganglionic neurons supply t h e smooth muscles a n d t h e glands of t h e bronchial t r e e , thereby producing bronchiolar constriction a n d glandular secretion. 3. What triggers an asthma attack?

Asthma is currently c o n s i d e r e d to be a n inflammatory disease t h a t is triggered by inhaled irritants, allergens, or other factors. Irritarzts a ~ Other d Factors S o m e people like Patty h a v e bronchial airways that a r e hyperreactive to nonimmunogenic stimuli such as cigarette smoke, air pollutants, cold dry air, exercise, a n d emotional factors. Sensory nerves stimulated b y t h e irritants cause a reflex Gro~chospasmvia t h e parasysmpathetic efferents (Figure CS8-2B). In addition, t h e stimulated sensory nerves r e l e a s e s u b s t a n c e s from their peripheral n e r v e e n d i n g s via a n axon reflex (e.g., s u b s t a n c e P, a sensory n e u r o t r a n s m i t t e r ) . T h e s e s u b s t a n c e s h a v e e f f e c t s s i m i l a r to t h o s e of inflammatory m e d i a t o r s (i.e.,s m o o t h m u s c l e contraction a n d glandular secretion). This mechanism is referred to as rzeurogerzic i ~ f l a m m a t i o(see ~ Fig. CS8-2A). Both reflex bronchospasm a n d neurogenic inflammation are normal responses to irritants. They are minor in nonasthma sufferers, b u t they are exaggerated in asthma patients. T h e specific pathogenesis of this form of a s t h m a is n o t w e l l u n d e r s t o o d , b u t it m a y also i n v o l v e r e l e a s e of inflammatory mediators from inflammatory cells. Specialist Information Breathing is controlled by inspiratory and expiratory neurons that are found in widely dispersed sites in the brain stem. Respiratory neurons drive the somatic motor neurons that control the striated muscles involved in breathing as well as the autonomic neurons described above. Respiration and circulation act together to effect respiratory gas exchange between the cells and the external environment. Many of the respiratory neurons reside in the same brain stem areas as do cardiovascular neurons. This anatomic arrangement may facilitate integration of cardiac and pulmonary function. There may also be a population of “cardiorespiratory” neurons, single neurons projecting to both cardiac and respiratory neurons, that coordinate circulation and respiration.

Case Study 8 - Patty's Puffer 223

Figure CS8-2 Reflex responses of pulmonary autonomic nerves to irritants These normal responses are exaggerated in some asthma sufferers: (A) Neurogenic inflammation; ( B ) Reflex bronchospasm.


Allergens Allergies contribute to s y m p t o m s in approximately 40 p e r c e n t of a s t h m a sufferers. Like Marilyn, s o m e people have a genetic predisposition to readily d e v e l o p IgE antibodies to common environmental allergens such as pollens, horse hair, or cat dander. When allergens initially e n t e r t h e body, they stimulate B cells which then d e v e l o p into antibody-forming plasma cells. Plasma cells synthesize a class of immunoglobulins called IgE. The IgE molecules bind to surface receptors o n m a s t c e l l s in t h e c o n n e c t i v e t i s s u e , t h u s s e n s i t i z i n g t h e m . T h e s e “sensitized” mast cells produce a n d store granules filled with inflammatory mediators (chemicals such as histamine a n d leukotrienes), which cause a n inflammatory response when they are released. S o m e sensitized mast cells then migrate into t h e pulmonary epithelium, which is t h e first site of contact for i n h a l e d allergens. O t h e r inflammatory cells such as e o s i n o p h i l s a n d neutrophils are also involved in t h e inflammatory process. During s u b s e q u e n t exposures to t h e s a m e antigen, t h e antigen reaches t h e sensitized mast cells, cross links surface-bound IgE, a n d causes t h e mast cells to degranulate a n d release inflammatory mediators. The inflammatory mediators cause t h e airway obstruction shown in Figure CS8-3.

Figure CS8-3 Events leading to an allergic asthma attack: 1 . Allergens are inhaled into the respiratory tract. 2 . These allergens bind to antibodies on sensitized mast cells in respiratory epithelium, or 3 . They pass through small breaks in the respiratory epithelium, and 4. Bind to antibodies on sensitized mast cells in submucosal space. 5. This antibody binding causes release of inflammatory mediators from mast cell granules (degranulation).

Inflammatory mediators cause the following clinical symptoms: 6. Contraction of bronchiolar smooth muscle cells + bronchiolar constriction; 7. Increased secretion of mucous glands in respiratory epithelium and mucoserous glands in bronchi + narrowing of lumen; 8. Relaxation of vascular smooth muscle + vasodilation; 9. Increased permeability of vessel walls -+ edema and swelling of tissues + further bronchiolar constriction; 10. Increased permeability of bronchiolar epithelium to allergens + enhanced clinical symptoms in submucosal space.



4. What causes airway obstruction during an asthma attack?

T h e t h r e e key e v e n t s that cause airway obstruction a r e as follows (Fig. CS8-3 a n d Figure CS8-4B): Bronc hospas m B r o n c h o s p a s m is t h e c o n t r a c t i o n of t h e b r o n c h i o l a r s m o o t h m u s c l e in response to inflammatory mediators a n d to parasympathetic nerve activity. Excess Secretion of Mucus Excess mucus secretion from t h e submucosal mucoserous glands is caused b y parasympathetic secretomotor signals (presumably in r e s p o n s e to t h e irritation p r o d u c e d b y t h e a l l e r g e n s ) a n d b y inflammatory m e d i a t o r s . Inflammatory mediators also cause oversecretion of mucus from goblet cells in t h e respiratory epithelium. Presumably, t h e mucus is i n t e n d e d to remove t h e molecules that are irritating t h e bronchi. However, t h e result is a further narrowing of t h e lumina. Edema (Swelling) of the Respiratory Tissues Edema of t h e respiratory tissues is caused b y fluid leaking out of t h e small blood vessels of t h e lungs. Inflammatory mediators released from inflammatory cells cause both vascular dilation (relaxation of smooth muscle cells) a n d increased vascular permeability.

Figure CS8-4 (A) Under normal conditions the diameter of the bronchiole and mucus secretion are controlled by sympathetic and parasympathetic nerves; (B) Inflammatory mediators from degranulating mast cells cause bronchiolar constriction and excess secretion of mucus; ( C ) Drugs from the puffer bind t o f32 receptors on bronchiolar smooth muscle and mast cells causing relaxation of the smooth muscle and inhibiting mast cell degranulation.


5. How did the drugs in the puffer relieve Patty's symptoms?

(Figure CS8-4C) The drugs in t h e puffer relieved Patty's symptoms in two ways:

* They caused relaxation of bronchiolar smooth muscle, thereby allowing t h e bronchioles to dilate, a n d They inhibited release of inflammatory mediators from inflammatory cells. The drug molecules that Patty inhaled passed through h e r pulmonary epithelium in large numbers a n d reacted with local adrenergic receptors. The most common antiasthmatic drugs a r e sympathomimetics (drugs that m i m i c t h e a c t i o n of s y m p a t h e t i c n e r v e s ) s u c h a s s a l b u t a m o l , metaproterenol, a n d terbutaiine. T h e s e drugs a r e selective agonists for p2a d r e n e r g i c r e c e p t o r s , which a r e e x p r e s s e d o n s u r f a c e m e m b r a n e s of pulmonary smooth muscle cells a n d mast cells. When inhaled drugs bind t h e p2 receptors, t h e y elicit a n intracellular c a s c a d e of c h a n g e s via t h e cyclic AMP (CAMP)s e c o n d - m e s s e n g e r s y s t e m . Within t h e p u l m o n a r y s m o o t h muscle cells, a n increase in cAMP m e d i a t e s relaxation, t h e r e b y allowing t h e bronchioles to dilate (see Fig. 6-20). Within t h e inflammatory cells, a n increase in cAMP inhibits t h e further r e l e a s e of i n f l a ~ m a t o r y mediators. Inflammatory m e d i a t o r s d e g r a d e quickly. O n c e t h e i r r e l e a s e from inflammatory cells is i n h i b i t e d , t h e i r concentration in t h e t i s s u e falls rapidly, a n d t h e bronchiolar d i a m e t e r , m u c u s s e c r e t i o n , a n d vascular changes all return to normal. Excess mucus is cleared from t h e airways b y t h e rhythmic action of t h e cilia.



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238 Autonomic Nerves Cranial nerve X.See Vagus nerve Craniosacral outflow, 95- I02 D

Deep cardiac plexus, 208 Defecation, 7 Defensive behavior, 63 Diabetes mellitus, 187-I88 Diurnal rhythm, 63 Dizziness. See Fainting; Lightheadedness Dorsal horn, 37, 40, 41 Dorsal vagal nucleus, 95

E Eating behavior, 59 Edema, 226 Edinger-Westphal nucleus, 50, 95, 97, 195 Effector cells, 73, 108, I 10, 1 16, 118-133 Efferent (motor)axons, 92 Ejaculation, 185-I87 Electrical synapses, I06 Emesis. See Vomiting Endocrine system, 58 Energy, 14 1 - 142 Enteric afferent fibers, 30 Enteric nervous system, 17, 103-104, 148, 150 Enteric neurons, 82, 96, 103, 104, 114, 1 I8 Erection, 1 78, 181 - 184, 187-188 Exocrine glands, 127 Exocrine secretory cells, 73 Extrinsic nerves affecting movement through gut, 150 modulating heart action, 208-21 I Eye accommodation of, 8, 50-51 effects of sympathetic and parasympathetic stimulation, 76 pu pi llary dilation/ constriction, 46, 192-193 Eyelid, 190, 191

F Fainting, 20 1-202,2 18 Familial dysautonomia, 28 Fenestrations, 162 Fever, 2 16 Flight or fight reaction, 134-I45 Fluid balance, 62 Fornix. 57

G Ganglia, 22-23 definition of, 67-68 See also specific types Gap junctions, 106, 107, 110, 1 I I Gastrointestinal tract, 76, 1 13114, 146-153

GDP. See Guanosine

dip hosphate Glandular epithelial cells, I 18 Glandular secretion, 127-128 Glossopharyngeal nerves, 35,44 Glucose, 141, 142 Glucose-6-phosphate, 14 1 - 142 C proteins, 119 GTP. See Guanosine triphosphate Guanosine diphosphate (GDP), 119

Guanosine triphosphate (CTP), 119

Gut innervation, 114, 157 movement, 7, 155-156 walls, 103, 157 See also Peristalsis

H Head, 24 Heart, 76, 138, 207-2 1 1 See also mder Cardiac Heart rate, 164 Heat conservation, 12 Heat loss, 2 15 Heat production, 2 15 Heat stroke, 2 17 Hirschsprung's disease, 152 Homeotherms, 2 I5 Horner's syndrome, 189-200 Hydroxyamphetamine, 196, 198 Hypothalamus, 49, 58-63, 79, 142 I

Inferior cervicaVstellate ganglion, 199 Inferior salivatory nucleus, 95, 98 Inflammatory mediators, 224225, 227 Insular cortex, 52, 53 Integrative neurons, 2 lntermediolateral cell column, 95-97 Intrinsic nerves coordinating heart action, 207 coordinating intestinal peristalsis, 148 Ips i Iateral sympathetic pathway, 190

L Lateral horn, 78, 79 Lateral zone, 58, 60 Lesions, 194-196, 198, 200 Lightheadedness, 144, 164 See also Fainting Limbic system, 49, 54-57 Liver, 138 Local circuits, 49, 70 Locus ceruleus, 67 Lower lumbar ganglia, 84 Lower motor neuron neurogenic bladder, 176

Lumbar ganglia, 84, 86, 88-90 Lungs, 76, 138

M Magnocellular neurons, 62 Mamillothalamic tract, 57 Mechanoreceptors. See Touch receptors Medial forebrain bundle, 57 Medial prefrontal cortex, 52, 53 Medial zone, 58, 60 Medulla, 66, 206 See also Adrenal medulla Megacolon, 152 Melanocytes, 19 Micturition, 66, 171, 173 Midbrain periaqueductal gray, 64 Middle cervical ganglion, 199 Midline nuclei, 60 Miosis, 192, 193 Mouth watering, 165, 166 Mucus secretion, 220, 221 , 226 Muscle acitivity, 137 Muscle cells, smooth. See Smooth muscle cells Myenteric plexus (of Auerbach), 103-104, 148, 149 Myogenic autoregulation, 2 14

N Nausea, 44-45 Neural crest cells, 16-20,25, 27, 150, 151, 152 Neural plate, 14, 15 Neuroeffector cells. See Gap junctions Neuroeffector junctions, 108, 109 Neuroeffector mechanisms, 106 N e u rofi brom atosis, 28 Neurogenic bladder, 174-1 76 Neurogenic inflammation, 222, 223 Neuromodulators, 1 12- 1 13 Neuronal cell bodies, 14 Neuropeptides, 1 13 Neuropeptide Y, 1 13 Neurotransmission, 1 12- 1 19 Neurotransmitters, 25-27, 106, 107 autonomic, 1 12- 1 14 classic, 112 major, 1 16-117 recently discovered, 1 12- 1 13 sympathetic, 137 Nicotinic receptors, 25, 1 15-1 18 Nociceptors, 34, 39 Nonreflex neurogenic bladder, 176 Noradrenaline, 6, 25, 26, 76, 112, 113, 116, 117, 132, 133, 137, 138, 196 Norepinephrine. See No rad re nal i n e Nucleus ambiguus, 95

Index 239 Nucleus of the tractus solitarius, 37, 206, 220 0

Olfactory tracts/stria, 57 Orbitofrontal cortex, 52, 53 Otic ganglion, 98, 99 Oxytocin, 59

P Pacemaker cells, 120- 126 Pain receptors, 34, 39 referred, 42-43 visceral, 30, 34, 35, 42 visceral and somatic in common pathway, 40-4 1 Parabrachial nucleus, 67 Paraganglionic neurons, 2 1 Parasympathetic afferents, 35-37 Parasympathetic autonomic nerves, 72 Parasympathetic axons, 150 Parasympathetic division, 75, 95- 102

Parasympathetic ganglia, 16, 20, 21, 24, 97-98

Parasympathetic innervation, 208

Parasympathetic neurotransmitters/ receptors, 27 Parasympathetic pathways, 209, 2 I 2

Parasympathetic postganglionic neurons, 99 Parasympathetic preganglionic neurons, 65, 74, 95, 96-98, 180, 222

Parasympathetic stimulation, 76, 103, 123-126, 197 Paravertebral ganglia, 79-82, 84 Parvocellular neurons, 62 Pelvic ganglia, 90-9 1 , I02 Pelvic splanchnic nerves, 9 1 Penis, 179, 181-188 Peristalsis, 70, 130, 146- 150, 16 1 Periventricular zone, 58, 60 Plasma osmolality, 62 Plasma volume, 62 Pons, 66 Postganglionic axons, 24, 77, 143 Postganglionic neurons, 4-5, 24, 49, 68-69, 74, 79, 82-84, 96, 99, 108, 116-1 18, 150, 180 Preaortic ganglia, 79, 81, 92, 93, 1 I4 Preaortic plexuses, 92, 93 Precapillary arterioles, I4 1 Preganglionic axons, 2 1-23, 74, 77, 78, 86, 97-98, 107, 143 Preganglionic neurons, 4-5, 2 1 23, 49, 65, 68, 72, 74, 79, 80, 95-98, 1 16, 180, 2 10, 220, 222 Prevertebral ganglia, I I 4

Primary afferent fibers, 30 Pterygopalatine ganglion, 98, 99 Ptosis, 190, 191 Pulmonary smooth muscle, 132 Pupillary dilation/ constriction, 46

Pyrogens, 2 16

R Receptors adrenergic, 1 18, 133, 2 10 chemoreceptors, 32, 33, 34 cholinergic, 1 18, I33 at effector cells, 1 18-I 19 nicotinic, 25, I 15- I 18 pain, 34, 39 on postganglionic cells, 1 151 I8

Reflex bronchospasm, 2 2 2 , 223 Reflex neurogenic bladder, 174, 175 Reproductive behavior. See Sexual behavior Respiration. See Breathing Respiratory neurons, 66 Respiratory tissues, 226 Reticular centers in brain stem. See Brain stem, reticular centers in Riley-Day syndrome. See Fa mi lial d ysau tonomia S

Sacral ganglia, 84, 89-91 Sacral spinal cord, 95-97 Sacral splanchnic nerves, 9 I Salivation, 44 Salivatory nuclei, 95, 98 Secretomotor signals, 165 Secretory cells, 127-128 Semen, 185, 186 Sensorimotor cortex, 52, 53 Sensory (afferent)axons, 72, 92 Sensory fibers, 30 Sensory ganglia, 18 Sensory neurons, 2 , 35, 37 Sensory nucleus, 65 Sexual behavior, 12, 59, 1 78- I88 Sinoatrial node, 207 Skin, 76, 164 Smooth muscle cells, 73, 118, 129- I32

Somatic effectors, 4 Somatic motor neurons, 4, 6, 1 1 , 180

Somatic motor neuron terminals, 6 Somatic motor pathways, 158, 160

Somatic motor response, 8 Somatic nervous system, 2 interaction with components of autonomic nervous system, 6- 10 motor components, 4-6

organization of, 2 Somatic pain, 39, 40 Somatic receptors, 39 Somatic sensory information, 39-43

Somatic sensory pathways, 38, 40

Spinal cord, 77,88 dorsal horn, 37, 40, 41 formation of, 14- 15 lateral horn, 78, 79 paravertebral ganglia, 82-83 sacral, 95-97 transection’s effect on bladder, 174 Spinal shock, 65 Stretch receptors, 32, 34 Stria medullaris thalami, 57 Stria terminalis, 57 Submandibular ganglion, 98, 99 Submucosal plexus (of Meissner), 103- 104, 148 Superficial cardiac plexus, 208 Superior cervical ganglion, I99 Superior salivatory nucleus, 95, 98

Swallowing, 7 Sweat glands, 73, 79, 1 17, 1 18, 216

Sweating, 144, 198 Sympathetic afferents, 35 Sympathetic autonomic nerves, 72 Sympathetic cascade, I37 Sympathetic division, 75, 78-95 Sympathetic ganglia, 16, 20, 2 1 , 24, 82, 83

Sympathetic innervation, 2 10 Sympathetic nervous system, 190

Sympathetic neurotransmitters/receptors, 25-26

Sympathetic paravertebral ganglia. See Paravertebral ganglia Sympathetic pathways, 2 1 1, 2 1 2 , 213

Sympathetic postganglionic neurons, 74, 79, 82-84, 116, 117, 180

Sympathetic preganglionic axons, 74, 80-81 Sympathetic preganglionic neurons, 74, 79, 80, 1 16, 2 10, 220,222

Sympathetic stimulation, 76, 103, 122, 142, 198

Sympathetic vasoconstrictor system, 2 18 Synaptic cleft, 107, 108 Synaptic structure, 106-1 1 I Syncope, 202 Synergistic action, 72


T

V

Taste, 44 Tearing, 165, 166 Temperature, 58-59, 2 15-216 Terminal boutons, I07 Testes, 179 Thalamocortical fibers, 57 Thermal receptors, 34, 39 Thermoregulation, 58-59 Thoracic ganglia, 84, 86-89, 100 Thoracolumbar outflow, 78-95 Touch receptors, 39 Toxins, blood-borne, I62 True synapses, 107, 109 Trunk, 24

Vagus nerve, 35, 44, 100- 10 I , 150, 208 Varicosities, 108 Vasa deferentia, 179 Vascular beds, 140, 2 13, 2 14 Vascular smooth muscle, 132 Vasoconstriction, 2 12 Vasodilation, 2 12 Vasomotion, 2 14 Vasomotor center, 2 18 Visceral afferents, 30, 35, 37 Visceral pain, 30, 34, 35, 38 Visceral receptors, 32-34 Visceral sensory fibers, 220 Visceral sensory information, 30-3I , 32-38 Visceral sensory nuclei, 37 Visceral sensory pathways, 35 Volume transmission, 108

U Upper motor neuron neurogenic bladder, 174, 175

Vomiting, 7, 154-166 autonomic motor pathways, 161 brain stem center coordinating, 158 emetic center in brain, 162 gastrointestinal events during, 158 sensory pathways, 163 somatic motor pathways, 158, 160 vo n R e ckl i ng h au sen 's d isease . See Neurofibromatosis

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