The Primate Nervous System, Part III

THE PRIMATE NERVOUS SYSTEM PART I11 This Page Intentionally Left Blank HANDBOOK OF CHEMICAL NEUROANATOMY Series Edi...

Author: Floyd E. Bloom | A. BjÃ¶rklund | T. HÃ¶kfelt

44 downloads 896 Views 37MB Size Report

This content was uploaded by our users and we assume good faith they have the permission to share this book. If you own the copyright to this book and it is wrongfully on our website, we offer a simple DMCA procedure to remove your content from our site. Start by pressing the button below!
Report copyright / DMCA form

DOWNLOAD PDF

THE PRIMATE NERVOUS SYSTEM PART I11

This Page Intentionally Left Blank

HANDBOOK OF CHEMICAL NEUROANATOMY Series Editors: A. Bjorklund and T. Hokfelt

Volume 15

THE PRIMATE NERVOUS SYSTEM, PART TIT Editors :

F.E. BLOOM Department of Neuropharmacology, The Scripps Research Institute, La Jolla, CA 92037. USA

A. BJORKLUND Department of Medical Cell Research, Wallenberg Neuroscience Center, University of Lund, S223 62 Lund, Sweden

T. HOKFELT Department of Histology and Neurosciences, Karolinska Institute. S104 01 Stockholm, Sweden

1999

ELSEVIER Amsterdam

~

Lausanne - New York

~

Oxford

~

Shannon - Singapore - Tokyo

EESEVIER SCIENCE B.V. Sara Burgerhartstraat 25 P.O. Box 21 1, 1000 A E Amsterdam, The Netherlands

0 1999 Elsevier Science B.V. All rights reserved.

This work is protected under copyright by Elsevier Science, and the following terms and conditions apply to its use: Photocopying Single photocopies of single chapters may be made for personal use as allowed by national copyright laws. Permission of the Publisher and payment of a fee is required for all other photocopying, including multiple or systematic copying, copying for advertising or promotionalpurposes, resale, and all forms of documentdelivery. Special rates are available for educational institutions that wish to make photocopies for non-profit educational classroom use. Permissions may be sought directly from Elsevier Science Rights & Permissions Department, PO Box 800, Oxford OX5 IDX, UK; phone: (+44) 1865 843830, fax: (+44) 1865 853333, e-mail: [email protected]. You may also contact Rights & Permissions directly through Elsevier’s home page (http:Nwww.elsevier.nl),selecting first ‘Customer Support’, then ‘General Information’, then ‘Permissions Query Form’. In the USA, users may clear permissions and make payments through the Copyright Clearance Center, Inc., 222 Rosewood Drive, Danvers, MA 01923, USA; phone: (978) 7508400, fax: (978) 7504744, and in the UK through the Copyright Licensing Agency Rapid Clearance Service (CLARCS), 90 Tottenham Court Road, London WIP OLP, UK; phone: (+44)171 631 5555; fax: (+44)171 631 5500. Other countries may have a local reprographic rights agency for payments. Derivative Works Tables of contents may be reproduced for internal circulation, but permission of Elsevier Science is required for external resale or distribution of such material. Permission of the Publisher is required for all other derivative works, including compilations and translations. Electronic Storage or Usage Permission of the Publisher is required to store or use electronically any material contained in this work, including any chapter or part of a chapter. Except as outlined above, no part of this work may be reproduced,stored in a retrieval system or transmitted in any form or by any means, electronic, mechanical, photocopying, recording or otherwise, without prior written permission of the Publisher. Address permissions requests to: Elsevier Science Rights & Permissions Department, at the mail, fax and e-mail addresses noted above. Notice No responsibility is assumed by the Publisher for any injury and/or damage to persons or property as a matter of products liability, negligence or otherwise, or from any use or operation of any methods, products, instructions or ideas contained in the material herein. Because of rapid advances in the medical sciences, in particular, independent verification of diagnoses and drug dosages should be made.

First edition 1999 Library of Congress Cataloging in Publication Data A catalog record from the Library of Congress has been applied for.

ISBN: ISBN:

@

0-444-50043-X (volume) 0-444-90340-2 (series)

The paper used in this publication meets the requirements of A N S I N S O 239.48-1992 (Permanence of Paper). Printed in The Netherlands.

List of Contributors G.F. ALHEID Department of Physiology and Institute for Neuroscience Northwestern University Morton, Rm. 5-654 303 E. Chicago Ave. Chicago, IL 60611-3008 USA

L. HEIMER Departments of Otolaryngology Head and Neck Surgery, and Neurological Surgery Health Sciences Center, Box 396 University of Virginia Charlottesville, VA 22908 USA

D.G. AMARAL Center for Neuroscience University of California, Davis 1544 Newton Court Davis, CA 95616 USA

Y. KOBAYASHI Department of Psychiatry Center for Neuroscience and California Regional Primate Research Center University of California, Davis Davis, CA 95616 USA and Department of Anatomy Kyorin University School of Medicine 6-20-2 Shinkawa Mitaka, Tokyo 181 Japan

C. BERGSON Medical College of Georgia Department of Pharmacology and Toxicology, Room CB3730 Augusta, GA 30912-2300 USA P.S. GOLDMAN-RAKIC Section of Neurobiology Yale University School of Medicine 333 Cedar Street New Haven, CT 06520-8001 USA

Section of Neurobiology Yale University School of Medicine 333 Cedar Street New Haven, CT 06520-8001 USA

A.M. GRAYBIEL Department of Brain and Cognitive Sciences Massachusetts Institute of Technology Bldg E25, Room 618 Cambridge, MA 02139 USA

M.S. LIDOW Department of Oral and Craniofacial Biological Science University of Maryland Dental School 666 West Baltimore Street, Room 5-A-12 Baltimore, MD 21201-1586 USA

L.S. KRIMER

J. MARKSTEINER Department of Psychiatry University of Innsbruck Anichstrasse 35 A-6020 Innsbruck Austria J.S. DE OLMOS Instituto de Investigacion Medica Mercedes y Martin Ferreyra Cordoba Argentina J. PEARSON 698 State Street Portsmouth, NH 03801 USA JOHN B. PENNEY t Neurology Research Massachusetts General Hospital Warren 508 55 Fruit Street Boston, MA 02114 USA N. SAKAMOTO Department of Anatomy Yokohama City University School of Medicine Fukuura 3-9, Kanazawa-ku Yokohama 236-0004 Japan

vi

K. SHINODA Department of Anatomy II Yamaguchi University School of Medicine 1144 Kogushi, Ube Yamaguchi 755 Japan R.C. SWITZER III NeuroScience Associates 10915 Lake Ridge Drive Knoxville, TN 37922 USA G.V. WILLIAMS Section of Neurobiology Yale University School of Medicine 333 Cedar Street New Haven, CT 06520-8001 USA S.M. WILLIAMS Department of Neurobiology Duke University Medical Center Bryan Research Bldg. for Neurobiology Research Drive, Room 319 Durham, NC 27710 USA

Preface This volume is the third and final part of the planned coverage of the neurochemical circuitry of the primate central nervous system. The five chapters included in this volume complement and integrate magnificently with the two prior volumes. Furthermore, these chapters further extend the goals of the primate series to develop a broadly based coverage of human and non-human primate chemical neuroanatomic details in a concentrated publication in order to make clear the known and desirable appreciation for differences between and among subsets of primate brains. In this final volume, the coverage of brain regions includes those which lie at the core of some of the most intensively studied human neurological and psychiatric disorders. Heimer, with his colleagues Alheid, de Olmos and Sakamoto, provides a two-fold exposition on the human forebrain. They first present a detailed and comprehensive overview and mini-atlas in chemically defined details of the entire human forebrain. Then, in a second extensive assessment and analysis, Heimer, Alheid and colleagues specifically focus on the basal forebrain, a region critical for a wide range of human problems ranging from substance abuse to Alzheimer's disease. Graybiel and Penney provide a critical synthesis of the primate basal ganglia, a region under intense scrutiny for the organization of motor programs, and for their dysfunctions in Parkinson's disease, Huntington's disease and other problems. Kobayashi and Amaral portray the chemical and anatomic details of the primate hippocampal formation in extenso, and with specific concern over the memory and emotional functions attributed to this complex. Lastly, Goldman-Rakic and colleagues examine the rapidly growing literature on the mesocortical projection of dopaminergic circuits onto the primate frontal cortex, a system highly linked to higher order mental abstractions, as well as the dysfunctions of schizophrenia. As extensive as these chapters and those of the prior volumes have been, scholars will recognize that the laying out of these status reports on our still vastly incomplete examination of the primate brains is an opportunity for progress. While we may now recognize the main properties of their major circuitry, we may now also recognize the need for far more detailed assessments of the inter-individual differences in qualitative and quantitative aspects of their circuits. If these volumes will have served their purpose, they will be really just another beginning for those who will complete these needed details. Tragically, during the production of this volume, Dr. J. Penney died quite unexpectedly. His contributions to our science and to the specific insights into the basal ganglia will long be remembered, and we dedicate this volume to his memory. La Jolla, Lund and Stockholm, July 1999 FLOYD E. BLOOM

ANDERS BJORKLUND

TOMAS HOKFELT

vii


Contents I.

THE HUMAN BASAL FOREBRAIN. PART I. AN OVERVIEW N. SAKAMOTO, J. PEARSON, K. SHINODA, G.F. ALHEID, J.S. DE OLMOS AND L. HEIMER 1. Introduction 2. Surface topography 2.1. Basal cortex 2.2. Olfactory peduncle and olfactory tract 2.3. Olfactory tubercle and anterior perforated space 2.4. Olfactory trigone 3. Overview of basal forebrain structures 3.1. Area diagonalis (diagonal band of Broca) and basal nucleus of Meynert 3.2. Olfactory bulb projection areas 3.3. The claustrum 3.4. Dorsal striatum and dorsal pallidum 3.5. Ventral striatum and ventral pallidum 3.6. Striatum in the temporal lobe 3.7. Extended amygdala 3.8. Amygdaloid body 3.9. Small-celled islands 4. Coronal sections through the basal forebrain 4.1. Materials and methods 5 . Acknowledgements 6. References Mini-atlas of coronal sections through the basal forebrain

1 1 2 2 3 6 6 6 7 7 8 9 9 10 11 11 11 11 12 13 15

11. THE HUMAN BASAL FOREBRAIN. PART 11.- L. HEIMER, J.S. DE OLMOS, G.F. ALHEID, J. PEARSON, N. SAKAMOTO, K. SHINODA, J. MARKSTEINER AND R.C. SWITZER I11 Introduction 1.1, ‘Basalis’ region 1.1.1. ‘Basalkerncomplex’ of Brockhaus 1.1.2. Basal nucleus of Meynert 2. Ventral striatopallidal system 2.1. Ventral striatum 2.1.1. The heterogeneity of ventral striatum 2.1.2. Interface islands 2.1.3. Core and shell subdivisions of the accumbens 2.2. Ventral pallidum 3. Extended amygdala 3.1. Bed nucleus of stria terminalis 3.1.1. Lateral division of bed nucleus 1.

57 60 60 63 64 65 67 82 89 90 93 98 98 ix

4.

5.

6. 7.

8. 9. 10.

3.1.2. Medial division of bed nucleus 3.2. Sublenticular components of extended amygdala 3.2.1. Central division of the sublenticular extended amygdala 3.2.2. Medial division of sublenticular extended amygdala 3.3. Centromedial amygdala 3.3.1. Central amygdaloid nucleus 3.3.2. Medial amygdaloid nucleus 3.4. Stria terminalis components of the extended amygdala 3.4.1. Supracapsular part of the stria terminalis 3.4.2. Subcapsular part of the stria terminalis 3.5. Transition areas between extended amygdala and the striatopallidal system Olfactory system 4.1. Primary non-amygdaloid olfactory bulb projection areas 4.1.1. Anterior olfactory nucleus (retrobulbar area) 4.1.2. Primary olfactory cortex (‘piriform cortex’) 4.1.3. Insular and temporopolar periallocortical areas 4.1.4. Ventral striatum vs olfactory tubercle 4.2. Olfactory association areas in the orbitofrontal cortex 4.3. Olfactory amygdala 4.4. Olfactory entorhinal field Superficial amygdala and the laterobasal complex 5.1. General structure of the amygdala 5.2. Superficial amygdala 5.2.1. Is the superficial amygdala a cortical or subcortical structure? 5.2.2. Superficial amygdala: a plethora of terms 5.2.3. Review of superficial amygdaloid structures 5.3. Laterobasal amygdaloid complex 5.3.1. Lateral amygdaloid nucleus 5.3.2. Basolateral amygdaloid nucleus 5.3.3. The basomedial amygdaloid nucleus 5.3.4. The paralaminar amygdaloid nucleus 5.4. Intramedullary gray substance and intercalated (interface) islands Concluding remarks Appendix: comparison of nomenclature for the human amygdala 7.1. Preface 7.2. Footnotes to tables Acknowledgements Abbreviations References

105 105 107 114 114 116 122 124 125 138 144 146 147 I47 148 151 152 153 154 155 156 156 161 161 162 169 176 178 181 183 185 186 187 187 187 188 206 206 209

111. CHEMICAL ARCHITECTURE OF THE BASAL GANGLIAA.M. GRAYBIEL AND J.B. PENNEYt 1. Introduction 2. Systems approach to the basal ganglia 2.1. The basal ganglia proper and their allied nuclei 2.2. The connections of the basal ganglia: An overview X

227 228 228 23 1

2.2.1. 2.2.2. 2.2.3. 2.2.4.

The direct pathway The indirect pathway The striosomal output pathway General modular architecture of the striatum : striosomes and matrisomes 2.2.5. Loop systems of the basal ganglia 2.3. Transmitter-related compounds associated with basal ganglia pathways 2.4. Neuropeptides in basal ganglia pathways 2.5. Neurotransmitter-related compounds in striatal interneurons 3. Functional concepts about the basal ganglia 3.1. Movement disorders 3.1.1. Ballism 3.1.2. Parkinson’s disease 3.1.3. Huntington’s disease 3.1.4. Dystonia 3.2. Neuropsychiatric disorders 4. Chemically specified subsystems : receptor systems in the basal ganglia 4.1. Receptors associated with basal ganglia afferents 4.1.1. Glutamate receptors 4.1.2. Dopamine receptors 4.1.3. Serotoninergic receptors 4.1.4. Adrenergic receptors 4.1.5. Glycine receptors 4.2. Receptors associated with intrinsic basal ganglia pathways 4.2.1. GABA receptors 4.2.2. Cholinergic receptors 4.2.3. Adenosine receptors 4.2.4. Opiate receptors 4.2.5. Tachykinin receptors 4.2.6. Cannabinoid receptors 4.2.7. Somatostatin receptors 5. Future directions 5.1. Functional considerations: The involvement of basal ganglia dysfunction in the production of disordered movement 6. Acknowledgement 7. References

232 232 235 235 237 240 245 247 247 247 248 249 252 255 256 257 258 258 26 1 262 263 263 263 263 265 265 265 266 266 267 267 267 270 270

IV. CHEMICAL NEUROANATOMY OF THE HIPPOCAMPAL FORMATION AND THE PERIRHINAL AND PARAHIPPOCAMPAL CORTICES - Y. KOBAYASHI AND D.G. AMARAL

1. Introduction 1.1. Why the hippocampal formation? 1.2. Why include the perirhinal and parahippocampal cortices? 1.3. Organization of the chaptcr 2. Overview of the components of the medial temporal lobe 3. Cytoarchitectonic organization of the hippocampal formation

285 286 286 288 293 297

xi

Regional and cytoarchitectonic features of the perirhinal and parahippocampal cortices 5. An overview of the connectivity of the hippocampal formation 5.1. Intrinsic connections of the hippocampal formation 5.2. Connections between the perirhinal and parahippocampal cortices and the hippocampal formation 5.3. Other extrinsic connections of the hippocampal formation 6. Dentate gyrus 6.1. Glutamate system 6.1.1. Glutamate 6.1.2. Glutamate receptors 6.1.3. NMDA receptors 6.1.4. AMPA/kainate receptors 6.1.5. Metabotropic glutamate receptors 6.1.6. Aspartate 6.2. Cholinergic system 6.2.1. Cholinergic fiber systems 6.2.1.1. Molecular layer 6.2.1.2. Granule cell layer 6.2.1.3. Polymorphic cell layer 6.2.2. Cholinergic receptor systems 6.3. GABAergic system 6.3.1. GABAergic fiber innervation 6.3.2. GABAergic cell bodies 6.3.3. GABAergic receptors 6.4. Monoamines 6.4.1. Noradrenaline 6.4.2. Adrenaline 6.4.3. Dopamine 6.4.4. Serotonin 6.5. Peptides 6.5.1. Substance P 6.5.2. Cholecystokinin 6.5.3. Vasoactive intestinal peptide 6.5.4. Neurotensin 6.5.5. Somatostatin 6.5.6. Neuropeptide Y 6.5.7. Opioid peptides (dynorphin, enkephalin) 6.5.8. Galanin 6.6. Calcium-binding proteins 6.6.1. Parvalbumin 6.6.2. Calbindin 6.6.3. Calretinin 6.7. Hormone receptor sites 6.8. Enzymes 6.8.1. Cytochrome oxidase 6.8.2. Nitric oxide synthase and NADPH-diaphorase 6.9. Trophic factors 6.9.1. Nerve growth factor 4.

xii

304 306 306 336 336 337 337 337 337 337 338 338 339 339 339 339 340 340 34 1 341 34 1 342 343 343 343 344 344 344 345 345 346 346 346 346 347 347 347 348 348 350 350 35 1 351 351 352 352 352

353 353 353 7. Hippocampus 353 7.1. Glutamate system 353 7.1.1. Glutamate 353 7.1.2. NMDA receptors 354 7.1.3. AMPA-kainate receptors 354 7.1.4. Metabotropic glutamate receptors 354 7.1.5. Aspartate 355 7.2. Cholinergic system 355 7.2.1. Cholinergic fiber systems 356 7.2.2. Cholinergic receptors 356 7.3. GABAergic system 356 7.3.1. Fiber innervation 357 7.3.2. GABAergic cell bodies 359 7.3.3. GABAergic receptors 359 7.4. Monoamines 359 7.4.1. Noradrenaline 7.4.2. Dopamine 359 360 7.4.3. Serotonin 360 7.5. Peptides 360 7.5.1. Substance P 3 60 7.5.2. Cholecystokinin 361 7.5.3. Neurotensin 361 7.5.4. Somatostatin 361 7.5.5. Neuropeptide Y 362 7.5.6. Opioid peptides 362 7.5.7. Galanin 362 7.6. Calcium-binding proteins 362 7.6,l. Parvalbumin 7.6.1.1. Distribution of parvalbumin-positive fibers 362 7.6.1.2.Distribution of parvalbumin-positive cell bodies 363 364 7.6.2. Calbindin 365 7.6.3. Calretinin 365 7.7. Hormone receptor sites 365 7.8. Enzymes 365 7.8.I . Cytochrome oxidase 366 7.8.2. Nitric oxide synthase and NADPH-diaphorase 366 7.8.3. Other enzymes 366 7.9. Trophic factors 366 7.9.1. Nerve growth factor 366 7.9.2. Ciliary neurotrophic factor 366 7.9.3. Brain-derived neurotrophic factor 366 8. Subiculum 366 8.1. Glutamate system 366 8.1.1. Glutamate 367 8.1.2. NMDA receptors 367 8.1.3. AMPA-kainate receptors 8.1.4. Metabotropic glutamate receptors 367

6.9.2. Ciliary neurotrophic factor 6.9.3. Brain-derived neurotrophic factor

...

Xlll

8.1.5. Aspartate 8.2. Cholinergic system 8.2.1. Cholinergic fiber systems 8.2.2. Cholinergic receptors 8.3. GABAergic system 8.3.1. Fiber innervation 8.3.2. GABAergic cell bodies 8.3.3. GABAergic receptors 8.4. Monoamines 8.4.1. Noradrenaline 8.4.2. Dopamine 8.4.3. Serotonin 8.5. Peptides 8.5.1. Substance P 8.5.2. Cholecystokinin 8.5.3. Neurotensin 8.5.4. Somatostatin 8.5.5. Neuropeptide Y 8.5.6. Opioid peptides 8.5.7. Galanin 8.6. Calcium-binding proteins 8.6.1. Parvalbumin 8.6.1.1. Distribution of parvalbumin-positive fibers 8.6.1.2. Distribution of parvalbumin-positive cells 8.6.2. Calbindin 8.6.3. Calretinin 8.7. Hormone receptor sites 8.8. Enzymes 8.8.1. Cytochrome oxidase 8.8.2. Nitric oxide synthase and NADPH-diaphorase 8.9. Trophic factors 8.9.1. Nerve growth factor 8.9.2. Ciliary neurotrophic factor 8.9.3. Brain-derived neurotrophic factor 9. Presubiculum and parasubiculum 9.1. Glutamate system 9.1.1. AMPA receptors 9.2. Cholinergic system 9.2.1. Cholinergic fiber systems 9.2.1.1. Presubiculum 9.2.1.2. Parasubiculum 9.2.2. Cholinergic receptors 9.3. GABAergic system 9.3.1. Fiber innervation 9.3.2. GABAergic cell bodies 9.3.3. GABAergic receptors 9.4. Monoamines 9.4.1. Noradrenaline 9.4.2. Dopamine

xiv

367 367 367 368 368 368 368 368 369 369 369 369 369 369 369 369 370 370 370 370 370 370 370 37 1 371 371 372 372 372 372 372 372 372 372 373 373 373 373 373 373 373 374 314 374 374 375 375 375 375

9.4.3. Serotonin 9.5. Peptides 9.5.1. Substance P 9.5.2. Cholecystokinin 9.5.3. Neurotensin 9.5.4. Somatostatin 9.5.5. Neuropeptide Y 9.5.6. Opioid peptides 9.5.7. Galanin 9.6. Calcium-binding proteins 9.6.1. Parvalbumin in the presubiculum 9.6.1.1. Distribution of parvalbumin-immunoreactive fibers 9.6.1.2. Distribution of parvalbumin-immunoreactive cells 9.6.2. Parvalbumin in the parasubiculum 9.6.2.1. Distribution of parvalbumin-immunoreactive fibers 9.6.2.2. Distribution of parvalbumin-immunoreactive cells 9.6.3. Calbindin 9.6.4. Calretinin 9.7. Hormone receptor sites 9.8. Enzymes 9.8.1. Cytochrome oxidase 9.8.2. Nitric oxide synthase and NADPH-diaphorase 9.9. Trophic factors 10. Entorhinal cortex 10.1. Glutamate system 10.1.1. AMPA-kainate receptors 10.2. Cholinergic system 10.2.1. Cholinergic fiber systems 10.2.2. Cholinergic receptors 10.2.2.1. Muscarinic receptors 10.2.2.2. Nicotinic receptors 10.3. GABAergic system 10.3.1. Fiber innervation 10.3.2. GABAergic cell bodies 10.4. Monoamines 10.4.1. Noradrenaline 10.4.2. Dopamine 10.4.3. Serotonin 10.5. Peptides 10.5.1. Substance P 10.5.2. Cholecystokinin 10.5.3. Neurotensin 10.5.4. Somatostatin 10.5.5. Neuropeptide Y 10.5.6. Opioid peptide

375 375 375 375 375 376 376 376 376 376 376 376 376 377 377 377 377 377 378 378 378 378 378 378 378 378 379 379 380 380 380 38 1 38 1 38 1 382 382 382 383 383 383 384 384 384 385 385 xv

10.5.7. Galanin 10.6. Calcium-binding proteins 10.6.1. Parvalbumin 10.6.1.1. Distribution of parvalbumin-immunoreactive fibers 10.6.1.2. Distribution of parvalbumin-immunoreactive cells 10.6.2. Calbindin 10.6.3. Calretinin 10.7. Hormone receptor sites 10.8. Enzymes 10.8.1. Cytochrome oxidase 10.8.2. Nitric oxide synthase and NADPH-diaphorase 10.9. Trophic factors 10.9.1. Nerve growth factor 10.9.2. Ciliary neurotrophic factor 10.9.3. Brain-derived neurotrophic factor 11. Perirhinal cortex 1 1.1. Glutamate system 11.2. Cholinergic system 11.3. GABAergic system 11.4. Monoamines 11.4.1. Noradrenaline 11.4.2. Dopamine 11.4.3. Serotonin 11.5. Peptides 1 I S.1. Somatostatin 11.5.2. Neuropeptide Y 11.6. Calcium-binding proteins 11.6.1. Parvalbumin 11.7. Hormone receptor sites 11.8. Enzymes 11.8.1. Nitric oxide synthase and NADPH-diaphorase 11.9. Trophic factors 11.9.1. Nerve growth factor 12. Parahippocampal cortex 12.1. Glutamate system/cholinergic system/GABAergic system/monoamines 12.2. Peptides 12.2.1. Substance P 12.3. Calcium-binding proteins 12.4. Hormone receptor sites 12.5. Enzymes 12.5.1. Nitric oxide synthase and NADPH-diaphorase 12.6. Trophic factors 13. Concluding remarks 14. Abbreviations 15. References

xvi

385 385 385 385 386 386 387 387 387 387 387 388 388 388 388 388 388 388 388 388 388 389 389 389 389 389 389 389 389 390 390 390 390 390 390 390 390 390 390 39 1 39 1 39 1 39 1 392 393

V.

THE PRIMATE MESOCORTICAL DOPAMINE SYSTEM P.S. GOLDMAN-RAKIC, C. BERGSON, L.S. KRIMER, M.S. LIDOW, S.M. WILLIAMS AND G.V. WILLIAMS 1. 2. 3. 4.

5.

6. 7. 8. 9.

10. 11.

Introduction Primate specialization in the brainstem origin and organization of the mesocortical dopamine system Qualitative organization of the dopamine innervation of cerebral cortex Quantitative analysis of dopamine contacts on pyramidal and nonpyramidal neurons Electronmicroscopic evidence of dopamine synaptic triads and D 1 receptor localization in spines Dopamine innervation of the microvasculature Dopamine D1 and D2 family of receptors in the cerebral cortex 7.1. Localization of the D1 family of DA receptors in prefrontal cortex 7.2. Localization of the D2 family of DA receptors in prefrontal cortex Role of dopamine receptors in cortical function Regulation of cortical dopamine receptors as targets of antipsychotic drugs 9.1. Effect of antipsychotic medications on the D2 receptors in the primate cerebral cortex Summary and future directions References

Subject Index

403 403 406 408 409 41 1 412 412 413 416 420 420 422 423 429

xvii


CHAPTER I

The human basal forebrain. Part I. An overview N. SAKAMOTO, J. PEARSON, K. SHINODA, G.F. ALHEID, J.S. DE OLMOS AND L. H E I M E R

1. I N T R O D U C T I O N Most of the detailed anatomy of the basal forebrain has been established in rats over the period of the last two decades. This introduction is entirely based on sections of the human brain. (When needed for clarification of an anatomical detail or choice of terms, occasional reference to non-human primates will be made in this and the succeeding chapter). A rapidly increasing collection of papers on monkeys and humans is expanding our understanding of primate chemical neuroanatomy. Our description will focus on those cytoarchitectonic and neurochemical markers which are most relevant to understanding the organization of the human basal forebrain. In this chapter the surface topography of the basal forebrain will be discussed and its underlying structures will be introduced. We provide a mini-atlas of the human forebrain consisting of coronal Klfiver-Barrera (K1-B) stained serial sections with matching sections stained for enkephalin (ENK), substance P (SP) and acetylcholinesterase (ACHE) that will also serve as a base for the more detailed anatomical descriptions in the next chapter. Accordingly, the individual sections in the atlas are identified in both chapters with their atlas titles K1-B 1, K1-B 2..., E N K 1, E N K 2... etc., rather than figure numbers related to this chapter alone; abbreviations for both chapters are combined and included at the end of chapter II. The mini-atlas extends from the orbitofrontal cortex slightly behind the point where the olfactory stalk attaches to the orbital surface to a level through the posterior end of the amygdaloid body and the rostral subthalamic nucleus. The first 9 levels (K1-B 1-9) are chosen at roughly equal intervals; the distances between each of the last 3 coronal levels (K1-B 10-12) are approximately double those of the others. In order to facilitate discussion of the various functional-anatomical basal forebrain systems in the following chapter, we have applied color-highlighting for several forebrain areas (magenta for olfactory bulb projection areas, yellow for central division of extended amygdala and green for medial division of extended amygdala).

2. S U R F A C E T O P O G R A P H Y

Most of the systems of the basal forebrain reach the ventral surface of the brain and contribute to its topography. The surface anatomy can be partly delineated with reference to some olfactory structures within or in close relation to the anterior per-

Handbook of Chemical Neuroanatomy, Vol. 15." The Primate Nervous System, Part III F.E. Bloom, A. Bj6rklund and T. H6kfelt, editors 9 1999 Elsevier Science B.V. All rights reserved.

Ch. I

N. Sakamoto et al.

forated space (Figs. 1 and 2) and provides a valuable introduction to this complex region. 2.1. BASAL CORTEX Anteriorally, the surface of the basal forebrain is comprised of the orbitofrontal cortex (OF) laterally, and the gyrus rectus (GR) medially (Figs. 1D and K1-B 2). Immediately caudal to the anterior olfactory nucleus (AO) or retrobulbar area (K1-B 3) the orbitofrontal cortex tapers and is replaced by the frontal prepiriform cortex PirF (K1-B 4) and, deep to it, the ventral claustrum (VC1). More caudally still, the ventral limit of the basal forebrain is formed by the nucleus accumbens (Acb) and that part of the ventral striatum which receives olfactory input (K1-B 6 and 7). Together these comprise the anterior perforated substance. The subcallosal cortical area (SCA) diminishes posteriorally so that by the levels which include the rostral end of the anterior commissure (K1-B 6 and 7), the diagonal band (db) is fully exposed medially on the basal forebrain surface (Figs 1C and 2). 2.2. OLFACTORY PEDUNCLE AND OLFACTORY TRACT In most textbooks of anatomy an erroneous picture of the surface of this region depicts a common olfactory stalk or peduncle bifurcating into lateral and medial olfactory striae, or tracts, in front of the anterior perforated space. This space is flanked caudally by the diagonal band (db) which is located alongside the lateral margin of the optic tract (opt) as it proceeds in a caudolateral direction from the optic chiasm to the lateral geniculate nucleus (Figs 1C and 2). Although a medial olfactory tract or stria 1 has sometimes been indicated on the ventral surface of the primate brain (e.g. Fig. 24 in Economo and Koskinas 1925, Part I; Kuhlenbeck 1927; see Figs. 4-10 in Nauta and Haymaker 1969), a collection of medially directed bulbofugal fibers is not recognizable as an entity in the human brain, nor in any other mammalian brain (see also Price 1990). In other words, one of the building blocks in the notion of the 'limbic system', i.e. a medial olfactory tract which purportedly terminates in the septum (see Fig. 18-2 in MacLean 1989), does not exist. While a superficially located medial olfactory tract appears in most textbooks of neuroanatomy, its existence has been denied by most scholars for over a century (e.g. Retzius 1896; see also review by Stephan 1975). Apparently, what has often been identified as a medial olfactory tract in the human (see for instance Fig. 21 in Duvernoy 1991) is a gyrus which results from the medial deviation of the olfactory sulcus (olfs), which separates the neocortex of the gyrus rectus from medially located tissue in the posterior orbital region, including parts of the retrobulbar area (Figs 1C and 2). Both in the monkey and the human, the olfactory bulb projections were analyzed in experimental material many years ago by Meyer and Allison (1949) and Allison (1954). Their results are generally supported by those of later monkey experiments ~The term medial olfactory stria (although as mentioned above, the existence of such a structure can hardly be justified) should be distinguished from the medial olfactory radiation (molfr, see KI-B 3) which, according to Schaltenbrand and Bailey (1959) and Riley (1960), denotes a myelinated bundle which proceeds in a ventrolateral-dorsomedial direction deep to the retrobulbar area to join the radiation of the corpus callosum. The deep olfactory radiation (D6jerine 1895) or olfactory radiation (olfr in KI-B 2) is a time-honored term used for the collection of fibers which form a massive structure deep to the caudal part of the orbitofrontal cortex and the retrobulbar area; they are directly continuous with the external capsule laterally and the radiation of the corpus callosum medially. Although fibers related to the retrobulbar area are undoubtedly part of the deep olfactory radiation, other axon types are in all likelihood present in this multifarious bundle.

The human basal forebrain. Part I

Ch. I

using transported tracers (Turner et al. 1978; Price 1990; Carmichael et al. 1994). Projection fibers proceed in a caudal direction through the olfactory peduncle to the point of fusion between the peduncle and the orbital surface (Fig. 1). The bulbofugal fibers then continue in the form of a broad band, the olfactory tract (olf), in a caudolateral direction across the posterior orbital surface bending sharply medialward at the limen insulae 2 (see white arrowhead in Figs 1A and 2) to enter the dorsomedial surface of the parahippocampal gyrus. By removing the temporal pole, it is possible to identify the otherwise hidden sharp bend of the olfactory tract in the region of the limen insulae (Fig. 2). The olfactory tract is clearly visible in the monkey as it proceeds in a lateral direction in front of the anterior perforated space (Fig. 1A). In the human, however, the tract is barely visible as it proceeds more or less diagonally in a lateral and slightly posterior direction in front of the anterior perforated space (Figs 1C, D and 2). 2.3. OLFACTORY TUBERCLE AND ANTERIOR PERFORATED SPACE The term olfactory tubercle was introduced by Rudolf Albert von K611iker in 1896. Following a study by Elliot Smith in the early part of this century (1909), its olfactory nature was seldom questioned. The tubercle is readily identified in macrosmatic mammals, where it usually appears as a well-formed, oval, slightly elevated structure surrounded by a more or less pronounced groove. Experimental studies in macrosmatic laboratory animals such as the rat have confirmed that the entire tubercle receives olfactory bulb projection fibers (see review by Shipley et al. 1995). The problem of identifying an olfactory tubercle is difficult in the primate, but ~particularly so in the human, where a bulge is either absent (Fig. 1D) or only vaguely evident (Figs. 1C and 2), and where controlled studies of olfactory bulb projections are impossible. Some authors have considered all of the anterior perforated space in the human as homologous with the olfactory tubercle of macrosmatic mammals (e.g. Rose 1927a,b; Crosby and Humphrey 1941; Turner et al. 1978), while others have confined the use of the term olfactory tubercle in human to a slightly elevated part of the anterior perforated space behind the attachment of the olfactory stalk (Figs 1C and 2, see also Fig. 4-2 in Nauta and Haymaker 1969; Fig. 32 in Stephan 1975; Fig. 21 in Duvernoy 1991). More than 20 years ago (Heimer et al. 1977), we urged that the term 'olfactory tubercle' in the human should be restricted to that region of the anterior perforated space which is the most probable recipient of olfactory bulb input. Of necessity, this definition is somewhat nebulous since, without any means of experimental verification, it is difficult to determine which parts of the anterior perforated space are being infiltrated with olfactory bulb projection fibers in the human brain. Histochemical approaches may ultimately be more fruitful, and the methods of modern chemical neuroanatomy may eventually provide a satisfactory solution to this puzzle in the human. In the monkey, an elevated tubercle can usually be identified behind the attachment of the olfactory stalk to the posterior orbital area (Fig. 1A). It appears, however, that only part of this slightly convex gray mass receives olfactory bulb fibers (Turner et al. 1978; Carmichael et al. 1994). Carmichael and his collaborators have recently shown that olfactory bulb projections invade a large part of the anterior perforated space (i.e. 2Limen: from the Latin, meaning 'threshold.' Limen insulae is that part lying between the base of the brain (including the orbitofrontal cortex and anterior perforated space) and the insula.

Ch. I

N. S a k a m o t o et al.

Fig. 1. Olfactory structures within or in close relation to the anterior perforated space. Whereas the monkey (A) has a clearly identifiable olfactory tubercle (Tu), it is more difficult to identify a tubercle in the human (B, C, and D). The region indicated by an asterisk in D is usually referred to as the olfactory trigone. Note the continuation between the olfactory peduncle (o. ped.) and the olfactory tract (olf) in the monkey (A). The olfactory tract continues in a caudolateral direction towards the limen insulae (white arrowhead) where it makes a sharp bend to enter the temporal lobe. The olfactory tract is more difficult to appreciate in the human (D). The large arrow in B points to the anterior choroidal artery and the small arrows to striate arteries. Further abbreviations: AO = anterior olfactory nucleus, Ant perf. = anterior perforated space, db = diagonal band, GR --- gyrus rectus, olfs = olfactory sulcus, opt = optic tract, ox = optic chiasm, U = uncus.


Ch.I

Fig. 2. Higher magnification view of anterior perforated space. Although a vague bulge appears behind the anterior olfactory nucleus (AO), it is highly questionable if this should be considered to be homologous with the olfactory tubercle in macrosmatic mammals (see text). The surface topography only hints at the presence of an olfactory tract (between arrows) and its bend (white arrowhead) at the region of the limen insulae.

the part labeled TOL2 by Rose 1927a,b) in a strip-like fashion. If the presence of olfactory bulb projections is a criterion for designating part of the anterior perforated space as being homologous with the olfactory tubercle of nonprimates, the structure should presumably include these multiple bands (see Fig. 2 in Carmichael et al. 1994). As defined by direct input from the olfactory bulbs, only part of that region in which an elevation resembling a tubercle is found in monkeys (Fig. 1) and sporadically in the human (Fig. 2) appears to be truly olfactory in nature. Where no tubercle can be identified - which is most often the case in the human brain - there is no reason to imagine one. There is also nothing to be gained by dividing the anterior perforated space into striatal- and olfactory-related parts (Carmichael et al. 1994). With the advent of the concept of the ventral striatum, a distinction between 'olfactory' and 'striatal' in this part of the brain became moot, since, in macrosmatic mammals, all of the mediumcelled parts of the olfactory tubercle, including its dense cell layer, are now considered striatal in nature (Heimer and Wilson 1975; Heimer 1978; Millhouse and Heimer 1984) even though they are specialized to receive input from the olfactory bulb (e.g. White 1965; Heimer 1968; Price 1973). In fact, based on developmental, histological, connectional and histochemical characteristics, the olfactory tubercle of macrosmatic

Ch. I

N. Sakamoto et al.

mammals is a specialized, albeit integral part of the basal ganglia. It contains both striatal and pallidal components. There are as many similarities between the olfactory tubercle and the rest of the striatopallidal complex in the rat as there are differences between the olfactory tubercle and the laterally adjoining primary olfactory cortex (see reviews by Heimer 1978; Heimer et al. 1995). In view of this fact, for non-primates the term olfactory striatum might be preferable to that of olfactory tubercle. While the anterior perforated space in the human is often equated with the laminated olfactory tubercle of nonprimates (e.g. Rose 1927b; Crosby and Humphrey 1941; Allison 1954; Turner et al. 1978) many early investigators emphasized the fact that striatum reaches the ventral surface in this region of the brain (e.g. Beccari 1911 ; Brockhaus 1942a,b; Macchi 1951). Economo and Koskinas (1925, p.32) presciently used the term 'colliculus nuclei caudati' (a term originated by D6jerine 1895) as a synonym for 'tuberculum olfactorium'. As discussed further in the following chapter their conclusion is in part confirmed in later studies by the use of 'striatal' markers such as acetylcholinesterase (e.g. Saper and Chelimsky 1984; Alheid and Heimer 1988; Alheid et al. 1990; Saper 1990) and choline acetyltransferase (e.g. Holt et al. 1996). The same is true for virtually every histochemical label that is found in high density in striatal areas compared to adjacent cortex (see folio.wing chapter). In microsmatic mammals, including the human, the ventral striatum reaches the surface of the brain as it does in macrosmatic species, but only part of this striatal extension is likely to be homologous to the olfactory tubercle or 'olfactory striatum' of the macrosmatics. As we shall discuss further in the next chapter, that part of the striatal complex which reaches the ventral surface of the human brain at the anterior perforated space has some locally unique characteristics. 2.4. OLFACTORY TRIGONE Another term of somewhat shaky legitimacy is that of the olfactory trigone, used mostly in the human to denote a 'triangular (surface) area between the diverging medial and lateral olfactory striae' (Lockhard 1991), or between the 'Gyrus olfactorius lateralis und medialis' (Stephan 1975), in front of the anterior perforated space. Because there is no medial olfactory stria (see above) and since the lateral olfactory stria is not always easy to recognize on the surface, the delineation of a human 'olfactory trigone' requires a creative imagination. The general location of the region to which the term is usually attached is indicated by an asterisk in Fig. 1D. Brockhaus (1942a), likewise, used the term tuber or trigonum olfactorium for the slightly elevated region in close relation to the olfactory tract as it makes its way laterally towards the limen insulae.

3. OVERVIEW OF BASAL FOREBRAIN S T R U C T U R E S

3.1. AREA DIAGONALIS (DIAGONAL BAND OF BROCA) AND BASAL NUCLEUS OF M E Y N E R T The diagonal band of Broca (db) superficially appears as a diagonally oriented tract between the medially located septal area and the amygdaloid body in the temporal lobe (Figs 1C and 2). Although some projections from the medial amygdala to the septum may be included in the region referred to as diagonal band of Broca (e.g. Caff6


Ch. I

et al. 1987), septohypothalamic, corticopetal, corticostriatal and amygdalo-diencephalic projections are major fiber components in this region. Rose (1927b) and Stephan (1975) referred to this diagonally oriented region as 'area diagonalis', rather than diagonal band, in order to emphasize the fact that the underlying substance contains a mixture of neurons and a wide variety of fiber systems. Consistently identified among the diagonal band nuclei and within the basal nucleus of Meynert 3 are magnocellular hyperchromic neurons generally shown to be choline acetyltransferase positive (Mesulam et al. 1983). The nuclei of the diagonal band (VDB and HDB in K1-B 6 and 7) and the compact part of the basal nucleus of Meynert (B in K1-B 7-12) form an aggregate of neurons which traverses the basal forebrain obliquely between its rostromedial and caudolateral regions (see Fig. 5 in DeLacalle and Saper 1997). Anteriorally placed clusters of magnocellular basal nucleus neurons are also found, being especially frequent at the ventral aspect of the accumbens and among the fiber bundles of the external capsule below the ventral putamen at the level shown in K1-B 4. 3.2. OLFACTORY BULB PROJECTION AREAS The likely distribution of human olfactory bulb projection fibers (for references, see discussion in following chapter) is highlighted with magenta in the Kltiver-Barrera sections included in the mini-atlas at the end of this chapter. Rostroventrally (K1-B 2) the olfactory tract (olf) fibers terminate in the anterior olfactory nucleus (AO), which borders on the gyrus rectus (GR) medially (K1-B 1-3). Farther back, the broad band of olfactory tract fibers turns sharply in a lateral direction (Fig. 2 and K1-B 4), accompanied by the frontal part of the primary olfactory cortex (here labeled piriform cortex (Pir), to conform to common usage). Some fibers reach the ventral striatum at the levels shown in K1-B 6 and 7. At the limen insulae (Fig. 2), fibers deviate laterally from the main part of the olfactory tract to terminate in the ventral part of the agranular insula (K1-B 2-5); other bulbofugal projection fibers turn sharply in a medial direction onto the dorsal surface of the temporal lobe where they terminate in a rather extensive region within the parahippocampal gyrus both rostral (K1-B 1 and 2) and caudal (K1-B 4-9) to the place where the temporal lobe attaches to the rest of the brain. Included in the termination areas for olfactory bulb projection fibers in the temporal lobe are the temporal part of the primary olfactory cortex (PirT), temporopolar periallocortex (TPpall), amygdalopiriform transition areas (Apir), cortical amygdaloid nuclei (ACo and VCo) and the olfactory field (EO) of entorhinal cortex (ENT). The endopiriform nucleus (En) is often conceived of as the deep layer of the primary olfactory cortex (K1-B 5 and 6), but it is not the direct recipient of olfactory projections. The primary non-amygdaloid and amygdaloid olfactory bulb projection areas will be described more extensively in the following chapter. 3.3. THE CLAUSTRUM (C1) The claustrum (C1), which is represented by a sheet of gray matter located in large part between the extreme (ex) and the external (ec) capsules (K1-B 1), is included within all sections in the atlas. It is thin in its dorsal aspect underneath the dorsal part of the

3Meynert (1872) described this nucleus for the first time in the human brain as a cellular 'ganglion' in the substantia innominata. He included this 'ganglion' together with the nucleus of the diagonal band in the broader term 'ganglion ansae peduncularis'. The 'basal nucleus of Meynert' or 'Meynert's basal ganglion', has sometimes been referred to as the 'Nucleus substantiae innominatae' (e.g. Hassler 1938; Vogt and Vogt 1942).

Ch. I

N. Sakamoto et aL

granular and dysgranular insula (Id in K1-B 3) but widens ventrally and is especially prominent in the temporal lobe (VC1 in K1-B 4-8). Only the olfactory tract and a thin layer of associated olfactory tissue (frontal piriform cortex, PirF) prevents the claustrum from reaching the basal brain surface posterolateral to the retrobulbar region (K1-B 4 and 5). The term ventral claustrum (VC1) was used by Macchi (1951) to denote this ventromedial continuation of the claustrum into the orbitofrontal region, as well as the rather massive component located in the temporal lobe (claustrum temporale of Brockhaus 1940). It should be appreciated that both in some earlier and some contemporary reports (e.g., see Morys et al. 1996), the term 'ventral claustrum' has been applied to the area designated as the 'endopiriform nucleus' (K1-B 5, 6). While the distinction between these two areas is discussed at greater length in the following chapter (see Section 4.1.2.), it is worth emphasizing here that these areas are distinct on cytoarchitectural grounds, as well as by dint of their presumed embryological origins (Bayer and Altman 1991) and phylogeny (see Striedter 1997 for a recent review). These two areas may also be discriminated on the basis of their connections (Sherk 1986; but see Witter et al. 1988). Interpretation of functional-anatomical reports relevant to them is likely to be confusing unless a distinction is made between ventral claustrum and the endopiriform nucleus. Widespread reciprocal connections, often topographically organized, with much of the cortex, make the claustrum an interesting area from the standpoint of sensory processing and sensorimotor integration. Some research supports the participation of claustrum in the discrimination of sensory features, as opposed to their mere detection (e.g. Horster et al. 1989; Vanduffel et al. 1997), while other reports note claustral involvement in a variety of behaviors, involving stress (Blake et al. 1987, Guidobono et al. 1991, Beck and Fibiger 1995a,b; Smith et al. 1995), or nociception (Persinger et al. 1997), and possibly the control of vocalization (Jtirgens et al. 1996). In these latter instances it is likely that the ventral portions of claustrum are more relevant. 3.4. DORSAL STRIATUM AND DORSAL PALLIDUM The dorsal striatopallidal system is discussed by Graybiel elsewhere in this volume (Graybiel 1999); here we only wish to remark on the general features of this territory insofar as they are relevant for comparison with their ventral counterparts. Since the initial development of the acetylcholinesterase method, the dense staining of the caudate nucleus, putamen and accumbens that comprise the striatum has been dramatically apparent (ACHE 2-12). Additionally, the continuity of the dorsal striatum with ventral striatum is readily seen (ACHE 3-4 and 5-6). This continuity is also evident in sections stained for enkephalin or substance P (ENK 1-5; SP 1-6). The entire dorsal pallidum is readily distinguished from the adjacent striatum because of the relative poverty of the cholinesterase reaction in the pallidal areas. The parcellation of the dorsal pallidum is clearly shown by the distribution of substance P and enkephalin. The external pallidal segment is distinguished laterally from striatum, and to a lesser extent medially from the internal pallidal segment by its extremely dense complement of enkephalinergic terminals (ENK 8-12). Conversely, the internal pallidal segment (and the pars reticulata of substantia nigra) is particularly dense in substance P terminal labeling compared to the striatum and external pallidal segment. This complementary staining pattern (Haber and Elde 1981; Haber and Watson 1985) is not absolute, but has been useful since it reflects the fact that, for the most part,


Ch. I

afferents to these two pallidal segments originate from at least two different populations of striatal neurons containing either enkephalin or substance P. 3.5. VENTRAL STRIATUM AND VENTRAL PALLIDUM Fundamental to the understanding of the rostral basalis region is the concept that the accumbens (Acb), as the major component of ventral striatum, extends to the ventral surface of the brain behind the gyrus rectus and lateral to the subcallosal area (K1-B 4 and 5). The accumbens, which is located at the confluence between the caudate nucleus and the putamen underneath the anterior limb of the internal capsule (K1-B 1-5), has a lower density of myelinated fiber bundles and the medium-sized neurons are relatively more crowded, somewhat smaller, and more intensely Nissl-stained than is the case for the bulk of putamen and caudate nucleus. Accumbens, together with neighboring regions of caudate nucleus and putamen below the anterior limb of the internal capsule, forms part of the ventral striatum which corresponds approximately to the fundus striati of Brockhaus (1942a), who included the bed nucleus of stria terminalis (BNST) in this term. In current usage, however, the term fundus striati as applied in the primate does not include the bed nucleus of stria terminalis. As we shall discuss more fully in the next chapter, ventral pallidal tissue (VP in K1-B 6-8) accompanies the accumbens and the rest of ventral striatum to the basal forebrain surface (SP 6). The additional presence of fibers peeling off the anterior commissure and traversing the ventral striatum (K1-B 6), together with neurons associated with the basal nucleus of Meynert and islands of small cells, conspire to make this part of the basal forebrain a highly complex region. The continuity between dorsal pallidum and ventral pallidum is made evident by enkephalin and substance P immunoreactivity. Enkephalin terminals typical of pallidal areas extend as a dense wedge below the anterior commissure (Enk 5-8), but are also found anteroventrally as a lacework of terminations that invest coarse dendrites within the nucleus accumbens itself (see following chapter). Substance P terminals on ventral pallidal dendrites are found in great profusion ventromedially below the anterior commissure (SP 6). It should be appreciated that in the basal forebrain substance P and enkephalin immunoreactivity are not uniquely associated with ventral pallidum, but may also represent terminations on elements of the sublenticular extended amygdala that mainly traverse the area just caudal to ventral pallidum but which may also invade caudomedial accumbens. The ventral pallidum and extended amygdala are described in greater detail in the next chapter. 3.6. STRIATUM IN THE TEMPORAL LOBE Striatal tissue is prominent in the more posterior sections of the basal forebrain located medial and ventral to the temporal limb of the anterior commissure (K1-B 11 and 12). This part of striatum is directly continuous with the rest of putamen and is generally referred to as the ventral putamen (PuV; putamen limitans by Brockhaus 1942a). The tail of the caudate nucleus (which is not included within the levels depicted by the mini-atlas) is closely related to association areas in the frontal and temporal lobes (e.g. Selemon and Goldman-Rakic 1985) and appears slightly more posteriorally where, in some sections, it is directly continuous with the temporal part of the putamen via cell bridges interpolated between the sublenticular bundles of the internal capsule. It is important to note that the gross anatomic subdivision of the striatum

Ch. I

N. Sakamoto et al.

into caudate nucleus and putamen is not a good indicator of the functional division between 'association neostriatum' and 'motor neostriatum' (Selemon and GoldmanRakic 1985). Ventral putamen, for example, is related to association areas in the temporal lobe (e.g. Kemp and Powell 1970; van Hoesen et al. 1981; Middleton and Strick 1996) rather than to the cortical motor areas. The amygdalostriatal transition area (Astr) is interposed between the ventral putamen and caudally located parts of the amygdaloid body (K1-B 11 and 12). Little is known about this region which, like the ventral putamen, contains significant amounts of enkephalin (ENK 11-12) and is clearly differentiated from the ventral putamen by its weak staining for both substance P (SP 11-12) and acetylcholinesterase (ACHE 11-12). Ventral putamen likewise can be distinguished from the dorsal main part of putamen by its considerably stronger SP-staining (SP 11-12), but its weaker AChE staining (ACHE 11 and 12) is comparable to the situation in the medial part of caudate. 3.7. EXTENDED AMYGDALA The extended amygdala (EA) is a major component of the basal forebrain region. The term 'extended amygdala' (Alheid and Heimer 1988) was introduced to denote a cellular continuum that had been earlier described as 'an extension of the amygdala into the forebrain' (de Olmos et al. 1985). This macrostructure includes, in addition to the centromedial amygdaloid complex and the bed nucleus of stria terminalis, columns or groups of cells that bridge the gap between these two structures, both within the subpallidal or sublenticular region (K1-B 8-10) and as neurons within and alongside the entire length of the stria terminalis (K1-B, 11 and 12). The parts of the extended amygdala which include the central amygdaloid nucleus (Ce in K1-B 11 and 12) and the lateral bed nucleus of stria terminalis (BSTL in K1-B 5-9) are referred to as the central subdivision (yellow color) whereas the parts related to the medial amygdaloid nucleus (Me in K1-B 11 and 12) and the medial bed nucleus of stria terminalis (BSTM in KI-B 7-10) are termed the medial subdivision (green color). That part of the 'extended amygdala' which is situated transversely in the basal forebrain parallels the orientation of the basal nucleus of Meynert and the diagonal band. The central nucleus of the amygdala forms a distinctive round profile in coronal sections posteriorally (K1-B 11 and 12) and extends obliquely anteromedially (SLEA in K1-B 10; SLEA in ENK 10-11) where it ultimately divides into finger-like processes (K1-B 9; SLEA in ENK 9 and 10) extending towards the lateral part of the bed nucleus of the stria terminalis (KI-B 8). The medial nuclei of the amygdala has its posterior part located between the central nucleus and the optic tract (K1-B 11 and 12). More anteriorally it extends ventral to the central nucleus (K1-B 10) and has sublenticular extension towards the medial division of the bed nucleus of the stria terminalis (green in K1-B 9). At this point it is useful to emphasize the fact that the term 'extended amygdala' does not encompass the cortical amygdaloid nuclei (e.g., ACo and VCo in K1-B 9-11), which are closely related to the olfactory system (coded with magenta color), and the

10


Ch.I

large laterobasal 4 complex (La = lateral, BL = basolateral, and BM = basomedial nuclei in K1-B 7-12), which is often conceived of as a modified portion of cortex (Johnston 1923; Crosby and Humphrey 1941; Lauer 1945; Hall 1972a,b; Millhouse and de Olmos 1983; McDonald 1984; de Olmos et al. 1985; Carlsen and Heimer 1988; McDonald 1992; Alheid et al. 1995). These structures do, however, provide inputs to the extended amygdala and basal ganglia, as do other cortical areas. The extended amygdala will be discussed in detail in the next chapter. 3.8. AMYGDALOID BODY The amygdaloid body (K1-B 6-12) which lies within the temporal lobe is functionally intimately linked to the basal forebrain. Since the central and medial amygdaloid nuclei are parts of the extended amygdala, the term amygdaloid body can be used in a restricted sense to denote the cortical and laterobasal group of nuclei. This is consistent with the usage proposed by several of the pioneering neuroanatomists in the early part of this century (e.g., 'amygdaleum proprium' by Brockhaus 1938; see following chapter). Detailed cytoarchitectonics and histochemistry permit subdivision of the amygdaloid body into multiple subnuclei. In general, there is good agreement about the major subdivisions, but unanimity is lacking concerning the nomenclature of the smaller ones. Only major subdivisions are indicated in the mini-atlas. Finer distinctions will be tackled in the following chapter. 3.9. SMALL-CELLED ISLANDS Numerous compact, island-like clusters of small neurons are widely dispersed in the basal forebrain. They are often located where distinctive major nuclear structures abut one another, lying for example between the ventral claustrum and the nucleus accumbens, between the accumbens and the diagonal band, and where ventral pallidum is intimately related to the ventral striatum. These cell islands are also prominent features of the extended amygdala. As many as twenty-five of these islands may be present in coronal sections passing through the level of the anterior perforated substance. The nomenclature and nature of these islands will be discussed in the next chapter.

4. CORONAL SECTIONS THROUGH THE BASAL FOREBRAIN

The sections that constitute the atlas presented on pp 15-56, as well as the majority of those used for the following chapter, were prepared by Dr. Noboru Sakamoto. 4.1. MATERIALS AND METHODS Three adult human brains from patients without neurological disease, aged 15, 25 and 4It should be noted that an alternative summary term applied to the laterobasal complex is the 'basolateral complex'. In our earlier discussions of these areas, we have generally used the latter designation, but have decided to alter this practice here. As we discuss in the subsequent chapter, the earliest designations of this area recognized the lateral nucleus but included the basomedial nucleus within a 'basal nucleus' that also included the large-celled basolateral nucleus of our present usage. Combined, this made up the basal + lateral complex, or basolateral complex. Most authors now agree that the basomedial nucleus is a separate nucleus from the 'basal or basolateral' on histochemical, connectional, and functional grounds. It therefore seems preferable to modify the aggregate term to laterobasal. This avoids using a term that is too readily confused with a subdivision of the larger complex, or which connotes some unwarranted preeminence for the basolateral subdivision.

11

Ch. I

N. S a k a m o t o et al.

60 years were obtained within 4 and 5 hours of death respectively. The sections in this atlas were prepared from the last-mentioned brain. The brains were immediately flushed via carotid and vertebral arteries with 0.5 1 of 0.9% sodium chloride at a pressure of 100 cm H20. Fixation was initiated by perfusion at the same pressure, with 0.5 1 of 4% paraformaldehyde in 0.1 M phosphate buffer at pH 7.4. After 30 min the hardened tissue was cut into 10-mm slabs, embedded in egg yolk, and immersed in formaldehyde for 15 days at 2 ~ After fixation, slabs were immersed in 30% sucrose and 0.2% sodium azide at 4 ~ until they sank, and then stored in this solution in the refrigerator. Sections of tissues frozen on dry ice were cut on a cryotome set at 50 lam and sections were immediately picked up onto glass slides from a solution of 0.8% gelatin and 0.2% sodium azide. These were stained with the Klfiver-Barrera method (Klfiver and Barrera 1953) or the acetylcholinesterase procedure. For immunohistochemistry, free-floating sections were stained using a modification of the Sternberger PAP method in which non-specific sites were first blocked with human serum, incubated with dilute antibodies (1:3000- 1:5000) for up to four days at 4 ~ and very thoroughly rinsed between subsequent steps with secondary and bridging antibodies. In each incubation solution except that used for the peroxidase reaction, 0.1% sodium azide was included to suppress endogenous peroxidase. The final color was rendered blue-black by addition of 1.2% nickel ammonium sulfate to the final incubation mixture of diaminobenzidine and hydrogen peroxide. As controls for staining, diluted antibodies were adsorbed against the appropriate peptides where possible, after which no staining occurred. Neither was any staining seen when non-immune sera were used. For the immunostaining displayed in both the mini-atlas and the following chapter, well-characterized antibodies were generously provided by their originators: Monoelonal: Antibody against substance P (Dr. A. C. Cuello). Polyelonal: antibodies against: leu-enkephalin, substance P, somatostatin and neurotensin (Dr. M. Tohyama); tyrosine hydroxylase (Dr. M. Goldstein); glutamic acid decarboxylase (Dr. W. Oertel); met-enkephalin (Dr. S. Inagaki); and secretoneurin (Dr. R. Fisher-Colbrie). In addition, antibodies to cholecystokinin-8 were purchased from Amersham, Cambridge Research Biochemicals, and Immunonuclear Corporation. The antibodies gave staining patterns which were consistent and distinctive for the substances against which they were directed. They Selectively identified many neuronal groups which were appropriately analogous to those seen in lower animals and indicated the presence of stained structures in high frequency in areas of the human brain which had been peviously biochemically shown to contain high concentrations of the appropriate antigenic substrate. Thus it appears highly probable that the immunocytochemical results indicate the appropriate anatomic localizations of these antigens. Previous studies have shown good stability of peptides and catecholamine synthesizing enzymes within the first 24 hours after death. All the tissues used were obtained with postmortem intervals of 5 hours or less, well within the periods reported for suitable postmortem preservation of neuropeptides and enzyme protein antigens.

5. ACKNOWLEDGEMENTS This work was supported by USPHS Grant NS-17743 (L.H. and G.F.A.), and by 12


Ch. I

Consejo Nacional de Investigaciones Cientificas y Tdcnicas of Argentina (J.S.O.). The Judith R. Ossoff Memorial Laboratory at New York Medical Center was funded via the Dysautonomia Foundation. We would like to thank Dr. Reiji Kishida for valuable help. The authors would also like to thank Dr. Michael Forbes and Ms. Debra Swanson for their patient and superb production of digital images from our histology and Ms. Vickie Loeser for excellent secretarial assistance.

6. REFERENCES

The citations for this section are provided with the following companion chapter.

13

Mini-Atlas of Coronal Sections through the Basal Forebrain (pp. 15-56)


CHAPTER II

The human basal forebrain. Part II L. HEIMER, J.S. DE OLMOS, G.F. ALHEID, J. PEARSON, N. SAKAMOTO, K. SHINODA, J. MARKSTEINER AND R.C. SWITZER III

1. INTRODUCTION The basal forebrain, long considered so forbiddingly indecipherable as to be inappropriately referred to as a 'substantia innominata', a sort of neurological equivalent of the geographer's 'terra incognita' is in fact a fascinating region in which the confluence and interaction of multiple well-recognized systems provide a rich field of exploration for physiologists, neuropsychiatrists, pharmacologists and anatomists. This anatomic review will demonstrate that basal forebrain contains not only the superficially obvious continuations of the olfactory system but also associated cortical and amygdaloid areas, as well as major extensions of the striatum and globus pallidus. To these are added the basal forebrain magnocellular complex (basal nucleus of Meynert and diagonal band nuclei), ventral claustrum and extensions of the centromedial amygdala that links it via subpallidal cell columns and cell groups along the arch of the stria terminalis (Fig. 1) to the bed nucleus of the stria terminalis. In short, all parts of the basal forebrain are now well recognized as intrinsic nuclei or extensions of adjacent tissues, most notably the basal ganglia (Fig. 2). The chemical and functional anatomy of this basal region is likely to provide important insights into the basic physiology of the entire forebrain. This morphological review, which presents evidence for the anatomical composition of the human basal forebrain as it is portrayed schematically in Figs. 1 and 2, is intended as a foundation for further anatomic refinement and as a tool for those investigating the normal and pathologic functions of a region which plays profound roles in behaviors ranging from basic drives and emotions to cognition and memory. After some introductory remarks, we will first describe the anatomy of the ventral striatopallidal system and the extended amygdala which have received relatively little attention in the human brain. This will be followed by a review of the olfactory system and we will conclude the chapter with a discussion of the superficial amygdala and laterobasal amygdaloid complex, which together constitute what some anatomists referred to as the 'amygdaleum proprium' in the past (e.g., Brockhaus 1958). The human basal forebrain has a long history of anatomical descriptions (e.g. Reil 1809; Meynert 1872; Calleja 1893; Cajal 1911; Beccari 1910, 1911; Johnston 1923; Kodama 1926; Hilpert 1928; Papez and Aronson 1934; Kappers et al. 1936; Brockhaus 1938; Crosby and Humphrey 1941 ; Brockhaus 1942a,b; Allison 1954; Macchi 1951; Sanides 1957a,b; Klingler and Gloor 1960). Many of its components, including the septum, diagonal band of Broca, basal nucleus of Meynert and amygdala, as well as structures included in the olfactory system, have been described and Handbook of Chemical Neuroanatomy, Vol. 15. The Primate Nervous System, Part III F.E. Bloom, A. Bj6rklund and T. H6kfelt, editors 9 1999 Elsevier Science B.V. All rights reserved.

57

Ch. H

L. H e i m e r et al.

Fig. 1: The extended amygdala (in color) shown in isolation from the rest of the brain, with the extensions of the central (Ce) and medial (Me) amygdaloid nuclei alongside the stria terminalis (st) and through the sublenticular region to the bed nucleus of stria terminalis (BST). The central division of extended amygdala is color-coded in yellow and the medial division in green. The supracapsular part of the bed nucleus of stria terminalis (BSTS) is depicted as a continuum, although the neuronal cell bodies of especially the medial division (green) do not form a continuous column (see text). Associated dendrites and neuropil, however, are likely to form a continuous columnar structure within the stria terminalis. Note that the laterobasal complex of the amygdala (lateral, basolateral, basomedial and paralaminar amygdaloid nuclei) and cortical amygdaloid nuclei are not included as part of the extended amygdala. (Art by Medical and Scientific Illustration, Crozet, Virginia.)

r e v i e w e d in c o n s i d e r a b l e detail (e.g. A n d y a n d S t e p h a n 1968; N a u t a a n d H a y m a k e r 1969; S t e p h a n 1975; H e i m e r et al. 1977; H e d r e e n et al. 1984; M e s u l a m a n d G e u l a 1988; A l h e i d a n d H e i m e r 1988; T a k a g i 1989; P i o r o et al. 1990; Price 1990; A l h e i d et 58

The human basal forebrain. Part H

Ch. H

Fig. 2: Schematic drawings showing the human basal forebrain in a series of coronal sections starting rostrally at the level of accumbens (A) and ending at the level of the caudal amygdala (D). Striatum (caudate = Cd, putamen - Pu and ventral striatum - VS) is indicated in blue color, globus pallidus (GP) and ventral pallidum (VP) in pink, basal nucleus of Meynert (B) in brown, olfactory bulb projection areas in magenta, and extended amygdala in yellow and green colors. (Art by Medical and Scientific Illustration, Crozet, Virginia.)

59

Ch. H

L. Heimer et al.

al. 1990; de Olmos 1990; Saper 1990; Aggleton 1992; Arendt et al. 1995; DeLacalle and Saper 1997; Gloor 1997). 1.1. 'BASALIS' REGION The basal forebrain consists largely of intermingling extensions of structures that are adjacent to it and, as a consequence, it displays no distinct boundaries where it merges with surrounding brain. A diverse and sometimes bewildering terminology has historically tended to impede descriptive analysis of the region. A richly varied region of the human basal forebrain, located lateral to the anterior hypothalamus, has often been designated as the substantia innominata 1 or simply 'basalis' (e.g. Schaltenbrand and Bailey 1959; Klingler and Gloor 1960); in many descriptions it has become more or less synonymous with the basal nucleus of Meynert (see below). The 'basalis' region extends laterally underneath the anterior commissure and the globus pallidus into the dorsal aspect of the amygdaloid body. The region was tentatively delineated by Schaltenbrand and Bailey (1959); [see white line in the two coronal sections through the level of the anterior and middle hypothalamus (Figs. 3A and B)]. In most other illustrations or atlases, however, it either is not labeled (e.g. Reichert 1859-1861) or is designated by the term 'substantia innominata,' usually without any attempt to indicate boundaries. The lack of clear-cut anatomical margins, together with the difficulties of identifying the various cell groups which create this mosaic has, until recently, conspired against a satisfactory characterization of this part of the human brain. 1.1.1. 'Basalkerncomplex' of Brockhaus In an important series of papers, Brockhaus (1938; 1940; 1942a,b) undertook a detailed analysis of the anatomy of the human basal forebrain and provided important material for stereotaxic atlases published by Schaltenbrand and his colleagues (Schaltenbrand and Bailey 1959; Schaltenbrand and Wahren 1977). Of special interest is Brockhaus' description of the 'Basalkerncomplex', in which he included not only the basal nucleus of Meynert and scattered neurons of similar character, but also nuclear groups related to the diagonal band of Broca and other adjacent neuronal cell groups. He referred to the latter collectively as the 'tubercul~ire Gruppe' because of their close topographic relation to the olfactory tubercle, which he considered to be largely equivalent to the anterior perforated space (see below; compare Fig. 3B with Fig. 4, which is adapted from Saper 1990). Brockhaus referred to large aggregations of hyperchromatic cells (as seen in Niss| stains) as the 'compact part of the basal nucleus of Meynert' and collectively designated nonaggregated hyperchromatic cells scattered in nearby groups of generally smaller cells (e.g. Haber 1987) as the 'diffuse part of the basal nucleus of Meynert'. Brockhaus, who published in the late 1930s and early 1940s, was primarily restricted to the study of cyto- and myeloarchitecture. With the development of modern tracer ~The term 'substantia innominata', never properly defined, has been used in so many different ways as to render it useless as an anatomical term (Anthoney 1994, p. 520; Alheid and Heimer 1988; Heimer et al. 1997b). Even its origin is obscure. Because Reichert (1859-1861) left this part of the basal forebrain unnamed in his atlas of the human brain it is most often referred to as the substantia innominata of Reichert (e.g. Papez and Aronson 1934; Roussy and Mosinger 1934; Crosby and Humphrey 1941; Klingler and Gloor 1960; Nauta and Haymaker 1969). The German anatomist Johann Christian Reil (1809) referred to the area as 'die ungenannte Marksubstanz' because its functional organization was at that time indecipherable (see Alheid and Heimer 1988). The term substantia innominata of Reil was used more than one hundred years ago by the illustrious neuroanatomist Theodore Meynert (1872), and is probably a more accurate reflection of the term's origin.

60


Ch.H

Fig. 3: Coronal myelin-stained sections of the human brain at the levels of the subcommissural (A) and sublenticular (B) parts of the basal forebrain to indicate the location of the basalis region (B). Note that the label B in these figures is not synonymous with the basal nucleus of Meynert. Modified from Schaltenbrand and Bailey (1959).

61

Ch. H

L. Heimer et al.

methods and various histochemical techniques, many of the components he described have now been identified as belonging to specific functional-anatomical systems. In short, the rostral part of the 'basalis' region (Fig. 3A), referred to as the subcommissural substantia innominata (Miodonski 1967), is largely comprised of ventral parts of the basal ganglia (ventral striatum and ventral pallidum) and the basal nucleus of Meynert (compare Fig. 2 with K1-B 7 in the mini-atlas at the end of the previous chapter). The idea that the striatum reaches the ventral surface of the primate brain in the region of the 'substantia perforata anterior' was developed by some anatomists in the early part of this century (e.g. Beccari 1910, 1911 ; Economo and Koskinas 1925). Much later it" became apparent that the pallidum is also part of this region, not only in macrosmatic mammals but also in primates, and that it, together with striatum, extends towards the ventral brain surface (Heimer and Wilson 1975; Heimer 1978; Switzer et al. 1982; Heimer et al. 1982; Haber and Nauta 1983). This situation has since been demonstrated in many species, including the human (Alheid and Heimer 1988; Haber and Watson 1985; Sakamoto et al. 1988; Alheid et al. 1990; Martin et al. 199 l a). The ventral striatopallidal system will be described in Section 2 of this chapter. At a more caudal sublenticular level (Fig. 2C and 3B) the basal nucleus of Meynert is readily identified as large neurons forming aggregates among the other cell columns and groups that, with their accompanying neuropil, form bridges in the basal forebrain between the medially located bed nucleus of the stria terminalis and the central and medial amygdaloid nuclei in the temporal lobe (compare Fig. 2C with K1-B 9 in the mini-atlas). These sublenticular neuronal ensembles, identified first in the rat (de O1mos 1969, 1972), and subsequently in the rabbit (Schwaber et al. 1982), are part of a large continuum which includes, in addition to the bed nucleus of stria terminalis and the centromedial amygdaloid complex, groups of perikarya accompanying the stria terminalis (Johnston 1923; Sanides 1957a,b; Klingler and Gloor 1960; de Olmos 1972; de Olmos and Ingram 1972; Strenge et al. 1977; de Olmos et al. 1985; Alheid et al. 1994; 1995). This continuum has been referred to as the extended amygdala (Alheid and Heimer 1988) and both its subpallidal (or sublenticular) part and its dorsal (supracapsular) part are clearly identifiable in the human (Johnston 1923; Strenge et al. 1978; Alheid and Heimer 1988; Lesur 1989; Alheid et al. 1990; de Olmos 1990; Martin et al. 1991b). The extended amygdala as a functionally relevant anatomical macrostructure that incorporates central and medial amygdaloid nuclei will be presented in Section 3. This leaves the superficial (cortical) amygdala and the deep (laterobasal) group of amygdaloid nuclei to be discussed in Section 5 following a review of the olfactory system (Section 4). As demonstrated in this chapter, and elsewhere (e.g. de Olmos et al. 1985; Alheid and Heimer 1988; Alheid et al. 1990; 1995; de Olmos 1990; Heimer et al. 1991; 1997a, b) the distinction of the centromedial amygdala from the amygdaloid body is justified both by historic precedent (e.g. see discussion in Koikegami, 1963) and by contemporary anatomical studies (see Section 3). Analysis of the 'basalis' region was delayed by persistent attempts to deal with the area as a single unit. Although it is now clear that multiple systems intermingle in the region, it has taken almost two centuries to achieve a reasonable comprehension of its various components. In the meantime the term 'substantia innominata' seems to have taken on a life of its own (e.g. de Olmos et al. 1985; Alheid and Heimer 1988; de Olmos 1990; Anthoney 1994; Heimer et al. 1997b), and is still advocated in some quarters, as a term for the entire 'basalis' region in brain atlases of both primates (e.g. Martin and Bowden 1996) and non-primates (Swanson 1992; Kruger et al. 1995). Nonetheless, since it is now generally accepted that the striatum and the pallidum 62


.'~

Ch. H

IP

..'.'

Fig. 4: Schematic drawing of a coronal section through the sublenticular region showing acetylcholinesterase-stained neurons, w h i c h - in large part at this level signify cholinergic neurons. (Courtesy of Dr. C.B. Saper. Modified from Saper, 1990. Cholinergic System, In: G. Paxinos (ed.): The Human Nervous System, Academic Press.)

of the basal ganglia reach the ventral surface of the brain in this region in the human and many other species, and because we believe that 'chemical neuroanatomy' corroborates anatomical evidence for the extended amygdala in the human as well as the rat (e.g. Alheid et al. 1995), it seems high time to relegate the term substantia innominata to the graveyard of anatomic anachronisms. In effect this has been done in a recent atlas of the human brain by Mai et al. (1997). 1.1.2. Basal nucleus of Meynert

The basal nucleus of Meynert is an extensively studied, but volumetrically relatively minor, component of the 'basalis' region. It consists of a widely dispersed, more or less continuous collection of aggregated and nonaggregated, predominantly large, hyperchromatic projection neurons, and stretches obliquely from the septum-diagonal band area in the rostral part of the basal forebrain to the level of the caudal part of the amygdaloid body. The collection of cells belonging to the basal nucleus of Meynert and the diagonal band has also been referred to as the 'basal forebrain magnocellular complex' (e.g. Divac 1975; Koliatsos et al. 1990) or the 'magnocellular basal complex' (e.g. Saper 1990). The extent of this complex is best appreciated in three-dimensional reconstructions (e.g. Halliday et al. 1993) in horizontal sections (e.g. Fig. 4 in Jones et al. 1976; Fig. 1 in Tagliavini 1987; Fig. 19.32 in Alheid et al. 1990). The basal nucleus of Meynert projects to the cerebral cortex (Shute and Lewis 1967; Divac 1975; Kievit and Kuypers 1975) and the large majority of its corticopetal neurons are cholinergic (Shute and Lewis 1967; Mesulam and van Hoesen 1976; Mesulam et al. 1983). It also projects to other regions that include the basal ganglia, amygdaloid body and thalamus (see reviews by Koliatsos et al. 1990; Mesulam 1995). The basal nucleus of Meynert, including its non-cholinergic components and other issues, was reviewed 63

Ch. H

L. Heimer et al.

by DeLacalle and Saper (1997) in Part 1 of this series on the Primate Nervous System. DeLacalle and Saper also discussed problems related to nomenclature (see also Butcher and Semba 1989). While its comprehensive functional significance is not yet known (Reiner and Fibiger 1995), the basal nucleus is generally considered to be important for cortical arousal and related processes of learning and memory (e.g. Bartus et al. 1982; Butcher and Woolf 1986; Steriade and Buzsaki 1990; Mesulam 1995). Recent work has specifically emphasized its importance in attentional mechanisms (e.g. Robbins et al. 1989; Dunnett et al. 1991; Muir et al. 1994). The basal nucleus of Meynert apparently reaches its highest degree of development in the human (e.g. Kryspin-Exner 1922; Brockhaus 1942a). The report of cortical cholinergic deficit in Alzheimer patients (Davies and Maloney 1976) and the implication of the basal nucleus of Meynert as the major source of cholinergic afferents to cortex (e.g. Whitehouse et al. 1981; Etienne et al. 1986; Jacobs and Butcher 1986; Bigl et al. 1990; Giacobini 1990; Saper 1990) provided an added incentive for the current interest in the basal forebrain. The concentration of research on the basal nucleus of Meynert has led to relative neglect of other important cell groups in the 'basalis' region.

2. VENTRAL STRIATOPALLIDAL SYSTEM The rostral subcommissural part of the basalis region (Fig. 3A) is made up of ventral parts of the basal ganglia, i.e. the ventral striatum and ventral pallidum, which reach the undersurface of the human brain in the region of the anterior perforated space (Fig. 2B). The terms ventral striatum and ventral pallidum were first used in the rat (Heimer and Wilson 1975) when it became apparent that allocortex (olfactory cortex and hippocampus formation) have cortico-subcortical connections similar to the rest of the cortical mantle. Prior to that time, the prevailing notion was that allocortex and neocortex were characterized by differences rather than similarities in their subcortical connections. We showed that cytoarchitectural, connectional and histochemical data indicate that allocortex, like neocortex, is closely linked to basal ganglia structures via cortico-striatopallido-thalamic circuits 2. The corticosubcortical re-entrant circuits involving the ventral striatopallidal system relay allocortical, periallocortical and proisocortical afferents primarily via the mediodorsal thalamus to the prefrontal cortex. These circuits are analogous to those by which the dorsal parts of the basal ganglia relay neocortical afferents via the ventral-lateral thalamic complex to the premotor cortex. Re-entrant circuits involving the ventral parts of the basal ganglia have especially attracted attention because of their potential involvement in emotional and motivational behavior. The delineation of the

2The concept that different parts of the cortical mantle, in this case allocortex and neocortex, are subserved by separate cortico-striatopallidothalamic reentrant circuits (Heimer and Wilson 1975; Heimer 1978), was further pursued by DeLong and his colleagues (DeLong and Georgopoulos 1981; DeLong et al. 1983; Alexander et al. 1986; 1990) who identified several functionally distinct and segregated (parallel) corticostriatopallido-thalamocortical circuits. The notion that various cortical regions are subserved by functionally segregated cortico-subcortical reentrant loops which eventually terminate in different parts of the frontal lobe has received considerable attention among basic and clinical neuroscientists who have capitalized on the discoveries related especially to the circuits through the ventral parts of the basal ganglia to explain various symptoms of neuropsychiatric disorders (e.g. Modell et al. 1989; Swerdlow and Koob 1987; Cummings 1993; Deutch et al. 1993; Groenewegen and Berendse 1994; Mega and Cummings 1994; Salloway and Cummings 1994; Haber et al. 1995; Groenewegen 1996; Price et al. 1996; Middleton and Strick 1996). It is worth emphasizing that the nature of these corticosubcortical reentrant circuits, i.e. the extent to which they are 'closed' (parallel and independent of each other) or 'open' (interrelated with each other), is still being debated (Selemon and Goldman-Rakic 1990, 1991; Chevalier and Deniau 1990; Alexander and Crutcher 1991 ; Zahm and Brog 1992; Joel and Weiner 1994; Groenewegen 1996; see also review by Heimer et al. 1995).

64


Ch. H

ventral striatum and ventral pallidum in the human and other primates is therefore particularly relevant to those interestea in the functional imaging or neuropathology of individuals with neuropsychiatric disorders. Studies in the rat (McGeorge and Faull 1989) demonstrate that striatal projection areas for allocortex and mesocortex (periallocortex and proisocortex) overlap significantly with striatal areas receiving input from neocortex. Primates also lack a distinct border between the ventral and dorsal parts of the basal ganglia (e.g. Kunishi6 and Haber 1994; Haber et al. 1995; Eblen and Graybiel 1995). Therefore, it is unlikely that sharp functional distinctions can be made on the basis of a strict dorsal-ventral topography in the striatal complex (e.g. Gerfen 1992). In the following discussions of ventral striatopallidal system and of the extended amygdala (Section 3) we will refer frequently to the mini-atlas presented in the previous chapter which features Kltiver-Barrera, enkephalin, substance P and acetylcholinesterase-stained coronal sections through the basal forebrain. 2.1. VENTRAL STRIATUM The ventral striatum in the rat includes the accumbens, ventromedial caudate-putamen and extensive (medium-celled) parts of the olfactory tubercle (see review by Heimer et al. 1995); all these structures project to the ventral pallidum, which, with the ventral striatum extends in a rostroventral direction into the deep part of the olfactory tubercle. During the last twenty years numerous studies have confirmed and extended the original description of the ventral striatopallidal system (reviewed by Alheid and Heimer 1988; Alheid et al. 1990; Heimer et al. 1995). The nature of the accumbens, which is the most prominent part of the ventral striatum, has been the focus of considerable interest in recent years (see review by Heimer et al. 1997a). The accumbens and neighboring parts of the ventral striatal complex have distinctive features which set them apart from the dorsal parts of the striatum. In general, the ventral striatum tends to have somewhat smaller and more tightly packed cells (Brockhaus 1942a; Namba 1957) and to have considerably more specialized cell islands (Sanides 1957a; Meyer et al. 1989; Alheid et al. 1990; HartzSchfitt and Mai 1991) than the dorsal striatum. Furthermore, compared to dorsal striatal structures, the accumbens is more often invaded by pallidal elements especially in the primate (Haber and Elde 1982; Haber and Nauta 1983). As emphasized below, this intermingling of striatal and pallidal elements is particularly pronounced in the human nucleus accumbens. The characteristic striosome-matrix organization that is found in the dorsal caudateputamen (Graybiel and Ragsdale 1983; Herkenham et al. 1984) is not readily applied to the ventral striatum where the relationship between the different neurochemical markers is considerably more complex (Groenewegen et al. 1989; Voorn et al. 1989; Zahm and Brog 1992; Meredith et al. 1993; Pennartz et al. 1994; Heimer et al. 1997a). The specialized and histochemically highly diverse nature of the ventral striatum is well established in the primate (e.g. Haber and Elde 1982; Alheid and Heimer 1988; Alheid et al. 1990; Martin et al. 1991a; Ikemoto et al. 1995) including the human (e.g. Nastuk and Graybiel 1988; Zezula et al. 1988; Berendse and Richfield 1993; Kowall et al. 1993; Hurd and Herkenham 1995; Voorn et al. 1995; Holt et al. 1996). The accumbens in .the monkey merges imperceptibly with the rostroventral parts of the caudate nucleus and putamen which may also be considered as components of the ventral striatum (Fig. 5A; see also Haber et al. 1990). 65

Ch. H


Fig. 5: A. Schematic representation of the 'functional' map of the striatum based on cortical input. Levels of overlap are indicated by intermediate shades of gray. Light gray: input from allo-, periallo-, proiso- and some isocortical orbitofrontal and temporal regions. (All of these areas are sometimes referred to as 'limbicrelated cortex'). Medium gray: input from a wide range of association cortices. Dark gray: input from sensorimotor cortex and supplementary motor areas. B. Composite drawing of the midbrain projection to the striatum in two rostrocaudal views. The dorsal tier of dopaminergic neurons projects to the ventral striatum, whereas the densocellular part of the ventral tier projects throughout the striatum. (A and B, courtesy of Dr. Suzanne Haber. From Heimer et al. 1997. The Accumbens; Beyond the Core-Shell Dichotomy. J. Neuropsychiat., 9(3), pp. 354-381, 1997; with permission from American Psychiatric Press).

66


Ch. H

In earlier discussions (de Olmos et al. 1985, p. 226; Heimer et al. 1985, p. 62; Alheid and Heimer 1988) we have revisited one of J.B. Johnston's (1923) original ideas, suggesting that the nucleus accumbens is the rostral end of the extended amygdala. Based on histochemical and hodological evidence we have adopted this proposition in a modified form, i.e., that elements of amygdala are intermingled with striatal components in the caudomedial part of the accumbens, which merges imperceptibly with the bed nucleus of stria terminalis (see also section 3.5.). The accumbens is certainly a ventral extension of the striatal complex, but is not so homogenous as its dorsal consort. The ventral striatum receives its dopaminergic innervation from the dorsal tier of mesencephalic dopamine neurons (Fig. 5B), i.e. dopamine cells of the dorsal part of substantia nigra, pars compacta, and the contiguous ventral tegmental area (Haber et al. 1995). This distribution in the monkey corresponds in general to the ventral striatum in the human, as defined by Voorn et al. (1996) on the basis of the distribution of la opioid receptor binding. Thus delineated, the ventral striatum in the human is represented predominantly by the accumbens plus the ventral part of the putamen and a ventral 'transition zone' of the head of the caudate where it borders on the accumbens. The ventral part of the striatal complex, in large part, corresponds to the fundus striati 3 of Brockhaus (1942a) who drew attention to its many specialized cytoarchitectonic features and, on this basis, divided it into several subterritories (Fig. 6). With regard to our proposition of a gradual transition between the caudomedial part of the accumbens and the extended amygdala, it is interesting to note that Brockhaus included the bed nucleus of stria terminalis in his definition of fundus striati. This topic, which is currently the focus of much attention, will be discussed further in Sections 2.1.3. and 3.5. 2.1.1. The heterogeneity of ventral striatum

Ventral striatum, including accumbens, continues to be a focal point for those interested in drug abuse and neuropsychiatric disorders, particularly schizophrenia. Consequently, reports describing the distribution of various neurochemical markers and receptors in the human accumbens or ventral striatum are appearing at an increasing rate. The ventral striatum appears at a rostral level shown in K1-B 1 (see atlas in previous chapter), where the head of the caudate first establishes direct continuity with the putamen. Despite a considerable intermingling with pallidal components, which becomes more pronounced posteriorly (see below), the ventral striatum can be identified as a more or less continuous area as far caudally as the level displayed in K1-B 7 and S P 7 (see atlas in previous chapter; see also Fig. 17 in this chapter). The cytoarchitecture of ventral striatum is more heterogeneous than that of the rest of the caudate nucleus or putamen. Many ventral striatal neurons are somewhat smaller (12-14 gm) and more intensively Nissl-stained than their dorsal counterparts (15-18 lam) and, as in the rat (e.g. Herkenham et al. 1984), have a greater tendency to

3Brockhaus (1942a) introduced the term 'fundus striati' (as an abbreviation of 'nucleus fundamentalis striati') for the nucleus accumbens and neighboring part of ventral putamen. It should be noted, however, that Brockhaus also included what we refer to as bed nucleus of stria terminalis in his definition of fundus striati (Fig. 59). He did not, however, include the clusters of granular cells and other parvicellular islands which, together with intermingling larger neurons, form a more or less continuous arch underneath Brockhaus' fundus striati, i.e. from the medial part of accumbens (including the large medial island of Calleja) through its ventral part to the border between ventral parts of putamen and claustrum, where many of the islands are closely related to the external capsule fibers. This 'archipelago' of cell islands (Sanides 1957b), which we include in ventral striatum, was referred to as 'Insulae olfactoriae striatales' by Brockhaus, who thought they were directly related to the olfactory system.

67

Ch. H


Fig. 6: A. Human coronal brain section showing the distribution of prominent glutamate decarboxylate (GAD)-immunoreactivity in the accumbens (Acb) and neighboring parts of the basal ganglia. The hyphenated line indicates the approximate boundary between the ventral and dorsal striatum as discussed in the text. Note that bed nucleus of stria terminalis (BST) is not included in our definition of ventral striatum. B. Diagram of 'fundus striati' by Brockhaus (1942a); the bed nucleus of stria terminalis was included in his concept of 'fundus striati'.

68


Ch. H

display irregular clumping (Brockhaus 1942a; Namba 1957). The cytoarchitectonic heterogeneity of the dorsal striatum is of lesser magnitude (e.g. Goldman-Rakic 1982). The heterogeneity of the ventral striatum is apparent in the pattern of its cholinergic innervation (Holt et al. 1996) and in the distribution of 3,-aminobutyric acid (GABA; as demonstrated by the aid of immunohistochemistry for glutamic acid decarboxylase, GAD) and for the neuropeptides met-enkephalin (ENK) and substance P (SP). In dorsal districts of the striatum, the two neuropeptides tend to follow the striosomematrix pattern in which the striosomes are often surrounded by a densely stained annular compartment which forms so-called ringed striosomes. This feature is especially prominent in the enkephalin-stained sections included in the mini-atlas (ENK 1-9; see also Graybiel and Ragsdale 1983; Beach and McGeer 1984; Faull et al. 1989; Holt et al. 1996). In the ventral striatum, by contrast, enkephalin, substance P, and GAD exhibit a more intense level of immunoreactivity in a blotchy and heterogeneous pattern (see ENK 1-4, SP 1-4 and Fig. 6A; Graybiel and Ragsdale 1983; Manley et al. 1994; Ito et al. 1992; Ferrante et al. 1986; Pioro et al. 1990; Bouras et al. 1984). While areas of weak tyrosine-hydroxylase (TH) immunoreactivity are embedded in a more densely stained matrix throughout the striatal complex, there is in general an accentuation of immunoreactivity in the ventral striatum including a large ventromedial territory of the caudate nucleus (Fig. 7; see also Ferrante and Kowall 1987; Pearson et al. 1990; Holt et al. 1996). Ventral striatum has higher prodynorphin messenger RNA levels and in general lower g opiate receptor binding than the rest of striatum (Hurd and Herkenham 1995). Voorn et al., however, (1996) found that the most medial and ventral parts of the caudal ventral striatum are exceptionally characterized by areas of very dense opioid receptor binding (Section 2.1.3). Multiple studies, including those describing the distribution of benzodiazepine receptors (Faull and Villiger 1988; Zezula et al. 1988), adenosine receptors (Martinez-Mir et al. 1991), M1 and M2 muscarinic binding sites (Nastuk and Graybiel 1988), and D1 and D3 dopamine receptors (Besson et al. 1988; Murray et al. 1994; Joyce and Meador-Woodruff 1997; Gurevich et al. 1997) emphasize the significant neurochemical differences between the ventral region and the rest of striatum. Dopamine D3 receptors, for instance, which have been proposed as an important target for antipsychotics (Sokoloff et al. 1992; Joyce and Meador-Woodruff 1997), are especially prominent in the ventral striatum (e.g. Landwehrmeyer et al. 1993; Murray et al. 1994; Diaz et al. 1995), where they show a heterogeneous pattern. Contributing to the complexity of the human ventral striatum are clusters of granular neurons and other parvicellular neuronal islands located primarily, but not exclusively, at the borders of ventral striatum with other basal forebrain structures or systems (see Interface Islands, below). Such 'interface' islands, which are concentrated primarily in the ventral parts of accumbens and putamen (K1-B 4 and 5 and Fig. 8), correspond in part to the 'neurochemically unique domains' of Voorn et al. (1996). Interface islands also appear somewhat more dorsally in the ventral striatum, especially at its interface with the main part of ventral pallidum (see below). Another distinct feature, especially in the caudomedial part of ventral striatum, is the occurrence of large (30-50 gm) neurons which are often located in the neighborhood of the above-mentioned parvicellular islands (Fig. 8D). Although some of the large cells shown in Fig. 8D do resemble the plump basal nucleus of Meynert cells in Fig. 8E, other triangular or fusiform, less densely stained cells could conceivably represent pallidal neurons. The heterogenous morphology produced by the clumping of striatal cells and the intermingling of medium-sized striatal neurons with large 69

Ch. H


Fig. 7: Tyrosine hydroxylase (TH)-immunoreactivityin the human striatum is patchy with a general accentuation of reaction in the ventral striatum including a large ventromedial territory of the caudate nucleus (Reprinted from Pearson et al. 1990. Catecholaminergic Neurons. In." G. Paxinos (ed.), The Human Nervous System. With permission from Academic Press).

neurons and interface islands is clearly evident in Nissl or Klfiver-Barrera preparations (Fig. 8A and B). Quite characteristic, furthermore, are prominent groups of large, hyperchromatic basal nucleus of Meynert-type neurons, which tend to invade the ventral striatum where it borders on the external capsule (Fig. 8E) or the core of the ventral pallidum (see Section 2.2). It is worth re-emphasizing that the complexity observed in the ventral striatum reflects not only clustering of striatal-like and small neurons, but also intermingling of pallidal components with the small neurons and medium-sized striatal neurons. Haber and her colleagues (e.g. Haber and Elde 1981, 1982; Haber and Nauta 1983; Haber and Watson 1985; Haber et al. 1990) and others (e.g. Beach and McGeer 1984) emphasized this subject many years ago, when they described how pallidal dendrites, 70


Ch. H

ensheathed in a network of thin ENK- or SP-positive fibers and boutons formed socalled 'woolly fibers' (Haber and Nauta 1983). Alternatively these have been depicted as 'pipe-shaped' structures by Bouras et al. (1984) or as 'ribbon-like' processes by Haber and Elde (1982) and Candy et al. (1985). In the monkey, they have a tendency to invade nearby structures, including ventral striatum. This tendency is pronounced in the human where groups of pallidal neurons give rise to prominent dendrites that are ensheathed by beaded enkephalin- (Figs. 9B and C) and substance P- (Fig. 10) immunoreactive fibers, referred to as peptidergic 'tubular profiles' by Mai et al. (1986). They are disposed in the ventral striatum both at the approximate level shown in Fig. 8A (e.g. Figs. 9B and 10) as well as in the subcommissural region rostral to the main part of ventral pallidum (Fig. 9C; see also Section 2.2). Much of the caudal part of ventral striatum is thus a patchy, indistinctly delineated, admixture of striatum and pallidum. Nevertheless, striatal cells by far outnumber collections of pallidal neuronal components at least as far caudally as the level represented in K1-B 6. The pallidal components, as indicated earlier, often appear closely related to the interface islands (Fig. 11C), which are widely dispersed in the ventral striatum. The presence of pallidal neurons in this region (Fig. l lB) is revealed by collections of a large number of peptidergic tubular profiles (Fig. 11C). Although it is certain that many of the peptidergic tubular profiles in this part of the CNS represent pallidal dendrites covered with striatofugal immunoreactive terminals (Fig. 12)4, it is important to recognize that the rostral portion of extended amygdala is an alternative source of dendrites with dense peptidergic innervation, especially within the caudomedial accumbens (e.g. Fig. 25H, inset). These profiles are not identical, however, and the differentiation between pallidal and extended amygdaloid tubular profiles are likely to be more problematic in regard to enkephalinergic, rather than substance P-positive profiles, since the former are abundant in both areas. The nature and nomenclature of the human ventral striatum. The extension of ventral striatum to the basal surface of the human brain in the region of the anterior perforated space (K1-B 5-7; ENK 4, 5-6 and SP 4 and 5; see atlas in previous chapter) was appreciated by classical neuroanatomists and is amply confirmed by 'striatal' markers such as acetylcholinesterase (e.g. Saper and Chelimsky 1984; Alheid and Heimer 1988; Alheid et al. 1990; Saper 1990; see also AChE 3), choline-acetyltransferase (e.g. Holt et al. 1996 1997) and tyrosine hydroxylase (Fig. 13A). Staining for glutamic acid decarboxylase (GAD; Fig. 13B) helps to identify both striatal and pallidal elements at the ventral surface on the medial side of the olfactory allocortex (PirF in Fig. 13B). Martinez-Mir et al. (1991) reported that the staining for adenosine 2 receptors, which is only found in striatum and external segment of globus pallidus, extends to the

4That the immunoreactive tubular profiles shown in Figs. 9 and l0 represent dendrites covered with peptidergic terminal fibers was suggested by Haber and Elde (1982) and Switzer et al. (1982), and the same conclusion was reached by Gaspar et al. (1987) in regard to the somatostatinergic innervation of dendrites in the bed nucleus of stria terminalis. This proposition has been firmly established. Especially revealing light-microscopic pictures of peridendritic patterns of immunoreactivity have been presented by Beach and McGeer (1984, Fig. 11) and by Haber et al. (1990, Figs. 1, 3, 4) in the primate. An electron microscopic picture of a ventral pallidal dendrite from the rat covered with GAD-positive boutons is shown in Fig. 12 (see also Fox et al. 1974, p. 15, and Heimer and Wilson 1975, Fig. 10). In this instance, one might refer to a GABAergic tubular profile, although in most cases GABAergic terminals in basal forebrain will also demonstrate neuropeptide immunoreactivity. As indicated by Martin et al. (1991b; see also Candy et al. 1985 and Gaspar et al. 1987), it is important to realize that the occurrence of peptidergic tubular profiles is not limited to striatopallidal connections. When comparing the 'tubular' profiles in globus pallidus with those in the ventral pallidum at this level, there is a difference in appearance. The dendritic plexi in globus pallidus (Fig. 9A) form continuous sheaths of terminals around the unlabeled dendrite (compare Fig. 12), which gives the dendrites a pipe-like appearance. The dendritic plexi in the ventral pallidum have a more granular appearance (Figs. 9B and C, and 10), presumably because of a lesser packing density of the immunoreactive terminals. A similar observation was made by Lesur et al. (1989) in regard to somatostatinergic terminal plexi in the bed nucleus of stria terminals (see Section 4.1.1.).

71

Ch. H

L. Heimer et al.

Fig. 8: A, B

ventral surface of the human brain to include what they refer to as the olfactory tubercle. In a recent cytoarchitectonic study of the human accumbens, Lauer and Heinsen 72


Ch.H

Fig. 8: Microphotographs of neurons in ventral striatum from one of the Kliiver-Barrera sections (K1-B 4) in the mini-atlas at the end of the previous chapter. A and B demonstrate the location of the various types of neurons shown in C, D and E. Two of the rectangles in A indicate the position of interface islands illustrated in Figs. 15 and 16. Although Kliiver-Barrera sections are not optimally suited for cytoarchitectural studies, they do provide a clear picture of the various cell types which intermingle with striatal neurons ((7) in the accumbens. Cells belonging to granular (gran) and parvicellular (parv) interface islands are shown in D and E. A group of large neurons are shown in the upper right corner in D. Note that some of the cells to the left in this group (arrows) are superimposed upon other neurons making it difficult to appreciate their size and configuration. A group of plump, densely stained basal nucleus of Meynert cells are illustrated in E.

73

Ch. H


Fig. 9: Enkephalinergic tubular profiles in the external globus pallidus (A), and in ventral pallidal 'pockets' within accumbens (B and C). The areas for the tubular profiles in B and C are indicated in ENK 4 and ENK 5-6 in the mini-atlas in the previous chapter.

(1996) address the subject of the h u m a n ventral striatum but limit it to the nucleus accumbens. A more realistic definition of ventral striatum based on its connectivity within corticosubcortical re-entrant circuits suggests that ventrally located parts of the putamen and caudate should be included. The subpial region of this part of the h u m a n basal forebrain, i.e., the anterior 74


Ch. H

Fig. 10: Substance P tubular profiles in the accumbens at the level shown in SP 5 in the mini-atlas.

perforated space, has been unjustifiably designated as the homologue of the nonprimate 'olfactory tubercle'. That this area should be regarded as a specialized component of the striatum rather than a dedicated olfactory structure, will be discussed in Section 4. It should be appreciated, however, that extensive further study will be needed to finally characterize the hodology and physiology of this complex zone. Lauer and Heinsen (1996) define the human olfactory tubercle as a series of superficial cell islands (their 'insulae terminales olfactoriae laterales') located in close rela75

Ch. H


Fig. 11. A. Coronal section through the caudal part of the accumbens, which forms part of the ventral brain

surface, between the frontal piriform cortex (PirF) to the left and the subcallosal area to the right (see KI-B 5 in the mini-atlas). The area outlined by the rectangle is shown in higher magnification in B. The presence of pallidal neurons is revealed by the dense accumulation of substance-P tubular profiles demonstrated in a neighboring section (see arrows in C). Granular and parvicellular interface islands are as frequent at this level (see insets) as they are in the more rostral section illustrated in Fig. 8. Asterisk in B and C demonstrates corresponding regions.

tion to the olfactory tract as it proceeds in a lateral direction on the anterolateral aspect of the anterior perforated space. By comparing their pictures (Figs. 12-17, Lauer and Heinsen 1996) with Figs. 8A, 11A and 14, it appears that most of the cell islands (characterized as containing a mixture of granule and pyramidal-like cells) are located in the thinning, poorly laminated caudal orbital part of olfactory allocortex (PirF) where it blends with the ventromedial extensions of the claustrum (Fig. 11A) and other ventral striatal components (Figs. 13 and 14). This rudimentary part of olfactory cortex (which in part is separated from the underlying putamen by an attenuated external capsule or by fiber bundles which are continuous with it (Figs. 8 and 11) is distinguished more by its content of cell islands (presumably corresponding in large part to the 'insulae terminales olfactoriae laterales' of Lauer and Heinsen (1996)) than by coherent laminae (e.g. Economo and Koskinas 1925). The most striking aspect of the islands of cells is that most, if not all of them are located lateral to the area where the basal ganglia, i.e. ventral striatum and ventral pallidum, reach the ventral surface of the brain (Fig. 13; see also A C h E 5-6). As suggested by Lauer 76


Ch. H

Fig. 11. B-C.

and Heinsen, it appears that these cell islands are in position to receive input directly from the olfactory bulb (K1-B 4-6). That part of the human brain labeled as olfactory tubercle by Lauer and Heinsen (1996) corresponds to what Brockhaus called tuber or trigonum olfactorium (T.o. in Fig. 6B). It is best conceived of as part of the olfactory allocortex, even though it exhibits a poorly developed laminar organization where it gradually merges with the ventral parts of the basal ganglia. This area of transition is best illustrated in Fig. 14 (compare with Lauer and Heinsen 1996, Fig. 15, in which the anterior commissure and the basal nucleus of Meynert are good landmarks). Although some of the superficial cell-islands on the lateral side of the blood vessel (marked by an asterisk in Figs. 14F 77

Ch. H


Fig. 12: An electron micrograph of a ventral pallidal dendrite covered with glutamic acid decarboxylate

(GAD)-immunoreactive terminals from a rat brain (Courtesy of Dr. D.S. Zahm).

and G) could conceivably belong to the insulae terminales olfactoriae laterales of Lauer and Heinsen, the two superficially located cell islands immediately medial to the blood vessel, one of them granular (Fig. 14B), the other parvicellular (Fig. 14C) in nature, can hardly be part of their lateral group of olfactory islands. Nevertheless, they may be within reach of olfactory bulb projections (K1-B 6 and Fig. 14H) and they are clearly within the boundaries of the ventral part of the basal ganglia based on immunohistochemical criteria (Fig. 14F). It is likely that only this area, the olfactory recipient part of ventral striatum, is the primate/human homologue of the olfactory tubercle of macrosmatic mammals (e.g. see also Heimer et al. 1977; Price 1990, p. 985). Hartz-Schfitt and Mai (1991) used acetylcholinesterase histochemistry and the selective pseudocholinesterase inhibitor tetra-isopropylpyrophosphoramide (iso-OMPA) to delineate a broad, superficially located, cholinesterase-poor zone in the floor of the ventral striatum and considered it to be a non-striatal olfactory tubercle. This superficial zone is, however, one of the most choline acetyltransferase-rich regions of the basal ganglia complex (compare Fig. 3f in Hartz-Schfitt and Mai 1991, with Fig. 6A in Holt et al. 1996), and dense choline acetyltransferase immunoreactivity appears to be a reliable striatal marker in this part of the brain. For the present, the finding of HartzSchfitt and Mai might be considered as only one of several distinctive features of the human ventral striatum, rather than as a means of distinguishing the human olfactory tubercle. It should be appreciated that the use of iso-OMPA as a pseudocholinesterase inhibitor does not result in a histochemical distinction between the acetylcholinesterase staining of the olfactory tubercle and the remainder of ventral striatum in animals such 78


Ch.H

Fig. 13: Coronal human brain sections at the subcommissural level, immunostained for tyrosine hydroxylase (A) and glutamic acid decarboxylate (B) to show the extension of the ventral striatum (VS) to the surface of the brain on the medial side of the frontal piriform cortex (PirF). The dense immunoreaction in B demonstrates the extent of the ventral pallidum (VP) at this level.

as the rat or mouse in which experimental tracing permits confident designation of primary olfactory projections. Nevertheless, we must concede that this superficial part of the ventral striatum has some cytoarchitectonically distinctive features, which make it difficult to directly compare it with the rest of the striatal complex. The extreme ventral part of the human striatum is a specialized subterritory that deserves extensive investigation. The previous discussion illuminates some of the difficulties in defining an 'olfactory tubercle' in the human brain, where a surface elevation is not usually detectable. As indicated earlier, the olfactory tubercle of macrosmatic mammals is part of the ventral striatopallidal system. It appears that input directly from the olfactory bulb to this part of the ventral striatum is rather limited, both in the monkey (Carmichael et al. 1994) and the human (K1-B 6 and 7, and Fig. 14H). For further discussion of the 79

Ch. H

L. Heimer et al.

Fig. 14: A. Coronal section at approximately the same level shown in Fig. 13, but stained with the KlfiverBarrera method to show the distribution of granular (B) and parvicellular (C) cell islands in this area of transition between ventral striatum and olfactory cortex (PirF). Note the concentration of pallidal cells (D) and the large medially located granular island (E). Parvicellular (arrowheads) and granular (arrows) interface islands are also prominent features in the lateral bed nucleus of the stria terminalis (BSTL). The area of transition between the piriform cortex (Pir) and ventral striato-pallidal region is shown in higher magnification in F, which represents a section at approximately the same level as K1-B 6 (in G) but which is stained for both substance P and acetylcholinesterase to show the extension of ventral striatum to the ventral brain surface. The color-coded drawing in H illustrates the various components in this part of the brain (blue = striatal tissue, light blue = parvicellular islands; pink = ventral pallidum; brown = accumulations of basal nucleus of Meynert cells; black = granular cell islands; magenta = presumed olfactory bulb projection area; yellow = bed nucleus of stria terminalis). 80


Ch. II

Fig. 14" F-H.

81

Ch. H

L. Heimer et al.

problems related to the definition of an olfactory tubercle in the human brain, the reader is referred to Stephan (1975, pp. 319-324), as well as to Heimer et al. (1977) and Price (1990). 2.1.2. Interface islands

In their studies of heterogeneous opiate receptor distribution, Voorn and his colleagues (Voorn et al. 1994; 1996; Vonkeman et al. 1996) have drawn attention to one of the most characteristic morphological features that distinguishes the human ventral striatum from the rest of the striatal complex, i.e. the number of cellular islands. We will use 'interface island' (a term originated by Drs. Sakamoto and Pearson) as a descriptor for these numerous, more or less distinct compact clusters of basal forebrain cells that are particularly prominent where the ventral striatum abuts structures which include the septum-diagonal band area, external capsule and ventral pallidum. We insert this novel term with some reluctance, but these clusters in the human brain do not all resemble the 'islands of Calleja' in macrosmatic mammals, nor can we assume them to be functional end zones as implied by the name 'terminal islands' used by Sanides (1957b). As further detailed in Sections 3 and 4, interface islands are by no means limited to ventral striatal areas, but occur throughout much of the basal forebrain and especially in relation to the extended amygdala (Section 3). Granular cell islands. One type of interface island is comprised of granule cell clusters which consist of small, round, tightly packed neurons (5-6 ~tm in diameter; Figs. 11B, and 14B and E; see also Fig. 14H in which granular cell islands are shown in black). Similar islands are well-known from studies in macrosmatic mammals in which they are known as 'islands of Calleja' and where they are confined primarily to the olfactory tubercle and the 'insula magna of Calleja' in the medial part of the accumbens. An insula magna is found at the medial border of the accumbens in all species studied (e.g. Meyer et al. 1989) including the human (Fig. 15). However, only the more diminutive cell island (marked with an arrow in Fig. 15A) contains a majority of granular or 'glia-like' cells which are typical for the 'islands of Calleja' in macrosmatic mammals. In the large elongated island (insula magna), which extends far ventrally alongside the diagonal band fibers, there is a mixture of granule cells and somewhat larger cells, with the larger cells in clear majority. We include such islands in the 'parvicellular' category (see below). Fallon and his collaborators (Fallon et al. 1983a,b) observed that many granular cell islands, including the insula magna in the rat, contain luteinizing hormone-releasing hormone (LHRH) and estrogen binding sites. They suggested that the islands might be targets for circulating hormones, but the function of these cell clusters, which were discovered more than a century ago, remains to be fully characterized. In the present era of chemical neuroanatomy renewed interest in these unusual structures might be promoted by the fact that in the rat they are the site of the most dense immunoreactivity for substances such as epidermal growth factor (Fallon et al. 1984), and display some of the most dense accumulations of D3 dopamine receptors (Sokoloff et al. 1992; see also Gurevich et al. 1997; and below). The latter are candidates for genetic alterations in schizophrenia (Griffon et al. 1996). Finally, as suggested by their relation to LHRH and estrogen receptors, some evidence indicates that these structures are sexually dimorphic, at least at the neurohistochemical level (e.g. Hill and Switzer 1984). Meynert (1872) was aware of these islands and Ganser (1882) drew attention to their presence in the olfactory tubercle of the rabbit, comparing them to 82


Ch.//

the granular cells in the olfactory bulb. Interestingly, when Calleja (1893) described cell-islands in the olfactory tubercle of the rabbit a few years later, he apparently did not refer to the granule cell islands which now generally bear his name, but rather to collections of 'pyramidal' cells in the tubercle, or to so-called 'dwarf' cells which lie in the cap regions of the dense cell layer (Sanides 1957a, Millhouse 1987). As suggested by Millhouse (1987), Calleja neither described nor depicted the 'islands of Calleja'. This case of 'mistaken identity' has led to some confusion in the literature. Golgi studies in the human (Meyer et al. 1989) and in several macrosmatic animals (e.g. Fallon et al. 1978; Meyer and Wahle 1986, Millhouse and Heimer 1984; Millhouse 1987; Meyer et al. 1989) tend to show that the granule cells have a variable but generally rather undifferentiated morphology. Both unipolar and bipolar neurons have been demonstrated with dendrites that are thin and usually poorly branched. Some granule cell dendrites have spines but others are smooth. Axons tend to be very short and confined to the islands. Meyer et al. (1989) emphasize that different kinds of granule cells (which in our definition also include parvicellular neurons) coexist in the same cell cluster, and they raised the question of whether transformations from one form to another might take place postnatally. Several granule cell islands, like the one in Fig. 15, exhibit weak ENK staining but relatively strong or moderate SP- and apparently moderate AChE staining. Some have strong AChE activity but weak peptidergic innervation, whereas still others have minimal activity in all three markers. Talbot et al. (1988) and Meyer et al. (1989) have described granule cell islands in various animals. It is clear from these and other studies that such islands are not predominantly related to olfactory structures, even though some of them may be in a position to receive input directly from the olfactory bulb. Furthermore, clusters of granule cells are present in anosmatic animals like the dolphin (Jacobs et al. 1971), and insular clusters of deeply stained small 'glia-like' neurons are more numerous and more widely distributed in the microsmatic human basal forebrain than in any other species (e.g. Brockhaus 1938; 1942a,b; Crosby and Humphrey 1941; Sanides 1957a,b; 1958; Strenge et al. 1977; Meyer et al. 1989). The location of granular cell islands is subject to great variations, although two medially placed large granular islands in the ventral striatum close to the surface are constant features of all human brains, according to Meyer et al. (1989). One of these is displayed in Figs. 14A and E. Because the granule cell clusters are different from the aggregations of cells that Calleja described in the rabbit, we will simply refer to them as 'granular cell islands'. This nomenclature is further justified by the fact that most investigators now associate islands of Calleja with the olfactory tubercle, an association that is inappropriate in the human where granular cell islands are widely dispersed (shaded in black in Fig. 14H) and a homologue for the tubercle is indistinct or absent. Sanides (1957b), who mapped and described the granule cell islands of the human in great detail, included them in his definition of '71 insulae terminales'. Since these granule cell clusters, like the 'parvicellular cell islands' to be described below, are in general located between major neuronal systems and in relation to major fiber bundles which interlace to form the human basal forebrain, we include them as a subset of the collection of 'interface islands'. As we shall discuss in Section 3, interface islands are also characteristic components of the extended amygdala. In the amygdaloid body, where practically all islands are of the parvicellular variety, they are known as intercalated islands, which, like the term interface islands, is appropriate since they are located almost without exception between the extended amygdala and the rest of the amygdaloid body or else between components of the extended amygdala. 83

Ch. H

84

L. Heimer et al.


Ch.H

10 lain) cells we will collectively refer to these cell aggregates as 'parvicellular islands'. The neurons which populate the parvicellular islands generally have densely spined dendrites and clearly visible axonal arborizations and thus resemble components of the striatum (Meyer et al. 1989). Since the parvicellular islands containing these striatallike cells are usually surrounded by pallidal-like neurons having dendrites covered with peptidergic-tubular profiles, they may function as miniature striatopallidal units. The neurochemical composition of the islands and their surroundings supports this proposition. Sanides (1957b) postulated that the admixture of granular and parvicellular neurons reflects a type of arrested development of small striatal-type cells. In addition to being especially pronounced in the human brain, 'interface islands' are subject to great individual variations. Granule cells and clusters of parvicellular cells are present in the human basal forebrain at all ages. Since they appear to be more numerous in early life (Sanides 1957b; Meyer et al. 1989), Sanides suggested that these might be neural progenitor cells arrested in development (hence, terminal islands or 'insulae terminales'). Their location, moreover, would suggest that continued postnatal development might lead to transformation into other striatal (or amygdaloid) elements (Meyer et al. 1989). While generally it has been taken for granted that the population of neurons in the adult brain is relatively stable with only a slow attrition with age, recent evidence suggests that cells in the vicinity of the lateral ventricle might be induced by neuronal growth factors to differentiate into mature neurons, and even to migrate to positions in striatum or cortex (Weiss et al. 1996). The relevance of these observations to the earlier postulates of Sanides or Meyer and colleagues is, as yet, unclear. The 'neurochemically unique domain'. A large number of interface islands are concentrated in the ventral part of the accumbens (Sanides 1957b) where they appear to 85

Ch. H

L. Heimer et al.

form an 'archipelago' extending from the dorsomedial accumbens alongside its border towards the septum-diagonal band area and further laterally into the ventral putamen at its border with the external capsule (Fig. 16; area outlined in Fig. 8). Walter et al. (1990) pointed out that the parvicellular islands in this chain are characterized by fibers and cell bodies immunoreactive for neuropeptide Y (NPY) which, in the neonate brain, can be seen to establish continuity with NPY-positive regions in the lateral bed nucleus of stria terminalis. Many of the islands seem to be special targets for axons that contain cholecystokinin (CCK) or somatostatin (SOM), possibly from the central amygdaloid nucleus as suggested by Mufson and his collaborators (Mufson et al. 1988). Other likely places of origin would be the laterobasal amygdaloid complex (see review by Heimer et al. 1995) or the lateral bed nucleus of the stria terminalis (e.g. Brog et al. 1993; Heimer et al. 1997b). This elongated, arc-like chain of interface islands corresponds in general to the 'neurochemically unique domains in the accumbens and putamen' (NUDAP) 5 which Voorn and his colleagues (Voorn et al. 1996) have identified on the basis of their distinct neurohistochemical characteristics that includes a high density of la opioid receptors. This characterization, exemplary of the importance of comparing histochemical data with cytoarchitecture, has permitted correlation of the areas of highest binding density with the chain of granular and small-celled islands identified by Sanides (1957b) along the ventral curvature of accumbens and ventral putamen. A recent study (Gurevich et al. 1997) of the ventral striatum of a patient with schizophrenia, who was not receiving antipsychotic drugs at the time of death, includes an illustration (Fig. 4, top right) that appears to show the 'neurochemically unique domain' of Voorn et al. (1996) to be prominently represented within the area of the highest increment of D3 receptor binding as compared to a normal control. In addition to those in the archipelago-like unique domain, other parvicellular islands are scattered in more caudal parts of ventral striatum, especially at the level where its components are gradually replaced by large numbers of ventral pallidal cells (Figs. 14 and 17), by components of the basal nucleus of Meynert and by the extended amygdala. The intermingling of interface islands with ventral striatal and ventral pallidal cells, as well as with hyperchromatic basal nucleus of Meynert cells, is particularly pronounced at these levels, making this subcommissural part of the basal forebrain one of the most complex regions of the human brain. Our immunocytochemical studies indicate that many of the parvicellular islands, like the clusters of granule cells, show a moderate to strong AChE reactivity (Fig. 16). Since the islands do not possess intrinsic cholinergic neurons, the AChE marker is presumably contained in fibers and terminals, and thus resemble granule cell islands in macrosmatic mammals (e.g. Phelps and Vaughn 1986; Wahle and Meyer 1986; Talbot et al. 1988). Although many interface islands exhibit a stronger AChE activity than surrounding striatal areas, cholinesterase-poor islands are sometimes encountered both in the monkey and the human (asterisk in Figs. 16A and B; see also Alheid et al. 1990, Figs. 19.20 19.21 and 19.22). Sometimes, the AChE-reactivity varies within a single island, resulting in patchy staining as, for example, in the large medial parvicellular island (insula magna) in the accumbens (Fig. 15; see also Hartz-Schfitt and Mai 1991). Many parvicellular islands have moderate to strong SP-immunoreactive processes and

5This archipelago of interface islands is not unique to the human. Similar arc-like chains of small-celled islands appear in other mammals, including the rat (Zahm and Heimer 1988, Fig. 4, Alheid et al. 1995, Fig. 18B), in which they tend to be located at the ventral, rostral, and lateral borders of ventral striatum, including the accumbens.

86


Ch. H

Fig. 16: Interface islands alongside the ventral putamen at its border with the external capsule (the location of the area represented by these sections is indicated by a rectangle in Fig. 8A). Many of the parvicellular islands (indicated by arrows in A) show a moderate to strong reactivity both in the acetylcholinesterase (B) and substance P (C) preparations but weak enkephalin-immunoreactivity (D). Note that the parvicellular island marked with an asterisk in A is negative for all three stains.

87

Ch. H

88

L. Heimer et al.


Ch. H

Fig. 17: Kltiver-Barrera (A) and substance P (C) stained sections from the subcommissural region where the ventral striatum intermingles in a labyrinthine fashion with the strongly substance P-positive ventral pallidum. B is a color-coded schematic based on information available from the two histologic sections (blue = ventral striatum; light blue = parvicellular islands; pink = ventral pallidum; brown = basal nucleus of Meynert; black = granular islands; magenta = presumed olfactory bulb projection area).

perikarya and weak ENK-immunoreactivity (Fig. 16C and D), but some have weak SP and moderate ENK immunoreactivity (upper right arrow in Figs. 16C and D; see also asterisk in Fig. 11B and C). Other islands, e.g. the medially located elongated island in Fig. 15, are poorly stained for both SP and ENK. Still others, like the one marked with an asterisk in Fig. 16, are negative for all three markers. Some 'islands' may be extensions of nearby territories. In addition to the islands described above, collections of medium-sized, oblong or stellate neurons with prominent cytoplasmic processes and weakly or moderately stained nuclei often appear in the form of compact clusters, especially at more posterior levels (Fig. 17). Since these 'islands' are comprised of neurons similar to those of both the ventral striatum and extended amygdala, and are neither granular nor parvicellular, we do not include them with the other small-celled aggregates. The packing density of these clusters may be higher than usual for striatum or extended amygdala, but without examining more extensive serial sections it is difficult to say whether they are truly isolated, or are peninsulae from nearby major compartments of striatum or extended amygdala. The presence of the morphologically ambiguous areas raises the possibility that there may be some structural and even functional gradations between distinctive islands and components of systems such as the striatum and extended amygdala. 2.1.3. Core and shell subdivisions of the accumbens

An important feature which distinguishes the ventral striatum from the rest of the striatal complex is the so-called 'core-shell dichotomy' of the accumbens. The distinction between a central core and a shell surrounding its medial, ventral and lateral sides was first suggested on the basis of staining for cholecystokinin and acetylcholinesterase in the rat accumbens (Zfiborszky et al. 1985). The concept has been amply confirmed in a number of anatomical and histochemical studies (see reviews by Zahm and Brog 1992; Groenewegen et al. 1996 and Heimer et al. 1993; 1997a). The functional significance of the core-shell dichotomy is reflected in the important observation that projections from accumbens to the hypothalamus, extended amygdala and midbrain tegmentum (all of which are atypical for a striatal structure) originate in the shell rather than in the core of the accumbens (Groenewegen and Russchen 1984; Zahm and Heimer 1990; Heimer et al. 1991). In the rat, important distinctions between core and shell have been demonstrated in regard to dopaminergic mechanisms and to putative differential roles in drug abuse (e.g. Pontieri et al. 1994; Sorg et al. 1995; Carlezon and Wise 1996a,b; Koob and Nestler 1997; Koob and Le Moal 1997). The shell rather than the core contains the majority of the neurons expressing dopamine D3 receptors (Diaz et al. 1995) and it also seems to be a significant target for the actions of antipsychotic drugs (Deutch and Cameron 1992; Graybiel et al. 1990; Merchant and Dorsa 1993; O'Donnell and Grace 1993). The urgent task of defining the core-shell subdivision in the human brain has proven difficult (e.g. Holt et al. 1997). Nevertheless, Meredith and Voorn and their colleagues have cogently argued that in the human the accumbens shell exhibits the same low 89

Ch. H

L. Heimer et al.

calbindin immunohistochemistry relative to the accumbens core and dorsal striatum (Meredith et al. 1996) as it does in the rat. The shell also has moderate and dense opioid receptor binding (Voorn et al. 1994; 1996; Vonkeman et al. 1996) in its medial and ventral parts, in contrast to the core and neighboring transition areas in putamen and caudate nucleus, all of which exhibit lower opioid receptor binding than the rest of striatum. Differential substance P-immunoreactivity in the human accumbens (SP 4) echoes to some extent the situation in the core-shell region of the rat (Fig. 18). It is noteworthy that some of the features that distinguish the shell (particularly its caudomedial part) from the core of the accumbens and the rest of the striatum, are also characteristic of the extended amygdala, especially the central division of the latter, which is directly continuous with the posteromedial accumbens (Fig. 2A). The large forebrain continuum formed by the shell of the accumbens and the extended amygdala appears especially relevant in the context of neuropsychiatric disorders and drug abuse (Alheid and Heimer 1988; Heimer et al. 1997; Koob and Le Moal 1997). The issue of transition areas between striatum and extended amygdala will be discussed in Section 3.5. 2.2. VENTRAL PALLIDUM Ventral pallidal components in the form of peptidergic tubular profiles intermingle with ventral striatal tissue as far anterior as the levels shown in ENK 4 and SP 5 (see higher magnification images in Figs. 9, 10 and 11C). Clusters of pallidal cells become increasingly more common in caudal parts of ventral striatum (e.g. Fig. 14D). Both

Fig. 18: Coronal section through the rat brain stained for substance P to show the distinction between core and shell of the accumbens. (Courtesy of Dr. D. S. Zahm.)

90

The human basal forebrain. Part II

Ch.H

enkephalinergic (Fig. 9B) and SP-positive tubular profiles (Fig. 10) are present rostrally. The SP-ensheathed pallidal dendrites become far more numerous at the subcommissural level where the ventral striatum intermingles with the ventral pallidum in a labyrinthine manner (Fig. 17). Here, striatal and pallidal components reach the ventral brain surface and partly intermingle with the basal nucleus of Meynert and slightly further back with parts of the extended amygdala to form a highly intricate pattern. The extension of the ventral pallidum from the subcommissural part of globus pallidus in an SP-stained human coronal section (Fig. 17C) is very similar to the picture of SP-immunostaining shown by Mai et al. (1986; Fig. 9e; see also Beach and McGeer 1984; Haber and Watson 1985 and Alheid and Heimer 1988, Fig. 8B). Sections through the subcommissural region (from a different brain from the one shown in Fig. 17A) stained for TH (Fig. 13A) and GAD (Fig. 13B) reaffirm that ventral pallidum extends almost to the ventral surface of the human brain in the region of the anterior perforated space. An even more striking picture of the ventral extension of the primate pallidal complex is seen in sagittal sections stained for 'pallidal' markers such as ENK, SP and GAD (Fig. 13 in Mai et al. 1986; Figs. 19.26 and 19.27 in Alheid et al. 1990). Endogenous iron (revealed by the diaminobenzidine-intensified Perl's reaction) is also an excellent marker for the pallidal complex, especially since it densely labels both its medial and lateral segments but leaves nearby striatal or extended amygdaloid components relatively unstained. We have capitalized on this feature in earlier papers (Alheid and Heimer 1988; Alheid et al. 1990) to illustrate the surprisingly large subcommissural ventral pallidal complex in the monkey and human (Figs. 29.28-29.30 in Alheid et al. 1990). The fingerlike extensions of ventral pallidum into the ventral striatum are particularly clear in iron-stained sagittal sections of the human brain (Fig. 19A). These peninsulae correspond to what appear to be islands of ventral pallidal components when viewed in the coronal sections in Figs. 11C and 14D (see also Fig. 14 F). The compact part of the basal nucleus of Meynert is recognizable by its large hyperchromic cells, and its position just caudal to ventral pallidum is shown in a higher magnification detail (Fig. 19B) of the iron-stained preparation counterstained with thionin. It is important to reiterate that ventral pallidal components (especially pallidal dendrites entwined by substance P- and enkephalin-positive axons and terminals) intermingle with striatal neurons in the posterior parts of ventral striatum (Section 2.1.1.). Added to these are similar (but not identical) dendrites in caudomedial accumbens representing forward elements of the extended amygdala (Sections 3.1. and 3.2.), also enmeshed in peptide terminals (e.g. enkephalin and VIP-rich terminations). Therefore, much of the caudal part of the ventral striatum in the human is actually a mixture of striatal and pallidal, and to some extent, extended amygdaloid components. Ventral pallidum, like dorsal pallidum, is not distinctly stratified. The distribution of ENK- and SP-immunoreactive (IR) tubular profiles in the human globus pallidus has been described by several authors (e.g. Beach and McGeer 1984; Haber and Watson 1985; Mai et al. 1986). In general, ENK-IR tubular profiles are packed throughout the external (lateral) segment of globus pallidus (ENK 3-12), but are relatively infrequent for its internal (medial) segment (ENK 10-12). An exception to this rule is found in a small anterior portion of the internal pallidum (ENK 9). SP-IR tubular profiles, on the other hand, are especially dense in the internal pallidal segment (e.g., SP 10), but are relatively sparse in the main part of the external segment, especially in its central part (SP 5-10). The rostral pole of the external pallidal segment, however, has a more 91

Ch. H


Fig. 19: A. Diaminobenzidine-intensified Perl's reaction for endogenous iron illustrates the ventral pallidum (VP) as it extends ventrally underneath the anterior commissure (ac) and behind the accumbens in a sagittal section of the human brain. Note the finger-like extensions of the ventral pallidum into the caudal regions of the accumbens. The preparation was counterstained with thionine to reveal the basal nucleus of Meynert cells (B; in 19B) behind the ventral extension of the ventral pallidum. Arrows in 19B point to groups of large hyperchromic basal nucleus of Meynert cells. For orientation a low-magnification photograph of a nearby iron-stained preparation is shown in C. Note the continuous iron-rich territory extending from globus pallidus through the cerebral peduncle into the substantia nigra (SN). 92


Ch. H

prominent accumulation of SP-immunoreactive tubules compared to the more caudal portions (SP 3-5). Further subcompartments are evident in the two segments of globus pallidus. For instance, the periphery of the external segment has somewhat less densely packed ENK-immunoreactive tubular profiles than its central part (e.g. ENK 8), but has more SP-IR tubular profiles (e.g. SP 6 and 8). Thus, the globus pallidus shares with the striatum the characteristic of a complex chemoarchitectonic subterritorial organization. The border between ventral and dorsal pallidum is as elusive as the border between the dorsal and ventral parts of the striatal complex. Since ventral pallidum is, by definition the area which receives input from ventral striatum, its borders are in effect dependent on the location of the ventral striatum. This problem has been addressed by Haber et al. (1990), who compared the relationship between ventral striatal efferents and the distribution of peptidergic tubular profiles in the forebrain of the monkey. Since the relative distribution of peptide-containing fibers in the monkey appears very like that in the human we will, in part, follow Haber and her colleagues in describing our ENK- and SP-stained sections as they relate to the ventral pallidum. The human ventral pallidum, like the dorsal pallidum (globus pallidus) can be subdivided chemoarchitectonically into regions by the relative richness of their ENK- and SP-innervation (Haber and Watson 1985). A direct ventral extension of the external pallidal segment directly under the temporal limb of the anterior commissure is strongly ENK-positive (ENK 3-8) but it also contains SP-positive profiles (SP 4-7). A strongly SP-positive subcommissural area (SP 5 and 7) extending further medially than the strongly ENK-positive area (compare ENK 5-8 with SP 7) also seems to be directly continuous with the external pallidal segment (compare ENK 5-6 with SP-5). Note that part of the medially located ENK-positive area in ENK 8 belongs to the extended amygdala rather than the pallidal complex (see Section 3.2.). Continuity between the internal pallidal segment and ventral pallidum is difficult to visualize in coronal (SP 7, 8 and 9) or sagittal sections (Mai et al. 1986, Fig. 12a) of the human, although such a direct continuity appears to occur at coronal levels caudal to the anterior commissure (K1-B 8) and is apparent in marmoset monkey (Alheid et al. 1990, Fig. 19.26). These illustrations and the previously mentioned intermingling of peptidergic tubular profiles with ventral striatal components indicate that SP and ENK are at least as incompletely segregated in the ventral pallidum as they are in the internal and external segments of the globus pallidus. The ventral striatum is defined on the basis of its input from allocortex, mesocortex and some isocortical association areas in orbitofrontal and inferior temporal regions (Section 2.1.). Haber et al. (1990) indicated that in the monkey ventral pallidum, defined in terms of these corticostriatal relays, includes areas underneath the temporal limb of the anterior commissure (ENK 4-8 and SP 4-8) and in the ventral part of the rostral pole of the pallidal complex (ENK 3 and SP 3).

3. EXTENDED AMYGDALA The extended amygdala is diagrammatically shown in yellow to represent its central division and green to denote its medial division in K1-B 5-12. It is now well documented that the bed nucleus of stria terminalis and the centromedial amygdaloid nuclei are in continuity with each other both through sublenticular cell islands in the basal forebrain and through attenuated columns of cells or cell islands that also 93

Ch. H

L. Heimer et al.

accompany the stria terminalis in its semicircular course behind and above the thalamus (K1-B 10-12; see also Fig. 1). The concept of the contiguous system that we have called the extended amygdala originated with the pioneering comparative and developmental studies by Johnston (1923) who delineated the close relationship between the bed nucleus of stria terminalis and the centromedial amygdala through continuous cell columns in the stria terminalis. Johnston also included the accumbens with the bed nucleus as well as the centromedial amygdala in his concept of a large forebrain continuum which he recognized in lower vertebrates and even in human embryos. As we discussed briefly in Section 2.1.3. the shell of the accumbens, especially its caudomedial part, has a number of characteristics typical for the central division of the extended amygdala but, since it is also part of the cortico-subcortical basal ganglia circuitry, we currently regard the caudomedial shell of the accumbens as a transition area between extended amygdala and the striatopallidal system (Section 3.5.). A sublenticular continuum between the central amygdala and the bed nucleus of stria terminalis was hinted at by Brodal (1947; see also von Bonin 1959), when he observed that the cells of the central amygdaloid nucleus in the rat 'make a gradual transition between the bed nucleus of stria terminalis and the anterior amygdaloid area'. A quarter of a century later, de Olmos (1969 1972), aided by the cupric silver method, identified a histochemically distinct sublenticular cell column between the central amygdaloid nucleus and the bed nucleus of stria terminalis. During the last 15 years, the original idea of a continuum between the bed nucleus of stria terminalis and centromedial amygdala has been reinforced and expanded by the results obtained in several normal anatomical and experimental studies, primarily in the rat (see review by de Olmos et al. 1985; Alheid and Heimer 1988; Alheid et al. 1995), but also in the cat (Holstege et al. 1985; Hopkins and Holstege 1978), rabbit (Schwaber et al. 1982) and hamster (Gomez and Winans-Newman 1992). Modern developmental studies based on migratory neurogenesis and expression of specific genes by Song and Harlan (1994a,b) and others (reviewed in Heimer et al. 1997b) are supportive of the concept of the extended amygdala, although there is not complete agreement in this regard (Canteras et al. 1995). The functional concept of the extended amygdala has been embraced especially by those interested in the neurobiology of drug addiction (e.g. Koob et al. 1993b; Koob and Nestler 1997), but deserves recognition by all who are interested in emotional disorders (e.g. Alheid and Heimer 1988; Heimer et al. 1997b). The extended amygdala in the human is fundamentally like that in other primates and non-primate mammals studied to date (Alheid and Heimer 1988; de Olmos 1990; Martin et al. 1991b; Walter et al. 1991; Marksteiner et al. 1993; Kaufmann et al. 1997). The extended amygdala has two major subdivisions. The extended amygdala has a central division involving its namesake, the central amygdaloid nucleus, and its rostral consort, the lateral bed nucleus of the stria terminalis. There is also a medial division of extended amygdala that is named after the medial amygdaloid nucleus and its rostral partner, the medial bed nucleus of the stria terminalis. As indicated in the color-coded illustrations (K1-B 5-12), the two divisions can be distinguished not only in the bed nucleus of stria terminalis and centromedial amygdala but also in the supracapsular and sublenticular regions (e.g. de Olmos et al. 1985; Grove 1988a,b; Alheid et al. 1998). The two major divisions of the extended amygdala in the rat have smaller sub-components within the bed nucleus of stria terminalis and the centromedial amygdala (Alheid et al. 1995). Not all of these may be represented in the 94


Ch.H

sublenticular and supracapsular corridors but where they are not continuous from rostral to caudal parts of extended amygdala, they most often appear as rostro-caudal pairs of subnuclei (e.g. see Alheid et al. 1995). Although various subcompartments of the human extended amygdala have been noted (de Olmos 1990; Martin et al. 1991b; Walter et al. 1991; Kaufmann et al. 1997), their delineation has not progressed to the same degree as in the rodent. That the two divisions of the extended amygdala are important functional-anatomical units in the human basal forebrain is supported by the presence of many homologous elements (with the rat) of these two divisions combined with supporting chemoanatomic evidence in a growing number of reports on the human forebrain (e.g. Strenge et al. 1977; Candy et al. 1985; Bennett-Clarke and Joseph 1986; Gaspar et al. 1985; 1987; Lesur et al. 1989; Mufson et al. 1988; Pioro et al. 1990; Walter et al. 1991). The following discussion will focus attention primarily on some of the cyto- and chemoarchitectural distinctions of the two major divisions of the human extended amygdala. Although there are some likely interactions between the two divisions of the primate extended amygdala, as reflected by the presence of interconnections between the central and medial amygdaloid nuclei (Amaral et al. 1992), evidence from experimental anatomical, pharmacological and physiological studies in the rat suggest that they may be better analyzed as separate functional-anatomical systems (see reviews by McDonald 1992; Alheid et al. 1995; Heimer et al. 1993; 1997b). The extended amygdala forms a ring around the internal capsule. As we shall describe below, the bed nucleus of stria terminalis and the centromedial amygdala are in cellular continuity with each other both along the stria terminalis and in the sublenticular region. The extended amygdala, therefore, forms a ring around the internal capsule and thalamus (Fig. 1). The supracapsular part of the extended amygdala forms partly interrupted arching columns of gray matter which loop up from the bed nucleus of stria terminalis and then descend posteriorally into the central and medial amygdaloid nuclei. This arrangement was originally observed by Johnston (1923) in the monkey and the human fetal brain and confirmed in greater detail by Strenge and colleagues (1977) in the human and by Alheid et al. (1998) in the rat. The sublenticular part of the extended amygdala is shown to be composed of continuous columns by a variety of staining techniques in the rat (de Olmos 1972; Fig. 21) and the monkey (Fig. 20; see also Alheid and Heimer 1988, Fig. 12; Amaral et al. 1989, Fig. 6 and Martin et al. 1991b, Fig. 25). In the human the sublenticular part of the extended amygdala appears as fingers or cell islands (K1-B 8-10). In the coronal sections presented here these have the appearance of partially interrupted columns but, based on serial sections of the human extended amygdala, Martin et al. (1991b) proposed that there is a cellular continuum in the human as well. A similar conclusion is suggested by the work of Walter et al. (1991). Earlier, Novotny (1977) described a sublenticular connection between the bed nucleus of stria terminalis and the amygdaloid complex in the monkey consisting of bundles of very fine myelinated axons. Although he did not draw attention to any cellular continuity between the bed nucleus and the amygdala, or the existence of neuropil related to these fiber bundles, it is certainly easy to discern its existence in his Fig. 20 and in many other preparations of the monkey brain published during the last several years (e.g. Fig. 12 in Alheid and Heimer 1988; Fig. 6 in Amaral et al. 1989; Kohler et al. 1989; Christopoulos et al. 1995; C6t6 et al. 1996). The entire extended amygdala is shown in isolation from the rest of the brain as a schematic drawing in Figure 1. We have conservatively presented the sublenticular 95

Ch. H

L. Heimer et al.

Fig. 20: Extended amygdala in Tamarin monkey demonstrated by immunostaining for secretoneurin (SECR) in A and B and with Timm's stain in C and D. The central (Ce) and medial (Me) amygdaloid nuclei as well as various components of the bed nucleus of stria terminalis (BST) are positive in both stains. The sublenticular part of the extended amygdala (SLEA) is also displayed as a continuum between the bed nucleus and the centromedial amygdala in both stains (B and D). Note that the posteromedial part of the accumbens shell is also stained in these preparations.

extended amygdala as two partly interrupted columns of cells. As depicted by Price et al. (1987; Fig. 11) the shape of this system reflects the two amygdaloid pathways, i.e. the stria terminalis and the ventral amygdalofugal pathway, which have been 'split 96


Ch. H

Fig. 20: C-D.

apart' by the massive internal capsule in development. The schematic in Fig. 1 emphasizes three additional points. First, it illustrates how stria terminalis is accompanied by a doublet of continuous or nearly continuous cell columns that loop alongside the body and tail of the caudate nucleus above and behind the thalamus and the internal 97

Ch. H

L. Heimer et al.

capsule. Second, it shows the two sublenticular cell columns which complete the ring of the extended amygdala around the internal capsule and the basal ganglia. Third, it emphasizes the fact that the cortical amygdaloid nuclei and the large laterobasal amygdaloid complex are not included within the operational definition of the extended amygdala, although they provide important inputs to its two divisions. The extended amygdala is characterized by long associative connections and has prominent projections to autonomic and somatomotor centers in lateral hypothalamus and brainstem (central division) and to endocrine-related medial hypothalamus (medial division). Thus, it represents a strategically placed ring formation capable of coordinating activities of multiple forebrain regions for the development of coherent behavioral responses through the above-mentioned output channels. 3.1. BED NUCLEUS OF STRIA TERMINALIS The bed nucleus of stria terminalis (BST), which exhibits its maximal development in primates and humans (Andy and Stephan 1968, 1976) is subject to a plethora of nomenclatures (Table 1 in Appendix). We advocate a system (de Olmos 1990) based on a classic 'zonal medial-lateral organization' (e.g. Brockhaus 1942b; Andy and Stephan 1968; Strenge et al. 1977; Gaspar et al. 1985; Walter et al. 1991). In contrast to Walter and his colleagues or Lesur et al. (1989), who recognized three major divisions (lateral, central and medial), we regard the bed nucleus as being comprised of just two basic divisions, lateral and medial (BSTL and BSTM). This bifurcation of the bed nucleus is supported by the developmental studies of Bayer and Altman (1987), and is consistent with the inclusion of the medial bed nucleus and lateral bed nucleus within medial and central divisions (respectively) of the extended amygdala. The medial division of Gaspar and Walter and their colleagues largely coincides with the medial bed nucleus of stria terminalis (BSTM) of de Olmos, whereas their central and lateral divisions are encompassed by his lateral bed nucleus (BSTL). The subdivisions of the human bed nucleus recognized by de Olmos (1990) were adopted (with slight modification) by Martin et al. (1991b) for their cytoarchitectonic study in the rhesus monkey and subsequently applied to their human material. In this chapter we also subscribe to the plan proposed by de Olmos for the additional subdivision within the medial and lateral bed nucleus of the stria terminalis. We will mainly describe the cyto- and chemoarchitecture (notably ENK, SP and ACHE) of the two major divisions of the bed nucleus to illustrate how cell columns related to them continue in a ventrolateral direction into the sublenticular area as well as in a posterodorsal direction into the stria terminalis. Where appropriate, further bed nucleus subdivisions are discussed or indicated in the figures. Where useful, additional histochemical markers such as neurotensin (NT), cholecystokinin (CCK), somatostatin (SOM) and secretoneurin (SECR) are depicted in figures and briefly discussed. For the most detailed description of the subdivisions possible for the bed nucleus, the reader should consult de Olmos (1990; see also table in the Appendix). 3.1.1. Lateral division of bed nucleus

The rostral end of the lateral bed nucleus (BSTL) is already apparent at the level shown in K1-B, 5 (e.g. Mufson et al. 1988, Fig. 5D, see also description in the monkey by Martin et al. 1991b, Fig. 2A). Walter et al. (1991, Fig. l a) suggest that it is the small-celled medial division of the bed nucleus that is the first to appear in a rostro98


Ch. H

caudal series of coronal sections. Our examination of human horizontal sections, however, suggests that it is the lateral part of the bed nucleus rather than its medial subdivision which reaches far rostrally and establishes an area of transition with the posteromedial accumbens. In coronal sections, however, it is especially difficult to appreciate the way in which the BSTL merges rostrally with the posteromedial accumbens. More caudally, both the ventral border of the BSTL with ventral pallidum and the border along the anterior commissure are populated by a series of interface islands (indicated by arrowheads for parvicellular and arrows for granular cell islands in Fig. 14A). At its medial border, a thick subependymal cell layer, the lamina cornea, separates the BSTL from the lateral ventricle. The cytoarchitecture in the rostral part of the BSTL is heterogeneous, its various areas being dominated by small to medium-sized neurons of different shape, i.e., round, oval, triangular or fusiform. The last type is especially common in the dorsomedial part of the nucleus, deep to the lamina cornea, where many of the cells appear to align themselves between stria terminalis fibers. Large cells are loosely dispersed, single or in clusters, throughout most of the nucleus. Lateral division of bed nucleus." dorsal component. A characteristic element of the lateral bed nucleus is the presence of apparent islets of rather loosely arranged medium-sized neurons (round, triangular, fusiform) against a translucent background due to the paucity of glial cells found within the neuropil of these zones (Fig. 22B). The largest o f these 'translucent' islands is oval (or tear-drop) in shape and is present throughout most of the supracommissural region of the lateral bed nucleus (Figs 21 and 22). Consistent with the homologous area in the rat (e.g. Alheid et al. 1995) the central part of this oval 'encapsulated island' is designated as the central subdivision of the dorsal part of the lateral bed nucleus, i.e., BSTLDcn. The surrounding, cell-poor area that forms the boundary of BSTLcn is designated the capsular subdivision of the dorsal part of the lateral bed nucleus, i.e., BSTLDc. BSTLD is a characteristic feature of the bed nucleus in most mammals. It is referred to as the central sector or subdivision of the human BST by Lesur et al. (1989) and by Walter et al. (1991) who emphasize its conspicuous content of a variety of peptides and other neurochemical markers (see below). Compartments of lightly stained medium-sized neurons (like those mentioned below in relation to the rostral part of lateral bed nucleus at the level shown in ENK, 5-6) are usually very similar to the large oval-shaped zone illustrated in Fig. 22 (de Olmos 1990), and are profitably considered as peninsulae of this structure, or possibly in some cases, as detached islets. In contrast to BSTLDcn, the capsular subdivision of the laterodorsal bed nucleus, i.e. the BSTLDc contains considerably fewer but somewhat larger, often fusiform, neurons. Among the rostral areas of the BSTL, loosely packed collections of lightly stained medium-sized neurons are evident. These cells are usually oval (though sometimes round or triangular) against a clear background with few glia cells. They are readily appreciated in a variety of histochemical preparations and are contained by a distinct cell-poor capsule. Many of the regions surrounding these 'islands' are densely populated by glial cells; they also contain more intensely Nissl-stained neurons, many of which are elongated and aligned in a capsular area surrounding the oval islets. The remaining cells are intermingled with the fibers of the stria terminalis. In the enkephalin-stained preparation (ENK, 5-6), representing a level in between K1-B 5 and 6, there appears an enkephalin-positive cell 'island' flanked by a capsule containing enkephalin-positive granular tubular profiles (see arrow in ENK 5-6). 99

Ch. H

L. Heimer et al.

Fig. 21: All pictures (A-D) show the characteristic oval shape of the central subdivision of the dorsal part of the lateral bed nucleus (BSTLDcn) surrounded by a capsular subdivision (BSTLDc) which is especially prominent because of its strong reaction for enkephalin (B) and negative reaction for acetylcholinesterase (D). (See text for further discussion of the chemoarchitecture of the bed nucleus.) The arrowhead in A points to a parvicellular cell island while the arrows point to granular islands. B in Fig. 21A points to a group of large hyperchromatic basal nuclei of Meynert cells.

100


Ch.H

Encapsulated cellular compartments, which are typical for the dorsal part of the lateral bed nucleus (BSTLD), can also be appreciated at more caudal levels (K1-B 7 and 8, ENK 7-8) where the lateral bed nucleus reaches its maximal mediolateral extent and where its cyto- and chemoarchitectonic subdivisions can be easily appreciated (see Fig. 22, showing the BST at the level represented in K1-B 8). At this level the dorsal component (BSTLD), abutting laterally on the internal capsule, is evident, as is the posterior part of the lateral bed nucleus of the stria terminalis (BSTLP) which extends further ventroposteriorally than BSTLD (K1-B, 8 and 9 in the mini-atlas). The juxtacapsular part of the lateral bed nucleus (BSTLJ) 6 is located between the internal capsule and the central and capsular parts of the lateral bed nucleus (Fig. 21B), and contains smaller and more darkly stained cells, which tend to form clusters (Fig. 22E). Interface islands in the form of granular and parvicellular aggregates are typically located between the various parts of the lateral bed nucleus (Fig. 22F) as well as in other parts of the nucleus (Fig. 21A; arrows = granular islands, arrowhead = parvicellular island; see also Fig. 22). The string of cell islands which can be seen between the central part of the dorsolateral bed nucleus (BSTLDcn) and its juxtacapsular part (BSTLJ) even at low magnification (arrowheads in Fig. 22A) are mostly of the parvicellular type although many of them also contain a varying number of granule cells. The central and capsular parts of the dorsolateral bed nucleus (BSTLDcn and BSTLDc) and the juxtacapsular part of the lateral bed nucleus (BSTLJ) are easily appreciated in stains for met-enkephalin and acetylcholinesterase. The central division is positive with both stains (Figs. 21B and D and 22H and L). The capsular part is strongly enkephalin-positive (Figs. 21B and 22H) but also stands out because of its lack of staining with acetylcholinesterase (Figs. 21D and 22L). The strongly enkephalinergic capsular subdivision of the dorsolateral bed nucleus (BSTLDc) features varicose fibers and peridendritic varicosities (Fig. 22I) reminiscent of the tubular profiles described in the ventral pallidum (Section 2.2.). The central division of the dorsolateral bed nucleus (BSTLDcn) contains ENK-positive puncta and varicose fibers in addition to a significant number of ENK-positive cell bodies (Fig. 22J). Most of the dorsolateral bed nucleus is moderately stained for substance P (Figs. 21C and 22K), exceptions being small areas in the juxtacapsular part. The juxtacapsular part of the lateral bed nucleus is moderately stained for ENK (Figs. 21B and 22H) but shows strong ACHEactivity (Figs. 21D and 22L). Staining for tyrosine hydroxylase (TH) is moderately strong in the dorsolateral bed nucleus but not in its capsular part (Lesur et al. 1989) and is especially pronounced in some of the parts surrounding its central subdivision including the juxtacapsular part as well as in part of the medial bed nucleus (Gaspar et al. 1985; Lesur et al. 1989). Immunostaining for dopamine-hydroxylase (DBH) is present in both divisions but is especially strong in the medial bed nucleus (Gaspar et al. 1985). Interestingly, DBH immunoreactivity also invades the caudomedial accumbens, both in the human (Gaspar et al. 1985) and in the rat (Berridge et al. 1997). The central part of the dorsolateral bed nucleus (BSTLDcn) contains multiple neurochemical markers (especially peptides), and has a distinct capsule (BSTLDc), fea-

6juxtacapsular here refers to the fact that this group of neurons abuts the medial wall of the internal capsule as it does in the rat brain where this term was originally applied. BSTLJ should not be confused with the capsular part of the dorsal lateral bed nucleus of the stria terminalis (BSTLDc), which refers to the border area (capsule) that is relatively cell-poor, and which surrounds a central core (BSTLDcn) that is more densely populated by neurons. The capsular part of the dorsolateral bed nucleus is much more evident in the human brain, compared to the homologous area in the rat which is only suggested by its chemical neuroanatomy rather than by a clear-cut cytoarchitecture (e.g. Alheid et al. 1995).

101

Ch. H


Fig. 22: A. Bed nucleus of the stria terminalis at the level of the crossing of the anterior commissure (see K1B 8 in mini-atlas). The insets (B-E) show the cytoarchitecture of some of the cell groups and subdivisions present at this level (see text). Arrowheads in A point to parvicellular interface islands. H, K and L are nearly matching sections stained for enkephalin (H), substance P (K) and acetylcholinesterase (L). Varicose enkephalinergic fibers and peridendritic varicosities are characteristic features of the capsular subdivision of the dorsolateral bed nucleus (/), whereas enkephalin-positive puncta, varicose fibers and neurons are prominent in the central part of the dorsolateral bed nucleus (J).

tures t h a t c o m b i n e to indicate t h a t it is a specialized c o m p a r t m e n t . S o m a t o s t a t i n , a n e u r o p e p t i d e t h a t attracts special interest because o f its n e u r o e n d o c r i n e significance, b u t which also has an implied role in A l z h e i m e r ' s disease a n d o t h e r n e u r o l o g i c disorders, has been described by m a n y a u t h o r s to be present in b o t h terminals a n d n e u r o n s in the central division o f the d o r s o l a t e r a l bed nucleus (e.g. C a n d y et al. 102

The human basal j&ebrain. Part H

Ch. H

Fig. 22: H-L,

1985; Bennett-Clarke and Joseph 1986: Gaspar et al. 1987; Mufson et al. 1988; Lesur et al. 1989; Walter et al. 1991). Other peptides such as cholecystokinin, galanin, and neurotensin are prominent in the central division and have potential relevance in neuropsychiatric disorders including schizophrenia and Alzheimer's disease (e.g. Nemeroff 1980; Chan-Palay 1988b; K6hler and Chan-Palay 1990; Levant et al. 1990; Mufson et al. 1993; Abelson 1995; Diaz et al. 1995). Walter et al. (1991) and Martin et 103

Ch. H


al. (1991 b) indicate that neurotensin terminals and cell bodies are especially prominent in the lateral bed nucleus. Like enkephalin and other peptides, neurotensin is present in the form of varicose fibers and puncta, but it does not form tubular profiles. From the pictures published by Martin et al. (1991b, Figs. 17A and 18B) it is evident that the concentration of neurotensin-immunoreactivity is stronger in the posterior part of the lateral bed nucleus than in its dorsal part, whereas neurotensin-positive cell bodies apparently are present in both areas. Cholecystokinin (CCK)-immunoreactive terminals are dense in the dorsolateral bed nucleus (BSTLD), especially its central part (Fig. 23; arrow in B points to a varicose fiber) and tend to form tubular profiles in the capsular subdivision (Fig. 23C). Only an occasional cholecystokinin-positive neuronal cell body is present in the bed nucleus in our material. As emphasized by Walter et al. (1991), the central compartment of BSTLD contains significant concentrations of many other markers, including glutamic acid decarboxylate (GAD; Fig. 13B), vasoactive intestinal peptide (VIP), synaptophysin (SYN), chromogranin-A (CHR-A) and calbindin (CAB).

Fig. 23: Dorsolateral bed nucleus in a cholecystokinin (CCK)-immunoreacted section showing CCK terminals in its central subdivision (B) and tubular profiles in the capsular subdivision (C).

104


Ch.H

Lateral division of bed nucleus." posterior compartment. This nucleus can be differentiated from the dorsolateral bed nucleus on the basis of its more heterogenous population of densely stained neurons and more numerous glial cells (Fig. 24A). Many of the neurons are somewhat smaller than those in the dorsolateral bed nucleus but there are also a significant number of large neurons. The posterior part of the lateral division (BSTLP) has a relatively larger number of myelinated stria terminalis fibers than does the dorsal part of the lateral division (BSTLD); these give it a distinct background-staining in Klfiver-Barrera sections. The posterior part of the BSTL is also less densely stained for AChE than most of the other divisions except the posterior part of the medial bed nucleus at the level shown in Fig. 24D. Immunoreactivity for substance P is in general somewhat denser in the posterior than in the dorsal part of the BSTL, but is not as dense as in the medial bed nucleus at the level shown in Fig. 22K. Staining for enkephalin is moderate but becomes increasingly weak in more ventral parts of the subdivision. 3.1.2. Medial division of bed nucleus

At the level shown in Fig. 22 (see also Figs. K1-B 7 and 8) the medial division of the bed nucleus (BSTM) is represented by its anterior component (BSTMA). It contains small and rather densely packed neurons and a few that are larger, darkly stained, often triangular in shape, and widely scattered (Fig. 22D). At a more caudal, postcommissural level (Fig. 24), the posterior part of the medial bed nucleus (BSTMP) can be divided into at least three different subcomponents (medial, intermediate and lateral with gradually increasing size of the neurons laterally). The medial part facing the lateral ventricle contains relatively densely packed and smaller neurons and more glial cells than the more voluminous intermediate portion, which contains more loosely arranged and lightly stained neurons. A large-celled lateral component is limited to the mid-section of the BSTMP and contains a heterogenous population of neurons, many of which are larger than in other parts of the medial bed nucleus. Most of the posterior (Fig. 24D) and anterior (Figs 21D and 22L) subsections of the medial bed nucleus exhibit very little acetylcholinesterase activity, especially dorsally. The staining for enkephalin is modest or very light in the anterior subregion of the medial bed nucleus (Figs. 21B and 22H), while immunostaining for substance P gradually increases in strength medially in the anterior part of the medial bed nucleus (Figs. 21C and 22K). This pattern in regard to these two peptides is not as readily apparent in the posterior part of the medial bed nucleus, especially in the supracommissural part, where both peptides have a rather heterogenous staining pattern (Figs. 24B and C). 3.2. SUBLENTICULAR COMPONENTS OF EXTENDED A M Y G D A L A The sublenticular components of the extended amygdala are illustrated in K1-B 8-10 where, apparently in the form of partly interrupted cell columns or islands, they bridge the gap between the medial and lateral divisions of bed nucleus of stria terminalis and the central and medial nuclei of the amygdala in the basal forebrain. It was suggested by de Olmos (1990) that it might be difficult or even impossible to illustrate the human sublenticular extended amygdala as a continuum in preparations which show only its neuronal cell bodies but, as described below and by others (e.g. Martin et al. 1991; Walter et al. 1991), continuity is indicated by stains for peptidergic fibers and terminals that are typical for the bed nucleus of stria terminalis and the centromedial amygdala. 105

Ch. H


Fig. 24: Bed nucleus of stria terminalis at the post-commissural level showing the posterior parts of the lateral and medial division of the bed nucleus (BSTLP and BSTMP). The hyphenated line indicates the approximate border between the two divisions.

106


Ch.H

3.2.1 Central division of the sublenticular extended amygdala (SLEAC) The central division of the sublenticular extended amygdala (SLEAC) connects the lateral division of the bed nucleus of the stria terminalis with the central nucleus of the amygdala. Cell columns corresponding to both the dorsal and posterior parts of the lateral bed nucleus appear to be located in the sublenticular region at the levels illustrated in K1-B 8 and 9. (Similar 'islands' can be seen at the level shown in K1-B 7, but because of their similarities to striatal cell clusters, and our lack of a nearby section stained with a marker typical for the central division of the extended amygdala we have not positively identified them.) The cell columns indicated underneath the internal capsule and ventral pallidum in K1-B 8 were stained in nearby sections for enkephalin (ENK 8), substance P (SP 8) and acetylcholinesterase (ACHE 8) and exhibit features typical for the BSTLD. At a slightly more caudal level (K1-B 9), the central division of the extended amygdala is more easily appreciated in the form of ventrolaterally directed sublenticular finger-like extensions of the BSTL and some sublenticular islands containing small to medium-sized cells often with typical fusiform appearance where they align themselves between the fiber bundles bridging the gap between the bed nucleus and the amygdala (Novotny 1977; the same fibers described by Novotny are often identified as part of ansa lenticularis or sometimes ansa peduncularis, e.g. Gaspar et al. 1987). In a nearby section stained for enkephalin, some of the extended amygdaloid islands correspond to immunoreactive patches, with peptidergic tubular profiles and puncta (see SLEA in ENK 9) reminiscent of the situation in the lateral bed nucleus. Martin et al. (199 lb) and Walter et al. (1991) have also demonstrated finger-like extensions into the sublenticular region from the lateral bed nucleus in the human, and especially convincing pictures of such finger-like extensions into the sublenticular region are illustrated in sections stained for cholecystokinin (CCK), neurotensin (NT), and vasoactive intestinal peptide (VIP) in Fig. 25. In an effort to demonstrate continuous columns of the sublenticular extended amygdala these sections were cut at a slight angle to the transverse plane. The CCK-immunoreactive extension (SLEA in Fig. 25A) contains immunoreactive puncta and tubular profiles typical for parts of the lateral bed nucleus of stria terminalis (Fig. 23). The corresponding NT-immunoreactive sublenticular columns display a wealth of immunoreactive puncta and varicose fibers, but no tubular profiles (Fig. 25D), corresponding to the situation in the bed nucleus. A nearby section stained with Heidenhain's technique (Fig. 25E) demonstrates a prominent cell column, continuous with the lateral bed nucleus and containing interface islands (the arrowhead points to a parvicellular island and the arrow to a granular cell island) which are typical components of the extended amygdala (see below). To complete the comparison, it should be mentioned that regions in this finger-like extension demonstrate a cytoarchitecture (Fig. 25G) which is very similar to that of the lateral bed nucleus. Compared to the surrounding dorsal and ventral striatopallidal areas, vasoactive intestinal peptide (VIP) is a specific marker for the dorsolateral bed nucleus of stria. This is evident in the VIP-stained section in Fig. 25H which also offers a convincing demonstration of the ventrolaterally directed continuum from the lateral bed nucleus into the sublenticular region. Depicted in Fig. 25I is the dense VIP immunoreactivity for the central division of the lateral part of the central amygdala (see section 3.3.1.) which is the counterpart in the temporal lobe of BSTLDcn. Neither the medial bed nucleus nor the medial amygdaloid nucleus is stained, suggesting VIP is preferentially 107

Ch. H


Fig. 25: A-D. Central division of the sublenticular extended amygdala (SLEA) demonstrated by immunostaining for cholecystokinin (A) and neurotensin (B). Note that cholecystokinin has a tendency to appear in the form of tubular profiles (C) whereas neurotensin primarily appears as immunoreactive puncta and varicose fibers (D). involved with the central subdivision of extended a m y g d a l a rather t h a n with its medial corridor. VIP i m m u n o r e a c t i v i t y in these areas has a characteristic tendency to a p p e a r 108


Ch.H

Fig. 25: E-G. A nearby section stained with Heidenhain's technique demonstrates the prominent sublenticular cell column which forms the immunopositive extensions in A and B. Interface islands are typical components of the extended amygdala. The arrow in F points to a granular interface island, whereas the arrowhead indicates a parvicellular island.

in the form of perisomatic and peridendritic profiles (see 25J and inset in 25H). Interestingly, the dorsolateral bed nucleus of the stria terminalis has been found to 109

Ch. H


Fig. 25: H-J. Vasoactive intestinal polypeptide (VIP) is an excellent marker for the central division of the extended amygdala as reflected in the specific staining of the lateral bed nucleus (H) and the central amygdaloid nucleus (/) and sublenticular cell islands (arrows in H). Dense perisomatic and peridendritic immunoreactivity (insets in H and J) are typical for this peptide within these areas. Note that the VIP immunoreactivity also involves the caudal accumbens (H).

be sexually d i m o r p h i c in that it is m o r e than 60% larger in males than females (Swaab 1997). The brain used to depict the B S T L D in this presentation (Fig. 25H) belonged to a 16-year-old male. Additional, similar pictures o f sublenticular cell c o n g l o m e r a t e s can be o b t a i n e d in sections stained for s o m a t o s t a t i n (SOM), a n d secretoneurin ( S E C R ; Fig. 26). Soma110


Ch.H

tostatin-positive neurons and terminals which are especially pronounced in the dorsolateral bed nucleus are arranged as a more or less continuous string of sublenticular island-like clusters (white arrowheads in Fig. 26A) in apparent continuity with the lateral bed nucleus of the stria terminalis (BSTL). Such islands have been described earlier by many authors (e.g. Candy et al. 1985; Bennett-Clarke and Joseph 1986; Gaspar et al. 1987; Mufson et al. 1988; Lesur et al. 1989; Walter et al. 1991). One of the illustrations in the paper by Mufson et al. (1989, Fig. 2A) beautifully demonstrates the string of sublenticular somatostatin-positive clusters and their continuity with the lateral BST. Another convincing picture of the sublenticular continuum between the central amygdaloid nucleus and the lateral bed nucleus in a coronal somatostatinstained section of the monkey has been published by Amaral et al. (1989; Fig. 6). Strings of immunoreactive patches in the sublenticular region are also apparent in material stained for secretoneurin, and since all subdivisions of the bed nucleus display a prominent immunostaining for secretoneurin (Kaufmann et al. 1997), it is reasonable to expect strings of islands both in the deep parts of the sublenticular region and in a more superficial position (i.e. close to the ventral brain surface) as illustrated in Fig. 26B. As discussed below, it is reasonable to suggest that this superficial string of immunoreactive patches represents the medial division of the sublenticular extended amygdala. An area surrounding the lateral margin of the anterior commissure and which, in the past, would usually be included as part of the putamen, is also densely stained for somatostatin in the above-mentioned picture by Mufson et al. In our own material this area (arrow in Fig. 26A), like several other sublenticular somatostatinergic 'islands', contains both somatostatin-positive neurons and terminals which form granular tubular profiles (see also Candy et al. 1985, Fig. 2B). One of the most intriguing features of this last-mentioned somatostatin-positive conglomerate is its location, i.e. in close relation to the posterior limb of the anterior commissure in a region generally recognized as the ventral part of the striatum. A secretoneurin-positive island is also present in this general region (arrow in Fig. 26B) which appears to correspond to the area which in the rat is called the interstitial nucleus of the posterior limb of the anterior commissure (IPAC) (de Olmos 1972; Alheid et al. 1995), and which has close relations to the central division of the extended amygdala (Alheid et al. 1995; Heimer et al. 1997a,b). The important subject of overlap between the extended amygdala and regions generally considered part of the striatum will be considered further in Section 3.5. Further laterally, where the sublenticular part of the extended amygdala approaches the temporal lobe (K1-B, 9 and 10), it is difficult to identify it in Nissl or KltiverBarrera sections and the areas color-coded with yellow and green are tentative in these two figures. Enkephalin, on the other hand, which is a good marker for the central division of the extended amygdala, illustrates the sublenticular continuity towards the central amygdaloid nucleus (SLEA in ENK 9, 10 and 10-11; see also Section 3.3.1.). Martin et al. (199 lb) illustrated this lateral part of the sublenticular extended amygdala with the aid of neurotensin, enkephalin and somatostatin. We have chosen to illustrate it with sections stained for cholecystokinin (CCK) and neurotensin (NT) (see arrows in Fig. 27A). Neurotensin is especially effective since it illustrates both fibers and cell bodies in the extended amygdala. (Note that the sections in K1-B, 9 and 10 belong to a different brain than the one in Fig. 27, which is the same as in Fig. 25, being cut at a slight angle to the transverse axis in order to obtain as much as possible of the extended amygdala continuum in one plane.) It is evident from the sections 111

Ch. H


Fig. 26: Sublenticular extended amygdala appears in the form of isolated sublenticular clusters (white arrowheads) in these sections stained for somatostatin (A) and secretoneurin (B). The coronal sections of this human brain are cut at a different angle from those displayed in the previous figure. Note the immunopositive areas (arrows) in close relation to the anterior commissure.

illustrated in Figs. 23 and 27A and B, that C C K , like N T , stains b o t h divisions of the extended amygdala, a l t h o u g h the central division is m o r e densely stained than the 112


Ch.H

Fig. 27: The lateral part of the sublenticular extended amygdala illustrated with immunostaining for cholecystokinin (A) and neurotensin (B). Neurotensin is an especially effective marker since it labels fibers and cell bodies in both the central (C) and the medial (E) divisions of the extended amygdala.

113

Ch. H

L. Heimer et al.

medial. These pictures, like those in K1-B 9 and 10, also demonstrate that significant parts of the anterior amygdaloid area (AAA) are in effect integral parts of the extended amygdala (see Section 5 for further discussions of the AAA). Figs. 27C, D and E demonstrate both NT-terminals and NT-positive neurons, often small to medium in size and fusiform, where they accommodate themselves between the fiber-bundles of the so-called ventral amygdalofugal pathway. The NT-positive cell bodies at the level shown in Fig. 27C do not generally mingle with the cell groups belonging to the basal nucleus of Meynert. Neurotensin does not colocalize with choline acetyltranferase in basal nucleus of Meynert neurons (De Lacalle and Saper 1997). This datum together with the fact that the relatively small size and fusiform shape of the neurotensin neurons are distinctly different from the large basal nucleus of Meynert neurons do support the idea that these cells are indeed part of the extended amygdala rather than the magnocellular basal complex. 3.2.2. Medial division of sublenticular extended amygdala

The medial division of the sublenticular extended amygdala links the medial nucleus of the amygdala with medial division of the bed nucleus of the stria terminalis. It is easy to recognize the medially located, descending part of the medial sublenticular extended amygdala (K1-B, 9), where it is directly continuous with the posterior part of the medial bed nucleus (BSTMP). Further laterally, sections stained for both CCK (Fig. 27A) and NT (Fig. 27B) provide unmistakable evidence of partly interrupted sublenticular columns close to the ventral brain surface (see also superficially located secretoneurin-immunoreactive patches in Fig. 26B). The NT-positive islands contain neurotensinergic terminals as well as typical medium-sized fusiform neuronal cell bodies (Fig. 27E) and are part of a string of NT-positive islands, which can be seen in more rostral sections to form a continuous arc in apparent continuity with the posterolateral part of the medial bed nucleus. As indicated above, secretoneurin (SECR) is also a useful overall marker for the extended amygdala (Kaufmann et al. 1997) in the sense that it labels both the central and medial divisions. This is reflected in distinct and prominent secretoneurin staining of the centromedial amygdala (Fig. 28B) leaving the rest of the amygdala unstained save for light labeling in its superficial part. Nevertheless, secretoneurin is less specific than CCK and NT since it also labels ventromedial parts of the striatopallidal system (e.g. compare human, (Fig. 28A, B), with monkey (Fig. 20A, B) secretoneurin sections). This creates some problems of interpretation especially in the sublenticular region where pallidal areas tend to adjoin the extended amygdala. The basal nucleus of Meynert, on the other hand, is not stained and long continuous finger-like columns representing both divisions of the extended amygdala can therefore be identified in the sublenticular region (arrows in Fig. 28A), provided the plane of sectioning is optimal. 3.3. CENTROMEDIAL AMYGDALA Starting with V61sch (1906, 1910) and Johnston (1923), several scientists have parcellated the amygdala into centromedial and cortical-basolateral groups of nuclei. This essential splitting of the amygdaloid complex into two adjacently linked but separate systems is becoming increasingly relevant with the growing acceptance of the concept of the extended amygdala. In fact, as should already be evident from the previous discussion, the central and medial amygdaloid nuclei cannot be adequately understood 114

The human basal forebrain. Part II

Ch.H

Fig. 28: Sublenticular parts of central and medial divisions of the extended amygdala are displayed with immunostaining for secretoneurin in A (white arrows). The section in B illustrates the prominent secretoneurin staining of the centromedial amygdala and part of the anterior amygdaloid area. Note that the ventral part of putamen (Pu) and the area surrounding the ascending part of stria terminalis (st) including the amygdalostriatal transition area (AStr) are also secretoneurin-positive.

unless they are described with the nuclei of the stria terminalis as integral parts of the extended amygdala. This fundamental viewpoint was to some extent p r o m o t e d by Brockhaus (1938) in his classic study of the h u m a n amygdaloid region. A l t h o u g h Brockhaus did not describe extensions of the central and medial nuclei as recognized in the concept of the extended amygdala, he designated the centromedial nuclei of the amygdala and related parts of the anterior amygdaloid area as the 'supra-amygdaloid' division in order to separate them from the cortical-basolateral group of nuclei which

115

Ch. H

L. Heimer et al.

he considered to be the true amygdala in the classic sense ('das Amygdaleum proprium').

3.3.1. Central amygdaloid nucleus The continuity from the sublenticular part of the central extended amygdala towards the central amygdaloid nucleus is clearly illustrated by stains for cholecystokinin and neurotensin (Fig. 27). Enkephalin is another excellent marker for the central extended amygdala (Fig. 29; see also Martin et al. 199 l b, Fig. 18H). The dorsomedially directed sublenticular continuation of the central amygdaloid nucleus (arrow in Fig. 29A; see ENK 10-11 in the mini-atlas for an overview of the location) is rich in granular-type tubular peptidergic profiles and immunoreactive puncta (Fig. 29C). Most contemporary scientists divide the central nucleus into lateral and medial divisions (see Tables in appendix) which can be easily distinguished by their different reactions for enkephalin. The components of the lateral division (CeL) are characterized by strong or moderately strong enkephalin reactions like those in the dorsal region of the lateral bed nucleus (BSTLD in Fig. 21B). As previously indicated by Martin et al. (1991b), the correspondence between the lateral part of the central nucleus and the dorsal component of the lateral bed nucleus is specific in the sense that some of the subsections of the dorsolateral bed nucleus have counterparts in the lateral division of the central amygdaloid nucleus. This is especially the case for the central and capsular parts of the dorsolateral bed nucleus which exhibit enkephalinergic reactions similar to those in the central core and capsular parts of the lateral central nucleus. To be specific, the central part (including both the core and the apical part in de Olmos' 1990 terminology) of the lateral division of the central nucleus (CeLcn) contains a large number of enkephalin-immunoreactive puncta and varicose fibers in addition to some enkephalin-positive neurons (Fig. 29B; compare with the central part of the dorsolateral bed nucleus in Fig. 22J), whereas the capsular part (CeLc) is characterized by granular-type tubular profiles and puncta (compare Fig. 29C with 22I). In VIP-stained sections this correspondence is more striking since the VIP reactivity favors the dorsolateral bed nucleus (central and capsular parts, Fig. 25H) and the lateral central nucleus (central and capsular parts; Fig. 25I) with little or no reactivity in the remaining portions of the bed nucleus or central amygdala. Adjacent pallidal and striatal areas (with the exception of caudomedial accumbens) are similarly unlabeled. Symmetry between parts of the lateral and medial bed nuclei of stria terminalis and parts of the central and medial amygdaloid nuclei has been prominently demonstrated in the rat brain (Alheid et al. 1995) and provides convincing support for the extended amygdaloid concept. As we shall see below, this type of substructural symmetry between the bed nucleus of stria terminalis and the centromedial amygdala components of the human extended amygdala includes cytoarchitecture as well as chemoarchitecture. The lateral division of the central nucleus, in addition to its main central part mentioned above, has a paracapsular part (CeLpc) which is located dorsolaterally, and a periparacapsular part (CeLppc) located dorsally. These accessory parts of the lateral central nucleus are, like the main part, surrounded by fiber-rich capsules characterized by tubular profiles in enkephalin-stained sections (Fig. 29A). As indicated by de Olmos (1990), the neuron-poor capsular parts of the periparacapsular, and dorsal paracapsular divisions seem to form one continuous sheet which is a prominent feature 116


Ch. H

Fig. 29: The central amygdaloid nucleus and its dorsolaterally directed continuity (arrow in A) into the lateral sublenticular area in an enkephalin (ENK) immunostained preparation. Whereas the central part of the lateral division of the central nucleus (CeLcn) contains a large number of ENK-immunoreactive puncta and varicose fibers and an occasional immunoreactive neuron (B), the sublenticular extension of the lateral division of the central nucleus is characterized by enkephalinergic tubular profiles (C). The apical part of the main lateral division is marked by an asterisk in A.

117

Ch. H


in enkephalin preparations (Fig. 29). Even the apical part of the main lateral division (indicated with an asterisk in Figs. 29A and 30F) appears to be surrounded by this capsular unit (de Olmos 1990). The medial division of the central nucleus (CeM) shows a moderately strong reaction to enkephalin (Fig. 29) similar to that in the posterior division of the lateral bed nucleus of stria terminalis (BSTLP in Fig. 24B). Cytoarchitectonically, the central and medial amygdaloid nuclei can be clearly distinguished from the rest of the amygdala on the basis of their generally smaller neurons. This is easily appreciated in cell-stains (Fig. 30; compare the large neurons in basomedial nucleus, BM [panel C], with the small ones in various parts of the centromedial amygdala [panels B, D, and E]). This cytoarchitectonic characteristic prompted several classic neuroanatomists (e.g. V61sch 1906; Hilpert 1928; Brockhaus 1938) to exclude the centromedial nuclear group from what they considered to be the amygdaloid body in a strict sense. The medium-sized, lightly stained cells of the central part of the lateral division (CeLcn, Fig. 29B) are similar to cells in the central part of

Fig. 30: The Klfiver-Barrera stained section in A (see KI-B 11 in the mini-atlas at the end of the previous

chapter for orientation) demonstrates the striking difference in cell size between the small to medium-sized cells in the centromedial amygdala (panels B, D and E) and the rest of the amygdaloid body, especially the laterobasal complex with its larger cells (panel C). The various subdivisions of the central nucleus, however, are more easily appreciated in the histochemical preparations in F (enkephalin), G (substance P) and H (acetylcholinesterase). See text for further discussion of the various subdivisions. 118


Ch. H

Fig. 30" F-H.

119

Ch. H

L. Heimer et al.

the dorsolateral bed nucleus (BSTLDcn, Fig. 22B); they usually appear as well defined or sharply outlined round, fusiform or triangular against a translucent background having few glial cells. The capsular part of the central nucleus of the amygdala is populated by loosely arranged, more darkly stained, usually fusiform neurons which accommodate themselves between the fibers in the capsule, similar to the situation in the capsular part of the dorsolateral bed nucleus (BSTLDc). The neurons in the paracapsular part, are, in general, smaller and more densely packed than in the central part of the lateral division. Although the basic cell morphology might suggest that the paracapsular and periparacapsular parts of the lateral subdivision corresponds to the juxtacapsular part of the lateral bed nucleus, the chemoarchitecture does not support such a proposition. The medial part of the central amygdaloid nucleus division (CeM in Fig. 30D) has a more heterogenous population of neurons and in general more glial cells than the central part of the lateral division of the bed nucleus of stria terminalis and thus would seem to resemble more closely the area of BSTL shown in panel C in Fig. 22. For a more detailed discussion of the various subdivisions of the human central amygdaloid nucleus and their cytoarchitecture see de Olmos (1990). Suffice it to say that the chemoarchitecture as revealed in sections matching the Klfiver-Barrera-stained section in Fig. 30A are coherent with his parcellation of this nucleus. The central core, apical (asterisk) and capsular parts of the lateral division are easily appreciated in the enkephalin-stained section shown in Figs. 29 and 30F, as are the paracapsular and periparacapsular parts. The medial subdivision (CeM), which encircles the dorsomedial aspect of the capsular part, can also be clearly identified because of its more modest content of enkephalin. Whereas most of the lateral division is lightly stained for substance P, the medial subdivision is somewhat more darkly stained (Fig. 30G). The acetylcholinesterase-stained preparation (Fig. 30H) reinforces the distinction between the central and capsular parts of the lateral division and provides a nice demonstration of the more or less continuous acetylcholinesterase-negative sheet encapsulating the central part of the lateral division. Additional support for the parcellation of the lateral division of the central nucleus of the amygdala is provided by sections stained for cholecystokinin (Fig. 31) and neurotensin (Fig. 32). As in the central and capsular parts of the dorsal division of the lateral bed nucleus of the stria terminalis (Fig. 23) there is a concentration of cholecystokinin-immunoreactive puncta and varicose fibers in the central part of the lateral division of central amygdaloid nucleus and a tendency for the labeling of peridendritic terminals to appear as tubular profiles (Fig. 31C), especially in the more dorsally located capsular part. Varicose fibers and immunoreactive terminals, sometimes in typical peridendritic pattern, also characterize the para- and periparacapsular parts of the lateral central nucleus. Peridendritic labeling is also apparent in the sublenticular part of the central extended amygdala (Fig. 31D). Although there are some cholecystokinin-positive neurons in the medial amygdaloid nucleus (and even more in basolateral and cortical parts of the amygdala), the central amygdaloid nucleus does not contain neuronal cell bodies stained for cholecystokinin in our material even though there is dense terminal staining. Neurotensin-immunoreactive puncta and varicose fibers are present both in the lateral and medial divisions of the central nucleus, although the intensity of the staining is considerably higher in the medial division (Fig. 32). In regard to the labeling of fibers and terminals, this is consistent with the findings in the human by Martin et al. (199 lb; Fig. 18b). Since Martin and his collaborators also found the posterior division 120


Ch.H

Fig. 31: Sections stained for cholecystokinin demonstrate strong reactivity especially in the central part of the lateral division of the central nucleus, which is filled with immunoreactive puncta, varicose fibers and some tubular profiles. Other parts of the centromedial complex show a more moderate immunoreactivity. The immunoreactive fibers in the CCK-positive sublenticular patch (arrow in A and inset D) are reminiscent of those in the central amygdaloid nucleus (inset C). On the other hand, some CCK-immunoreactive neurons are present in the medial amygdaloid nucleus (E) and in the sublenticular patch (D), but not in the central part of the lateral division of the central amygdaloid nucleus in the material shown here. 121

Ch. H

L. Heimer et al.

of the lateral bed nucleus to be more heavily populated with neurotensin-immunoreactive terminals than the dorsal division (see Martin et al. 1991b, Fig. 17A) the staining for neurotensin tends to confirm the symmetry between the lateral division of the central amygdala and the dorsolateral bed nucleus, as well as between the medial division of the central amygdala and the posterolateral bed nucleus. In regard to the distribution of neurotensin-containing perikarya, our material indicates that the majority of such neurons are located in the medial division of the central amygdaloid nucleus rather than in the central part of its lateral division. This is somewhat at odds with the description by Martin et al. (1991b), and reaffirms our contention that additional, detailed cytoarchitectonic and chemoanatomical studies of the various subdivisions and compartments of the human extended amygdala are needed before definitive statements can be made with regard to all its components and the degree to which 'paired symmetry' exists between the bed nucleus of stria terminalis and the centromedial amygdala.

3.3.2. Medial amygdaloid nucleus Whereas the rostral part of medial nucleus is located superficially in the region of the fundus of the endorhinal sulcus at the coronal level somewhere between K1-B 10 and 11, the main part of the medial nucleus is covered on its medial side by the optic tract (K1-B 11 and 12). After Brockhaus (1938), de Olmos (1990) has provided the most detailed description of the medial nucleus in the human and has divided it into a rostral and a caudal subdivision with the latter having dorsal and ventral parts (MePD and MePV). There is a tendency for the neurons of the medial nucleus to form layers, especially superficially, de Olmos identified these as a cell-poor molecular layer, a superficial dense cell-layer and a deep layer with somewhat less densely distributed neurons. Although the heterogeneous population of small- to medium-sized, relatively lightly stained neurons and a significant number of glial cells in the medial nucleus of the amygdala (Fig. 30E) is somewhat reminiscent of the situation in parts of the medial bed nucleus of the stria terminalis it is not, at present, possible to closely correlate various parts of the medial amygdaloid nucleus and the medial bed nucleus on the basis of cytoarchitecture alone for the human brain. Nor does the histochemistry for enkephalin, substance P and acetylcholinesterase offer much help in that regard (compare Figs. 30F, G and H with Figs. 21, 22 and 24). Nevertheless, the generally weak reaction for enkephalin and acetylcholinesterase combined with stronger reaction for substance P is consistent with the overall concept of the medial division of the extended amygdala, which is based on the premise of a general correspondence between the medial amygdaloid nucleus and the medial bed nucleus of stria terminalis. A more convincing argument for the existence of a medial division of the extended amygdala as defined on the basis of such a correspondence can be made with the aid of immunohistochemistry for cholecystokinin (Figs. 27A and 31A), secretoneurin (Fig. 28) and, especially, neurotensin which is located in both terminals and neuronal cell bodies in the medial amygdaloid nucleus (Fig. 32D). As mentioned in Section 3.2.2., neurotensin-immunoreactive fibers and terminals, intermingled with immunoreactive cell bodies, form a continuous column from the medial amygdaloid nucleus through the superficial anterior amygdaloid area and further medially towards the neurotensin-positive islands shown in Fig. 27E close to the lateral edge of the optic tract (opt).

122


Ch. H

Fig. 32: The pattern of neurotensin-staining in the central amygdaloid nucleus (A) is in large part complementary to the CCK-immunoreactive pattern shown in the previous figure in the sense that the intensity of NT-staining is considerably higher in the medial division than in the lateral division. The neurotensin immunoreactivity is also relatively dense in the medial amygdaloid nucleus, which, like the central nucleus (C), contains both neurotensinergic fibers and puncta as well as cell bodies (D).

123

Ch. H

L. Heimer et al.

3.4. STRIA TERMINALIS COMPONENTS OF THE EXTENDED A M Y G D A L A The stria terminalis, which makes a dorsally convex detour behind and above the thalamus, can be identified in the floor of the lateral ventricle where it accompanies the thalamostriate vein in the groove which separates the thalamus from the caudate nucleus (see BSTS/st in KI-B 12). The extreme lateral end of the stria terminalis is more or less tucked away underneath the ventromedial aspect of the caudate tail. Cell groups along the arch of the stria terminalis, referred to as the supracapsular bed nucleus of stria terminalis (BSTS) provide important evidence ' for the extended amygdaloid concept. Although such cell groups were identified over a century ago (e.g. Ziehen 1897; V61sch 1906, 1910), it was J. B. Johnston (1923) who advanced the theory that cells accompanying the arching stria terminalis might represent remnants of cell columns which in early development formed more prominent continuities between the lateral and medial bed nuclei and the central and medial amygdaloid nuclei, respectively. As demonstrated in Section 3.2., cell columns also bridge the sublenticular gap between these structures. In this section we will analyze the cell groups in the supracapsular part of the stria terminalis, with the purpose of demonstrating that the extended amygdala can be conceived of as two more or less parallel ring formations surrounding the internal capsule (as indicated in Fig. 1) in close association with the caudate nucleus and thalamus. The neuronal components of the stria terminalis have been the focus of only a few investigations (Sanides 1957b; Strenge et al. 1977; Alheid et al. 1998). The first two papers describe the groups of neurons which can be seen alongside and within the fiber bundles of the human stria terminalis from its point of continuity with the bed nucleus of stria terminalis at the level of the crossing of the anterior commissure (K1-B 8) to its continuity with the centromedial amygdaloid nuclei in the temporal lobe. Taken together, the two papers provide a detailed picture of the major cell groups related to this remarkable fiber bundle, and they form a necessary basis for the thesis to be elaborated below, i.e. that the cell groups within the stria terminalis in the human, like in the rat (Alheid et al. 1998) are integral parts of the central and medial extended amygdala. Sanides (1957b) in a classic study, classified and mapped the small-celled islands ('Insulae terminales') in the human forebrain. Such islands (referred to by us as 'interface islands'; see Section 2.1.2.) are located in varying constellations throughout most of the stria terminalis. One interface island, in particular, distinguishes itself by being generally larger than the others and is often partly or completely encapsulated by myelinated fibers. It is located between the stria terminalis and the caudate nucleus. Strenge et al. (1977) used a selective stain for intracellular lipofuscin granules on thick sections (400-800 lam) suitable for low-power examination with the stereomicroscope. They described the existence of two columns of cells, which they refer to as 'pars paracaudata' and 'pars medialis'. As mentioned by Strenge et al. their smallcelled 'pars paracaudata' corresponds undoubtedly to the large interface island described by Sanides at the ventromedial border of the arch of the caudate. Sanides did not describe the group of medium-sized neurons which Strenge and his collaborators labeled 'pars medialis'. In order to avoid confusion especially when comparing the situation in the human to that in the rat (see below) it is important to realize that the 'pars medialis' of Strenge et al. is located, like their 'pars paracaudata', in the lateral aspect of the stria terminalis (Strenge et al. 1977; Fig. 5a-d). In a recent combined light- and electron microscopic study of the supracapsular part 124


Ch. H

of the bed nucleus of stria terminalis in the rat (Alheid et al. 1998) we described the presence of a relatively large laterally located column of cells (BSTSL) which is directly continuous with the lateral bed nucleus of stria terminalis and which extends to the central amygdaloid nucleus. A considerably smaller medial subdivision of the supracapsular bed nucleus (BSTSM) in the rat appears to be continuous with the medial bed nucleus. The medial column of cells, which is located in the medial corner of the stria terminalis, tapers off in the caudal direction so that in the retrocapsular part of the stria terminalis it is represented only by interrupted small clusters of cells. A neuronal cell group corresponding to the pars paracaudata in the human was not identified in the rat where it was sometimes impossible, especially in rostral sections, to distinguish the lateral cell group in the stria from the caudate-putamen because the two cellular compartments were in direct continuity and contained similar types of medium-sized cells. Except for the additional presence of a pars paracaudata the situation in the human is reminiscent of that in the rat in the sense that both a lateral and a medial cell group (a lateral and medial supracapsular bed nucleus of the stria terminalis [BSTSL and BSTSM], for convenience referred to here as lateral and medial 'pockets') can be identified in many coronal sections, with the 'lateral pocket' being considerably more pronounced than the medial one. 3.4.1. Supracapsular part of the stria terminalis

The continuity between the rostral, voluminous part of bed nucleus of stria terminalis (K1-B 8) and the cell columns along the supracapsular (suprathalamic) part of the stria terminalis is easily appreciated in K1-B 10. The relevant part of this section is shown in higher magnification in Fig. 33. The cellular continuity is unmistakable. Both the substance P-positive, small-celled posteromedial part of the medial bed nucleus (Fig. 33, C and D) and the posterolateral part with generally larger cells (Fig. 33E) can be followed without interruption into the 'supracapsular' part of stria terminalis (above the 'knee' marked with an arrowhead in Fig. 33B). It is difficult at this level, however, to distinguish cellular areas that are continuous with the lateral part of the posterior part of the medial bed nucleus from those that are continuous with the lateral division of the bed nucleus. It appears, however, that the medium-sized cells located in the gliapoor 'pocket' (F in the dorsal part of Fig. 33A) do have the morphological features (i.e., mixture of round, triangular and fusiform) corresponding to those of the central part of the dorsolateral bed nucleus of stria terminalis (Fig. 22B). Unfortunately, we do not have, at this level, a matching section stained with a marker for the dorsolateral bed nucleus (e.g. enkephalin), but the appearance of a relatively lightly stained 'pocket' in a nearby SP-stained section (arrow in Fig. 33B) would be consistent with this proposition. At a somewhat more caudal level (corresponding approximately to K1-B 11) two pockets of cells are clearly seen even under low magnification (Fig. 34). The larger lateral pocket contains medium-sized round, triangular or fusiform cells which are distinctly outlined against a relatively glia-poor translucent background (Fig. 34C) similar to the situation in the central part of the dorsolateral bed nucleus (Fig. 22B) and the central part of the lateral division of the central amygdaloid nucleus (Fig. 30B). The adjacent medial part of the caudate nucleus (Fig. 34B) contains distinctly smaller cells, reminiscent of a paracaudate interface island (see below). The smaller 'medial' or ventromedially located pocket features a mixture of small and medium-

125

Ch. H


Fig. 33: Photomicrographs of Klfiver-Barrera (A) and substance P-stained (B) coronal section to show the cellular continuity between the rostral voluminous part of the bed nucleus of stria terminalis and the cell columns in the supracapsular part of the stria. Both the small-celled posteromedial part of the medial bed nucleus (panel C) and the posterolateral part with larger cells (panel E) can be followed into the supracapsular part (panels D and F) of stria terminalis. The black arrowhead shows the 'knee' referred to in the text. The arrow points to a relatively lightly stained substance P pocket.

sized, often fusiform n e u r o n s (arrow in Fig. 34D) against a considerably m o r e glia-rich background. It is i m p o r t a n t to realize that the distribution and cytoarchitecture o f n e u r o n s within the stria terminalis can change rather dramatically from level to level. In Fig. 35, which is close to the level shown in Fig. 34, a medially located substance P-positive pocket ( a r r o w h e a d in F i g . 35A a n d B; SP terminals in E) with a mixture o f small- a n d medium-sized n e u r o n s in a glia-rich b a c k g r o u n d can still be identified, but the laterally located cell g r o u p c o r r e s p o n d i n g in position to the lateral pocket shown in the previous 126


Ch. H

Fig. 34: Coronal Kliiver-Barrera stained section through the supracapsular stria terminalis to show the supracapsular parts (pockets) of the lateral (BSTSL) and medial (BSTSM) bed nucleus of stria terminalis, which represent the two divisions of the supracapsular extended amygdala. The cell picture in the lateral pocket (C) is reminiscent of that in the dorsolateral bed nucleus (see text). Note that the adjacent part of the caudate nucleus (B) contains distinctly smaller cells resembling those in parvicellular interface islands or paracaudate island (see Fig. 37). The white arrow in D points to one of the neurons in the medial pocket.

figure, contains a mixture of primarily parvicellular and granular neurons (Fig. 35C) rather than the distinctive medium-sized neurons seen in Fig. 34C. When comparing the size of the cells in this parvicellular island with those in the nearby part of the caudate nucleus shown in the previous figure (Fig. 34B), the similarities are striking; the ventromedial part of caudate nucleus, like the small-celled island embedded among the fibers of the stria terminalis, contains primarily small cells rather than mediumsized neurons typical for the rest of striatum. We shall return to this important organizational issue in our discussion of the paracaudate interface island below. In yet another nearby section (Fig. 36) the lateral pocket is quite large and populated by medium-sized, differently shaped (triangular, fusiform, round) neurons distinctly outlined against a translucent background, similar to the situation in the central part of the dorsolateral bed nucleus of stria terminalis (Figs. 22B and 33F). The correspondence between this lateral pocket in the stria terminalis and the dorsolateral bed 127

Ch. H


Fig. 35: This cross-section through the stria terminalis is rather close to that shown in Fig. 34. Nonetheless, the cytoarchitecture in the lateral pocket shown in C (granular cell island surrounded by small cells) is different from that in the lateral pocket in the previous figure. The medial 'pocket' (arrowhead in A and B), which would correspond to the medial bed nucleus of the stria terminalis, is considerably more substance Ppositive than the lateral pocket (arrow in A). A couple of neurons in the medial pocket are indicated by arrows in D. Substance-P-containing fibers and terminals within the medial pocket are shown in E.

n u c l e u s is e v i d e n t also in c h e m o a n a t o m i c a l p r e p a r a t i o n s . T h e cells in the l a t e r a l p o c k e t are s u r r o u n d e d by a s t r o n g l y e n k e p h a l i n e r g i c n e u r o p i l c h a r a c t e r i z e d by p r o m i n e n t v a r i c o s e fibers a n d a c o m b i n a t i o n o f c o a r s e g r a n u l e s a n d small p u n c t a very different f r o m the m o r e ' d u s t - l i k e ' e n k e p h a l i n e r g i c p a t t e r n seen in the n e a r b y c a u d a t e nucleus. 128


Ch. H

Fig. 36: A. Kliiver-Barrera stained section close to that in Fig. 35 reveals a large lateral pocket with a cell picture (inset in A) very similar to the situation in the central part of the dorsolateral bed nucleus. The correspondence between this lateral pocket and the dorsolateral bed nucleus is evident also in the enkephalin (B) and acetylcholinesterase (C) preparations.

129

Ch. H

L. Heimer et al.

The lateral pocket is also somewhat less densely stained for acetylcholinesterase than the caudate nucleus (Fig. 36C). Considering the characteristics described above for the lateral pocket, it can hardly be doubted that this roundish, encapsulated cell group corresponds to the dorsolateral part of the bed nucleus of stria terminalis and to the central part of the lateral division of the central amygdaloid nucleus. The lateral pocket can readily be identified in several of the more caudally located sections of the supracapsular stria terminalis (see below) but sometimes it is represented by only a few scattered medium-sized neurons. Strenge et al. (1977), who used a pigment stain on very thick sections, could identify a cell group which they called 'pars medialis', but which is located in the lateral part of stria terminalis. Although the smaller medially located pocket does have some characteristics reminiscent of the medial bed nucleus and medial amygdaloid nucleus, the correspondence in this case is more tenuous. The difficulty becomes even more pronounced further posteriorally and inferiorally where, in most coronal sections of the stria terminalis only scattered neurons can be identified in its medial half. It is important to reiterate that Strenge and his collaborators (1977) referred to the lateral cell group as 'pars medialis' in order to separate it from a laterally adjoining more prominent interface island, the 'pars paracaudata', which had earlier been identified by Sanides (1957b) as a large 'terminal island' on the ventromedial side of the caudate nucleus. Their 'pars medialis' would also seem to be an inappropriate designation giveia the correspondence between its cells and those of the lateral bed nucleus and the lateral part of the central amygdaloid nucleus. The paracaudate (interface) island. The prominent small-celled 'island' at the border between the stria terminalis and caudate nucleus deserves special recognition in the context of the extended amygdaloid concept. From the descriptions by Sanides (1957b) and Strenge et al. (1977), it appears that the paracaudate cell island is present alongside the entire course of stria terminalis but varies in shape and cellular composition (at some levels the cells are smaller than at others). This largest of the islands related to the stria terminalis is named for its shape in cross section but it almost certainly has the three-dimensional form of a distinct, continuous cellular column of variable diameter at the interface between the caudate nucleus and the stria terminalis. The paracaudate cell island appears encapsulated in most sections and is therefore easily identifiable in Klfiver-Barrera preparations (Fig. 37A and E; mid-thalamic level). Its neurons (Fig. 37C) are smaller than those in nearby caudate nucleus (Fig. 37B; note that the magnification in panels B-D is twice as large as in many of the other panels showing cells in this series of figures). The acetycholinesterase activity of the island changes gradually from being comparable to that of the rest of striatum ventrolaterally to almost zero in its dorsomedial part (Fig. 37F). The extent of encapsulation of the paracaudate island varies. In some sections a capsule can hardly be recognized and it is almost impossible to distinguish the island from the rest of the caudate nucleus, save for the smaller size of its neurons (as demonstrated in Fig. 34). Cholecystokinin- and neurotensin-immunoreactivity, which proved valuable for the illustration of the sublenticular part of the extended amygdala, have been used as well

Fig. 37: A. KliJver-Barrera stained section showing the general location of the supracapsular stria terminalis which is shown in higher magnification in E. This shows a large paracaudate, partly encapsulated, interface island with smaller cells (C) than in the adjoining part of caudate (B). The arrow in D points to a neuron in the medial pocket. The major part of the paracaudate island is acetylcholinesterase-positive (F).

130


Ch. H

131

Ch. H


Fig. 37: B-F.

to complement the cytoarchitecture of the supracapsular extended amygdala and to reveal some of the features of the paracaudate island. The results obtained confirm the presence of lateral and medial pockets. They also tend to show that the paracaudate island has characteristics at least as closely related to the extended amygdala as to the striatopallidal system. Fig. 38 represents a CCK-stained section cut through the rostral part of stria terminalis (but at a slightly different angle than the brain in the mini-atlas at the end of the previous chapter). It demonstrates a large bundle of CCK-positive fibers and coarse granules reminiscent of terminals, in the 'lateral pocket' (arrow in B; the 'pocket' contains a number of medium-sized cells as is evident in a matching section stained with Heidenhain's method). A smaller, dorsolaterally-located island containing immunoreactive terminals and cell bodies is also present close to the cau132


Ch.//

Fig. 38: Coronal section through the rostral part of the stria terminalis stained for cholecystokinin (CCK) demonstrates a CCK-positive large pocket (arrow in B) and a small island containing immunoreactive terminals and medium-sized cell bodies (C).

133

Ch. H


date nucleus (Fig. 38C). Considering the presence and the size of the CCK-positive neurons, this island appears to be representative of the lateral division of the supracapsular bed nucleus of the stria terminalis (BSTSL) rather than a small-celled paracaudate island. Figs. 39 and 40 feature matching cholecystokinin and Heidenhain's sections from levels through mid-thalamus and posterior thalamus respectively of the same brain as shown in Fig. 38. The overview figures (Figs. 39A and 40A) provide a guide to the supra- and subcapsular locations of the stria terminalis (compare the

Fig. 39: A. Coronal cholecystokinin-stained section through the middle part of the thalamus (Th) to show the general location of the stria terminalis which is shown in higher magnification in B. Medial (arrowhead) and lateral (arrow) CCK-positive pockets as well as a CCK-positive paracaudate island (asterisk) can be identified. The paracaudate island has smaller cells than the lateral pocket (see insets in C). Lateral (arrow) and medial (arrowhead) pockets can be identified even at low magnification in Heidenhain's stain (C).

134


Ch. H

Fig. 39: B-C.

135

Ch. H


l o c a t i o n o f optic t r a c t a n d lateral geniculate nucleus in the two figures). They also indicate the presence o f ' l a t e r a l ' a n d m e d i a l ' p o c k e t s ' in a d d i t i o n to a p r o m i n e n t p a r a c a u d a t e island; this is especially the case in r e g a r d to the s u p r a c a p s u l a r c o m p o nents (Figs. 39B a n d 40B). In this b r a i n it is possible to identify a lateral a n d sometimes a m e d i a l p o c k e t even at low m a g n i f i c a t i o n in the s u p r a c a p s u l a r stria terminalis o f several H e i d e n h a i n - s t a i n e d sections (see a r r o w a n d a r r o w h e a d in 39C a n d 40C). This is especially a p p a r e n t when the sections are m a t c h e d with sections stained for c h o l e c y s t o k i n i n showing t e r m i n a l fields (Figs. 39B a n d 40B). A c o m b i n e d cell-fiber stain like H e i d e n h a i n ' s o r the K l t i v e r - B a r r e r a m e t h o d is especially well suited for this p u r p o s e . The" p a r a c a u d a t e island is also c h o l e c y s t o k i n i n - p o s i t i v e in c o n t r a s t to the rest o f the c a u d a t e nucleus. This is p a r t i c u l a r l y evident at the level s h o w n in Fig. 40B. T h e

Fig. 40: A. Coronal section (from a somewhat more caudal level than that shown in Fig. 39), stained for

cholecystokinin, shows the position of the stria terminalis displayed in higher magnification in B and in a nearby section stained with Heidenhain's technique (C). The paracaudate island is strongly positive (asterisks in B) as are the lateral (arrows) and medial (arrowhead) pockets. The cells in the paracaudate island are considerably smaller than in the nearby part of striatum (inset in C). Note that lateral (arrow) and medial (arrowhead) pockets can be identified with Heidenhain's stain even at low magnification (C). 136


Ch. H

1 mm

Fig. 40: B-C

lateral pocket is typically populated by medium-sized cells rather than by the small cells characteristic of the paracaudate interface island (see insets in Fig. 39C and 40C; note that the magnification in 39C, like that in 37B-D is about twice that in many of 137

Ch. H

L. Heimer et al.

the other panels showing neurons in this series of pictures). The CCK-immunoreactivity in the lateral pocket features both cell bodies and terminals (inset in Fig. 39B) whereas the paracaudate interface island (asterisk) has only an occasional CCK-positive cell within the CCK immunoreactive terminal field. To emphasize the apparent relations between the paracaudate interface island or column and the extended amygdala we present a neurotensin-stained section of the stria terminalis (Fig. 41) from the same brain as that in Fig. 39 but from a somewhat different level. The terminal staining is typically confined to the paracaudate island (asterisk) and to a lesser extent to the lateral and medial pockets (arrow and arrowhead). 3.4.2. Subcapsular part of the stria terminalis The caudal supracapsular part of the stria terminalis makes a descending, curving sweep and then, ventrally located, passes forward to lie underneath the sublenticular part of the internal capsule which it has encircled. It is here lodged between the tail of the caudate (TCd), laterally, and the lateral geniculate nucleus (LG) medially (Fig. 40A). The stria terminalis forms a compact bundle on the ventral surface of the internal capsule facing the temporal horn of the lateral ventricle (LV in Fig. 42). It is difficult to positively identify lateral and medial pockets at this level. Two small CCK-positive interface 'islands' with typically small- to medium-sized cells can be recognized in a paracaudate position (asterisk in Fig. 42). Between these interface islands is another region which contains loosely arranged, medium-sized cells and which, like the dorsomedial rim of the main part of the tail of the caudate, contains CCK-positive terminals (arrow in Fig. 42A). At a slightly more rostral level (Figs 39 and 43) the tail of the caudate is much reduced, being represented only by a thin wedge of tissue ventral to the sublenticular part of the internal capsule. It continues to display CCK-positive terminals (Fig. 43A). This thin wedge of tissue may, much like the parvicellular paracaudate island, serve as a transition between the extended amygdala and the striatum (see Section 3.5.). The stria terminalis (st) at this level breaks up into bundles on the superior wall of the inferior horn of the lateral ventricle. Further rostrally still (Fig. 44) the stria terminalis bundles approach the central and medial amygdaloid nuclei and the rest of the amygdala from behind and below. A cell layer of variable thickness separates the temporal horn of the lateral ventricle from these strial bundles which more or less surround several parvicellular interface islands (asterisks in Fig. 44) as they proceed through this heterogenous caudal part of the amygdala. At a somewhat more rostral level (Fig. 45) the various subdivisions of the amygdala can be clearly recognized. Individual variation in regard to the stria terminalis and to interface islands in this part of the human brain as well as variations in section level and orientation may contribute to the differences in morphology, number and location when comparing the pictures in this review with those presented by Sanides (1957b). The breaking up of the stria terminalis into fiber bundles which proceed dorsally between the various cell groups of the basolateral amygdala is displayed in Fig. 45G. The Kltiver-Barrera section in Fig. 45A also displays a number of interface islands related to the stria terminalis system and an encapsulated island (marked C in Fig. 45A) of medium-sized cells close to the surface of the inferior horn. This cell island has features including characteristic enkephalin-immunoreactivity (Fig. 45B) similar to 138


Ch. H

Fig. 41: Neurotensin-stained section close to the level shown in Fig. 39. The terminal labeling is confined mainly to the paracaudate island and less prominently to the lateral (arrow) and medial (arrowhead) pockets. The black granules in the dorsal half of the stria terminalis are artifacts.

those of the lateral pocket in the supracapsular part of the stria terminalis, suggesting that it is representative of the cell column related to the central parts of the dorsolateral bed nucleus and the central amygdaloid nucleus (compare Figs 45C and E with D and F). The other regions surrounding the ascending stria terminalis bundles in Fig. 139

Ch. H

L. Heirner et al.

Fig. 42: Subcapsular part of stria terminalis at the level shown in Fig. 40. Two CCK-positive parvicellular

interface islands are indicated by an asterisk. The dorsomedial rim of the tail of the caudate, as well as the medially located area indicated by an arrow in A, contains a moderate number of CCK-positive terminals.

45A are populated by a rather heterogenous population of medium-sized and small neurons, which in m a n y way resembles components of the bed nucleus of the stria terminalis and centromedial amygdala. The adjoining, rather extensive, region lateral to the prominent stria bundles on the lateral aspect of the amygdaloid body (Fig. 45A and K1-B 11 in the mini-atlas) is referred to as the amygdalostriatal transition area by de Olmos (1990) or striatum accessorium by Brockhaus (1938). The neurochemical composition of this region (strong E N K and weak SP and A C h E - I R ) which gradually merges with ventral putamen laterally suggests that it is representative of that part of the stria terminalis component of the central extended amygdala which gradually merges with striatal tissue. The further delineation of the subcapsular parts of the extended amygdala, especially at the level of the caudal amygdala, deserves careful attention. Whereas vestiges of a medially located cell column, apparently representative of a medial supracapsular bed nucleus of the stria terminalis (BSTSM) have been demonstrated in the more rostral parts of the stria terminalis, the presence in more caudal sections of a few neurons in a medial location is not altogether convincing evidence for continuity. Nevertheless, histochemical demonstration (e.g. Figs. 39 and 40) of a pronounced medial pocket in the h u m a n which resembles that in the rat (Alheid et al. 1998) in having a dense collection of synaptic complexes like that of the medial amygdaloid nucleus is strongly suggestive of a continuum. 140

The hwnari basal forebrain. Part II

Ch. I1

Fig. 4 3 : CCK and Heidenhain’s sections (see Fig. 39A for location) showing the subcapsular part of the stria terminalis at a slightly more rostra1 level than in Fig. 42. The tail of the caudate has all but disappeared, and the wedge-like striatal region between the internal capsule and the lateral ventricle is moderately CCKpositive. Asterisks indicate CCK-positive islands.

Based on the material included in this study (see also Strenge et al. 1977) it is clear that the lateral (central) division of the extended amygdala is more prominently represented than the medial division both in the supracapsular and subcapsular parts of the stria terminalis. Features with characteristics in common with central part of the dorsolateral bed nucleus and the central amygdaloid nucleus can be easily recognized both in the supra- and subcapsular segments of the stria terminalis. Unlike the situation in the rat, however, the human possesses an additional prominent stria terminalis component, i.e. the paracaudate interface island or column which, at least in part, seems to serve as an area of transition between the extended amygdala and the striatum.

141

Ch. H

L. Heimer et al.

Fig. 44: Coronal section (see overview picture in Fig. 37) at the level where stria terminalis approaches the amygdala from behind. Asterisks indicate parvicellular interface islands. The arrow points to a mediumcelled island which has a cytoarchitecture similar to the central part of the lateral division of the central amygdaloid nucleus (see Fig. 45D).

142


Ch. H

Fig. 45: Coronal sections through the caudal part of the amygdaloid body stained with Klfiver-Barrera (A) and for enkephalin (B), substance P (G) and acetylcholinesterase (H). (For general location of this area see K1-B 12 in the mini-atlas.) The cell island marked with C in A has a cell picture (see panel C) and enkephalin-immunoreactive pattern (panel E) reminiscent of that in the central part of the lateral division of the central nucleus (panels D and F). Note that the amygdalostriatal transition area, labeled Astr in G, has a staining pattern which differs from the adjoining parts of ventral putamen in enkephalin (B), substance P (OD and acetylcholinesterase (H) stained preparations. 143

Cll. II

L. Heimer et al.

Fig. 45: G-H.

3.5. TRANSITION AREAS BETWEEN EXTENDED AMYGDALA AND THE STRIATOPALLIDAL SYSTEM

While we have generally focused our discussion on the ways in which elements of the extended amygdala in the human might be discriminated from the neural elements belonging to the adjacent striatopallidal system, it is also true that in some instances this border may be impossible to depict with a single line. This is certainly the case with the bed nucleus of the stria terminalis and the caudal accumbens. In the modern era of chemical neuroanatomy, many observers have noted the dense acetylcholines144


Ch.H

terase staining within the nucleus accumbens and have used this as a boundary marker towards the lateral and medial bed nucleus of the stria terminalis, which are less densely stained. For other transmitter markers, however, this division is not so clear. In fact, it is often the case that histochemical staining or receptor binding tends to blur the distinction between the bed nucleus of the stria terminalis and the accumbens (e.g. CCK, Zfiborszky et al. 1985; angiotensin II, Lind et al. 1985; Lind and Ganten 1990; Alheid and Heimer 1988, Fig. l lA; calcitonin receptors, Skofitsch and Jacobowitz 1985, 1992; amylin receptors, Sexton et al. 1994; vasopressin and oxytocin receptors, Veinante and Freund-Mercier 1997; secretoneurin, Marksteiner et al. 1995). The likelihood that these variations in chemical neuroanatomical measures also reflect unique afferents or intrinsic components has been borne out in comparative studies of the connectivity of the accumbens. While our early efforts and those of others documented the similarities of the ventral and dorsal striatum in the rat (see section 2), it became clear that some projections were difficult to encompass in a model of striatopallidal circuitry. These include projections to lateral hypothalamus, amygdala, and brainstem (Nauta et al. 1978; Groenewegen and Russchen 1984). The accumbens' projection to the amygdala, which is to some extent reciprocated, targets the extended amygdala, and especially its central division, with projections to the lateral bed nucleus of the stria terminalis, sublenticular extended amygdala, and to a lesser extent the central amygdaloid nucleus in the rat (Heimer et al.; Brog et al. 1993). A partial resolution of this issue was the observation that the more unique projections of accumbens seemed to originate from the shell area (Heimer et al. 1991) so that at least part of the accumbens, its central core, could be analyzed as a more uniform representative of striatopallidal circuitry. The projections from the accumbens shell, however, also engage part of the striatopallidal circuit, with projections to the medial part of ventral pallidum and a subsequent relay to mediodorsal thalamus. Faced with the histochemical similarity between the caudal shell areas of accumbens and adjacent areas of extended amygdala, and with their common projections to lateral hypothalamus and rostral brainstem targets, in addition to reciprocal connections with the central division of extended amygdala, we concluded that there may well be elements of the extended amygdala that are embedded within the caudal shell area of accumbens. In other words the caudomedial shell of accumbens may represent a 'transition area' between the ventral striatum and extended amygdala (e.g. Alheid and Heimer 1988). The likelihood that this argument is also true for the primate brain is supported by the histochemical features of the accumbens zones that are the apparent homologue of the accumbens shell of the rat (e.g. see Figs. 20A, 25H; also Gaspar et al. 1985; Walter et al. 1990), and which by and large seem to possess a similar network of projections, including efferents typical of the striatopallidal system, but also of extended amygdala, including projections to lateral hypothalamus and brainstem, as well as reciprocal projections with extended amygdala (e.g. see Haber et al. 1990a,b; Price and Amaral 1981). Beyond the close relation of the caudomedial accumbens with extended amygdala, we have over the past decade identified other potential transition areas between the ventral striatum and the extended amygdala in the rat. These include an area along the posterior limb of the anterior commissure that is continuous with the caudomedial accumbens, and shares the histochemistry and close connections with the central division of extended amygdala (Alheid and Heimer 1988, 1996; Alheid et al. 1994, 1995; Heimer et al. 1997a,b; Veinante and Freund-Mercier 1997). At the present time it is not possible to specify with any precision the homologous area of the primate or 145

Ch. H


human brain. As indicated in section 3.2.1., however, some histochemical evidence suggests that portions of the ventral striatum that are nearby to the temporal limb of the anterior commissure are differentiated from the overlying striatum and stain in a similar fashion to the ventrally adjacent elements of the extended amygdala (arrows in Figs. 26A and B; see also Fig. 28B). Further progress in specifying the homologous area in the human brain might be expected when specific chemical markers for this lateral zone are recognized and applied to this problem. For the rat a relatively specific indicator of the dopaminerich transition area along posterior limb of the anterior commissure appears to be immunohistochemistry for the tyrosine kinase, c-lyn (Chen et al. 1996). As discussed in the previous section (3.4.), the large paracaudate interface island appears to represent another important transition area between the extended amygdala and the striatum throughout the course of the stria terminalis in the human. In fact, this elongated transition area appears to be directly continuous with a zone that has generally been designated as the amygdalo-striatal transition area in the temporal lobe and we have retained this terminology (see AStr in K1-B 11 and 12 in the mini-atlas; see also section 5). The amygdalostriatal transition area and the caudal approach of the stria terminalis (with accompanying neurons) to the amygdala are best illustrated in Figs 42-45. In this material the distinction between the ventral putamen and the adjacent amygdalostriatal transition area is quite clear (Fig. 45), and there is even additional dorsalventral specialization within the amygdalostriatal area in terms of peptide immunohistochemistry (Fig. 45B). What is not clear, however, is whether this temporal amygdalostriatal transition area is the homologue of the caudal amygdalostriatal zone of the rat brain, which has a predominantly striato-pallidal type projection (Gray et al. 1989; Alheid, unpublished observations) or whether it involves elements resembling more rostral zones of transition alongside the temporal limb of the anterior commissure which seem to preferentially target the amygdala (Alheid et al. 1996). The amygdalostriatal transition zone, incidentally, may be a subcortical site with dense dopamine D3 receptor expression (Murray et al. 1994), a receptor subtype that is postulated to be a potential site of genetic polymorphisms related to the increased susceptibility to schizophrenia (Griffon et al. 1996).

4. OLFACTORY SYSTEM Although functionally important, the primary olfactory structures and pathways constitute a relatively small part of the human brain. Most of them lie on the ventral surface of the forebrain. The projections originating in the olfactory bulb form a compact bundle in the olfactory peduncle (or stalk) including the olfactory tract (olf, also referred to as lateral olfactory tract). As discussed in the previous chapter, the olfactory tract proceeds in a posterolateral direction on the orbital surface of the frontal lobe in front of the anterior perforated space (K1-B 4). Fibers from the olfactory peduncle or stalk have their main areas of termination in the anterior olfactory nucleus (AO, K1-B 1-3) and primary olfactory cortex (Pir, K1-B 3-6). The olfactory tract makes a sharp, medially-directed bend in the region of the limen insulae (white arrowhead in Figs. 1 and 2 in previous chapter), where the frontal part of the primary olfactory cortex

146


Ch. H

(PirF) is directly continuous with the temporal olfactory cortex (PirT) on the dorsomedial surface of the parahippocampal gyrus (K1-B 4 and 5). The main terminal areas of the olfactory projection fibers in the primate, described by Meyer and Allison (1949) and by Allison (1954), have been confirmed in part by modern tracer techniques (Turner et al. 1978; Carmichael et al. 1994). In short, the olfactory bulb projection fibers come together to form one large olfactory tract which proceeds in a caudal direction. Along the way, axons, often in the form of collaterals (Cajal 1911; Allison 1953; Luskin and Price 1982; Devor 1976), deviate to terminate in the various cortical and cortical-like olfactory projection areas alongside the olfactory tract as well as passing in a caudomedial direction to nearby parts of the ventral striatum deep to the anterior perforated space. It is unlikely that the situation in the human is radically different from that in other primates. In humans, there is no compact collection of bulbofugal fibers which can properly be referred to as a medial olfactory tract (Allison 1954). To be sure, some olfactory bulb fibers in the monkey and human (K1-B 2-4) do turn medially at the point where the stalk attaches to the ventral surface of the brain in order to reach medially located subdivisions of the anterior olfactory nucleus (retrobulbar area) but they are scattered and do not form a tract. None of them have been shown to reach the septal area, although some apparently reach the rostral hippocampus (ventral taenia tecta) in the monkey (Carmichael et al. 1994). The rostral hippocampus is quite rudimentary in the human brain (e.g. Rose 1927b, p. 380). 4.1. PRIMARY NON-AMYGDALOID OLFACTORY BULB PROJECTION AREAS The target regions of the olfactory bulb projection fibers in the basat forebrain (colored magenta in the Kltiver-Barrera atlas of the previous chapter) are somewhat speculative, since they are based largely on extrapolations from experimental data in the monkey (Meyer and Allison 1949; Turner et al. 1978; Carmichael et al. 1994) and on a 'degeneration' study in the human brain (Allison 1954). The staining of the superficial myelinated olfactory bulb fibers in the Kltiver-Barrera (K1-B) sections and the presence of a distinct 'subpial glia zone' related to paleocortex (e.g. Economo and Koskinas 1925; Sanides and Sas 1970; Price 1973; Stephan 1975) also provide some guidance in identifying the course and distribution of these fibers in the human brain. These features (see inserts in K1-B 2 and 5) are clearly evident in the sections presented in the mini-atlas at the end of the previous chapter (K1-B 1-10). Lacking a unique 'olfactory histochemical marker', it is obviously difficult to determine exactly how far the olfactory bulb projection fibers extend in the various parts of the human basal forebrain. The areas shaded in magenta in K1-B 1-10 should provide a reasonably good, if deliberately conservative estimate of the primary olfactory areas in the human brain. That there is difficulty in estimating the extent of the olfactory bulb projections in the regions where the myelinated olfactory tract fibers gradually disappear is indicated in the figures by a fading color.

4.1.1. Anterior olfactory nucleus (retrobulbar area) The gray substance behind the olfactory bulb (i.e. both in the free-standing olfactory peduncle and further back where it becomes attached to the orbital surface, K1-B 1 and 2) is considered to be subcortical by some investigators but others consider it to be 147

Ch. H

L. Heimer et aI.

cortical or cortical-like. Herrick (1910) introduced the term 'anterior olfactory nucleus', which is most commonly used by Anglo-American authors (e.g. Gurdjian 1925; Young 1936; Crosby and Humphrey 1939, 1941; Lohman 1963; Pigache 1970; Turner et al. 1978; de Olmos et al. 1978; Carmichael et al. 1994). Others have preferred the term 'regio retrobulbaris' or retrobulbar area because of structural similarities of the region to cortex (e.g. Rose 1927a,b; Popoff and Popoff 1929; Krieg 1946; Vaz Ferreira 1951; White 1965; Stephan 1975). As discussed in some detail by Stephan (1975), the peduncular gray in macrosmatic mammals does have a laminated appearance which would justify its inclusion in the paleocortex. The situation is somewhat different in the human, in which the structure does not exhibit a consistent lamination. Nonetheless, as noted recently by Zilles (1990), it seems reasonable to include the human retrobulbar area in the paleocortex because it is equivalent to the peduncular gray in macrosmatic mammals and is directly continuous with the rest of the paleocortex, i.e. the primary olfactory cortex. Cellular elements located in the rostral part of the olfactory stalk or peduncle, and even to some extent within the olfactory bulb itself, are referred to as the bulbar (rostral) part of the anterior olfactory nucleus or as the retrobulbar area (Crosby and Humphrey 1941; Stephan 1975). At the point where the peduncle merges with the orbital surface, the peduncular gray becomes more voluminous (AO in K1-B 1). Different parcellations have been recognized in humans (e.g. Crosby and Humphrey 1941; Stephan 1975). Nevertheless, as indicated by Zilles (1990, p.760), it is often difficult to perceive subdivisions comparable to those in macrosmatic mammals and individual variations may make such an effort fruitless. Further back, at the level where the peduncle has disappeared and an olfactory tract is clearly identifiable on the orbital surface (K1-B 2), subdivisions can be recognized both deep to the tract and on its medial and lateral aspects. They can reasonably be compared to the caudal, medial and lateral parts of the AO recognized at this level by Stephan (1975, Figs. 205-207). Carmichael et al. (1994) have identified a small cell group in the monkey, located partly within the olfactory tract itself, which they believe to be equivalent to the external part of the anterior olfactory nucleus in macrosmatic mammals. They made this suggestion partly on the basis of their retrograde tracing experiments which indicated a prominent projection from this cell group to the contralateral olfactory bulb. This is reminiscent of the situation in the rat (e.g. de Olmos et al. 1978; Alheid et al. 1984; Shipley et al. 1995). It is not known if an external subdivision of the anterior olfactory nucleus exists in the human.

4.1.2. Primary olfactory cortex ('piriform cortex') The retrobulbar gray substance gradually establishes continuity with the primary olfactory cortex (piriform or prepiriform cortex 7) laterally, and also with some periallocortical formations in the caudal orbitofrontal region. The primary olfactory cortex, which we have labeled Pir (piriform cortex) in K1-B 4-6, is closely related to the olfactory tract as it proceeds laterally towards the limen insulae. It has a three-layered 7The terms 'piriform' and 'prepiriform' cortex are often used interchangeably for the major cortical termination areas of olfactory bulb projection fibers in both macrosmatic and microsmatic mammals. As discussed by Stephan (1975), neither is satisfactory. The entorhinal area is traditionally included in the piriform lobe (Smith 1895; for definition of piriform lobe, see also Stephan 1975, p. 865) but it is usually not included in the term 'piriform cortex', which is ofien used for the area we prefer to call 'primary olfactory cortex'. Olfactory cortex, therefore, is not 'prepiriform', and Price and his colleagues (Haberly and Price 1978; Carmichael et al. 1994), following the lead of Powell et al. (1965), dropped the prefix 'pre'. As a concession to uniformity, we have labeled primary olfactory cortex 'Pit' as used by Price and his colleagues as well as in the widely used atlases by Paxinos and coauthors (e.g., Paxinos and Watson 1986; 1997; Franklin and Paxinos 1997; Mai et al. 1997).

148


Ch. H

appearance typical of paleocortex (insert in K1-B 5) and is most easily identified by a prominent superficial, densely populated pyramidal cell layer (layer II) which also contains many polymorphic neurons (see also review by Pigache 1970). In the human, there is a tendency for the superficial cell layer to form islands or clusters (Cajal 1911; 1955) in both the frontal (K1-B 4 and 5) and in the more extensive temporal part of the primary olfactory cortex. This clustering gives the superficial cell layer an undulating appearance (K1-B 4-6). In accordance with O'Leary (1937) and Pigache (1970), we prefer the term 'primary olfactory cortex' instead of piriform or prepiriform cortex although we have labeled it Pir in the figures in order to remain consistent with the widely adopted nomenclature used by Paxinos and his collaborators (Paxinos and Watson 1986; Mai et al. 1997). With the term 'primary' we emphasize the fact that this paleocortical area receives significant input from the olfactory bulb in all species, a characteristic shared with the anterior olfactory nucleus in the retrobulbar gray. Primary olfactory cortex has boundaries that can be reasonably well defined in most species (Pigache 1970) but, in humans, some of its boundaries are transitional in nature. These produce poorly-defined margins, especially at the border towards ventral striatum in the region of the anterior perforated space (K1-B 6 and 7; see also Section 2.1.1). It is important to realize that the boundaries of the primary olfactory cortex do not indicate the limit for the spread of olfactory bulb projection fibers in the brain. Besides the anterior olfactory nucleus, which is a prime target in all species, insular and temporal periallocortical regions, olfactory tubercle, amygdala and entorhinal area also receive bulbofugal fibers. The extent of their innervation shows species variation. For instance, in the monkey (e.g. Carmichael et al. 1994), only part of the olfactory tubercle receives input from the bulb, and a similar situation exists in regard to other structures, e.g. the superficial amygdala and the entorhinal area (see below). The olfactory tubercle, superficial amygdaloid areas and the entorhinal cortex should not be considered as 'primary olfactory cortex'. Following olfactory bulb removal, they, as well as the anterior olfactory nucleus, are spared from the rapidly developing transneuronal degeneration that occurs in the true primary olfactory cortex (Price 1976; Heimer and Kalil 1978; Carlsen et al. 1982). These atrophic changes, limited to the area which we, in accordance with the observations of O'Leary (1937) and Pigache (1970), have labeled primary olfactory cortex, have been described in many mammals, including the human (e.g. Winkler 1918; Uyematsu 1921; Allison 1953, 1954). These circumscribed degenerative changes indicate that the primary olfactory cortex is trophically dependent on incoming olfactory impulses to a greater degree than are other olfactory bulb projection areas. The cytoarchitecture and intrinsic organization of the primary olfactory cortex of macrosmatic animals have been the focus of a number of detailed studies and excellent reviews (e.g. Calleja 1893; Cajal 1911, 1955; Haberly 1990; Herrick 1924; O'Leary 1937; Valverde 1965; Stevens 1969, Pigache 1970; Stephan 1975; Price 1990; Shipley et al. 1995, 1996). Several of these authors have paid special attention to connections and transmitter histochemistry (e.g. Haberly 1990; Shipley et al. 1995, 1996). Comparable data from the human olfactory cortex are extremely sparse. Endopiriform nucleus. The term 'endopiriform nucleus', also known as the 'ventral prepiriform claustrum' (Macchi 1951) was originally introduced by Loo (1931) to denote a group of cells which, in the opossum, are located deep to the primary olfactory cortex and are in direct continuity with the claustrum dorsally. Loo's (1931) original proposal that the endopiriform nucleus is a structure separate from 149

Ch. H

L. Heimer et al.

the dorsally located claustrum receives some support from the developmental studies in the rat by Bayer and Altman (1991) who discovered that the two structures originate in different types of cortical primordia and are characterized by different developmental patterns. On comparative grounds (Striedter et al. 1997) it has also been argued that the endopiriform nucleus and the claustrum have different origin. Likewise, Krettek and Price (1978), who were the first to use the term 'endopiriform nucleus' in the rat, suggested that it might be conceived of as the deep layer of the primary olfactory cortex. They widened the use of the term in the rat to a ventromedial extension (labeled Epv on section 29 in the atlas by Swanson 1992) that has traditionally been considered part of the basolateral amygdaloid complex (see area labeled BLV in Fig. 29 in Paxinos and Watson 1986). Although we have retained the term endopiriform nucleus for the heterogenous collection of neurons deep to the primary olfactory cortex in the rat, we refrain from including the above-mentioned part of the basolateral amygdaloid complex (Alheid et al. 1995). In the human, as in the rat, it is difficult, in places, to identify a border between the endopiriform nucleus and the claustrum (which becomes especially voluminous in the temporal lobe where it attaches to the rest of the brain behind the limen insulae see VC1 in K1-B 5-9). In his review of the human olfactory system, Price (1990, Fig. 29.8) combines the claustrum and endopiriform nucleus into a single complex, labeled En! C1. The endopiriform nucleus, an integral part of the 'Regio claustralis allocorticalis' of Brockhaus' (1938) terminology for the human, was included in the 'ventral claustrum' by Macchi (1951). Claustral areas bordering on the rostral parts of the amygdaloid nuclei (ACA in K1-B 8) have been referred to as the 'amygdaloclaustral area' by Macchi (1951) and as 'claustrum preamygdaleum' by Brockhaus (1938). As described below in section 4.3.2., part of claustrum has been included in the anterior amygdaloid area by some authors. Bulbopetal fibers originating in the basal forebrain. The monkey basal forebrain areas which receive projections from the olfactory bulb also project back to the olfactory bulb (Carmichael et al. 1994). The majority of these bulbopetal fibers originate in the orbitofrontal olfactory structures, i.e., the anterior olfactory nucleus and frontal part of the primary olfactory cortex, rather than in temporal olfactory structures (Carmichael et al. 1994). Many cells in the ventral agranular part of the insula are prominently labeled following injection of retrograde tracer in the bulb (Fig. 5C in Carmichael et al. 1994) underscoring the strong association between the ventral insula and the olfactory system (see below). It is important to realize, however, that the gray substance in the anterior perforated space, labeled olfactory tubercle (TOL) by Carmichael and his collaborators, does not give origin to bulbopetal projections. Likewise, the 'olfactory tubercle' a term to which our objections have been previously stated, see Section 2.1.1., does not project to nearby primary olfactory cortex, although it receives significant input from the primary olfactory cortex (e.g. Haberly and Price 1978). Taken together, these facts would appear to reaffirm our previously stated position, that the 'olfactory tubercle' should not be considered as a medial extension of the olfactory cortex, but rather as an integral part of the striatal complex (Heimer 1978). Finally, it should be mentioned that the olfactory bulb in the rodent receives centrifugal projections from 'non-olfactory' parts of the basal forebrain, including in particular cholinergic and GABA-ergic input from the horizontal limb of the nucleus of the diagonal band (e.g. Price and Powell 1970; de Olmos et al. 1978; Zfiborszky et al. 1986). The situation regarding input to the olfactory bulb from the horizontal limb

150


Ch.H

of the nucleus of the diagonal band appears to be the same in the primate (Mesulam et al. 1983). 4.1.3. Insular and temporopolar periallocortical areas

At the region of the limen insulae, where the insula becomes continuous with the temporal lobe, the primary olfactory cortex of the monkey 'trifurcates', to borrow an expression from Mesulam and Mufson (1982a) who state, 'One limb remains in an orbital position, a second limb extends into the insula, and a third limb covers the medial aspect of the temporal pole' (in the region of the parahippocampal gyrus). This situation is clearly demonstrated in the Old World monkey (Fig. 5 in the MesulamMufson paper). Olfactory bulb fibers accompany the 'insular limb' of the primary olfactory cortex into the ventral part of the insula in the monkey (see Fig. 6 in Turner et al. 1978), as they do in other mammals (e.g. Switzer et al. 1985; Shipley and Geinisman 1984; Shipley et al. 1990). Although Carmichael et al. (1994) do not mention the existence of olfactory bulb projections to the ventral insula in the monkey, their retrograde tracing studies indicate that the primary olfactory cortex extends laterally to include the ventral insula. In the human, the existence of a characteristic superficial glia zone accompanying the myelinated olfactory bulb fibers suggests a projection area in the ventral agranular insula (Ia) indicated in magenta color in K1-B 1-5. This is reminiscent of the picture shown by Mesulam and Mufson (1982a) and Turner et al. (1978) in the monkey. In a fortuitous CCK-section (Fig. 46) corresponding to the level shown in K1-B 3, myelinated fiber bundles can be seen to radiate from the lateral olfactory tract towards the ventral part of insula. There the tract gradually tapers off in both dorsal and ventral directions. The presence of direct olfactory input to the ventral agranular insular area which joins the insular gustatory area (e.g. Pritchard et al. 1986; Yaxley et al. 1990) provides the opportunity for integration between olfaction and taste, and resembles the situation in the rat (Shipley et al. 1995). It is important to recall that both insular and orbitofrontal periallocortical regions (Ia and OFa in K1-B 2 and 3) receive projections from the anterior olfactory nucleus and the primary olfactory cortex (see below). Just rostral to the level of the limen insulae (K1-B 2) the distribution of myelinated olfactory tract fibers and accompanying subpial glia zone suggest that olfactory bulb projection fibers might reach a surprisingly large part of the temporopolar periallocortex (TPpall in K1-B 1-4), a region that has been delineated by several authors (e.g. Mesulam and Mufson 1982a; Moran et al. 1987 and Gower 1989). This myelinated fiber tract, which can be appreciated already at low magnification (see rectangle and inset in K1-B 2), is directly continuous with the main part of the olfactory tract as it turns the corner at the limen insulae (K1-B 3). It gradually diminishes in thickness and finally disappears at the level just rostral to that shown in K1-B 1 as well as in the two gyri immediately lateral and medial to the gyrus with the rectangle in K1-B 2. It is recognized that Carmichael et al. (1994) established that secondary olfactory projection fibers originate in the primary olfactory cortex of the monkey and tend to distribute their terminals in layer one in adjacent orbitofrontal areas. Nevertheless, a prominent myelinated fiber layer cannot be identified in the human posterior orbital and insular areas (Ia in K1-B 2 and OFa in K1-B 3) which, judging from the studies of Carmichael et al. (1994) in the monkey, would be the most likely candidates to receive such secondary projection fibers. Nor is any myelinated fiber layer deep to a subpial 151

Ch. H


Fig. 46: Coronal section at the level of the limen insulae (see K1-B 3 for approximate location of this region)

stained for cholecystokinin. Note how myelinated fiber bundles radiate from the lateral olfactory tract (olf) towards the ventral part of the agranular insula (Ia).

glia lamina present in any other parts of insula or temporopolar cortex in the human brain. While the most likely explanation for the prominent myelinated fiber tract illustrated in the insert in K1-B 2 is that it represents the peripheral distribution of olfactory bulb fibers, we are not in a position to indicate definitive discovery of projections to this part of the primate temporopolar cortex. Nevertheless, by coloring the region magenta we have indicated our strong bias toward considering it as part of the olfactory bulb projection area.

4.1.4. Ventral striatum

vs

olfactory tubercle

While some anatomists consider a variably distinguishable superficial dense cell layer in the human anterior perforated space to be representative of a rudimentary olfactory 152


Ch. H

tubercle, we suggest that this layer and its counterpart in the rat (Heimer 1978) should be regarded as striatal in nature (see Section 2.1.1.). In the monkey, Turner et al. (1978) and Carmichael et al. (1994) have demonstrated that olfactory bulb projection fibers do reach part of this region. Based on the distribution of myelinated fibers peeling off from the olfactory tract and the presence of a subpial layer, there is reason to think that the situation is similar in the human. In other words, part of the striatal complex, which extends to the ventral surface in the region of the anterior perforated space, does in all likelihood receive input directly from the olfactory bulb as indicated in K1-B 6 and 7. 4.2. OLFACTORY ASSOCIATION AREAS IN THE ORBITOFRONTAL CORTEX The agranular orbitofrontal cortex (OFa) and the ventromedial extension of agranular insular cortex (Ia) represent transitions between allocortex (represented here by primary olfactory cortex) and granular type isocortex. This form of transitional cortex or periallocortex is termed paralimbic by Mesulam and Mufson (1982a) and, with the neighboring orbitofrontal regions, has been parcellated in great detail in the macaque monkey on the basis of cytoarchitectonic and histochemical characteristics (Carmichael and Price 1994). Regional connections have been studied in the monkey by experimental-anatomical methods (e.g. Potter and Nauta 1979; Porrino et al. 1981; van Hoesen 1981; Mufson and Mesulam 1982; Mesulam and Mufson 1982b; Goldman-Rakic and Porrino 1985; Russchen et al. 1987; Barbas and Pandya 1989; Barbas and de Olmos 1990; Carmichael et al. 1994; Barbas and Blatt 1995; Haber et al. 1995; Carmichael and Price 1995a,b). Many of these connections have been summarized recently in reviews by Amaral et al. (1992) and by Price et al. (1996). The general consensus from all of these tracing studies is that the various areas in the basal orbitofrontal region, including the orbital and insular periallocortical regions displayed in K1-B 2-4, are closely interrelated by way of a highly organized system of short association fibers. For instance, the agranular insular and orbitofrontal transition areas, which border on the primary olfactory areas (i.e. anterior olfactory nucleus and primary olfactory cortex), are closely and reciprocally related to 'primary' olfactory regions (Carmichael et al. 1994). In fact, as mentioned earlier in regard to the insula, it appears that olfactory bulb projection fibers do reach some of these periallocortical areas in the orbitofrontal regions where they border on the primary olfactory cortex (K1-B 2 and 3). Such 'spilling over' of olfactory bulb projection fibers into periallocortical areas also occurs in macrosmatic mammals (e.g. Switzer et al. 1985, rat; Shipley and Adamek 1984, mouse) Systematic tracing studies in the monkey by Carmichael et al. (1994) confirm the existence of olfactory association areas in the orbitofrontal cortex, as had been suggested on the basis of electrophysiological studies in the dog by Allen (1943). Other parts of the posterior orbitofrontal cortex in the human receive input from sensory cortical or thalamic regions representing non-olfactory modalities (visual, gustatory, somatosensory and visceral). In other words, all sensory modalities are represented in posterior orbitofrontal regions. Price and his colleagues (Price et al. 1996) have recently reviewed the neuronal circuits that these orbitofrontal regions establish with other parts of forebrain, Van Hoesen and his colleagues (Van Hoesen et al. 1993; Morecraft and Van Hoesen 1998) have emphasized their close relations to the anterior cingulate cortex, and Haber and her associates (Haber et al. 1995; Chikama et al. 153

Ch. H

L. Heimer et al.

1997) have traced their output channels through the ventral parts of the basal ganglia in the monkey. Considering the various functional affiliations of the posterior orbitofrontal cortical regions and their overall connections, it is hardly surprising that lesions involving this part of the brain tend to have far-reaching effects. These are especially reflected by the inappropriate behavior which is an important part of the so-called orbitomedial frontal syndrome (e.g. Tranel and Damasio 1993; Malloy et al. 1993; Rolls 1995). 4.3. OLFACTORY AMYGDALA The olfactory bulb projection fibers which reach the anterior part of the parahippocampal gyrus in the temporal lobe terminate most prominently in the temporal part of the primary olfactory cortex (PirT, K1-B 9). The superficial part of the amygdaloid complex and part of the entorhinal cortex also receive olfactory bulb input, although the primate terminations (Turner et al. 1978; Carmichael et al. 1994) are not everywhere so prominent as those in the rat (e.g. Shipley et al. 1995, 1996) and other macrosmatic animals. Although extensive superficial parts of the amygdala are characterized by input from the olfactory system, the primate medial amygdaloid nucleus (Me, K1-B 11 and 12) does not appear to receive direct input from the olfactory bulb (Turner et al. 1978; Carmichael et al. 1994). (The medial amygdaloid nucleus was discussed in the context of the extended amygdala in Section 3.2.2.) Amygdalopiriform transition area. Most of the amygdalopiriform transition area, comparable to the subfields PACo, PACs, PAC1 and PAC2 of Price et al. 1987, appears to receive input from the olfactory bulb in the human (K1-B 5-7), as it does in the monkey (Carmichael et al. 1994). A possible exception is the most caudal part of the posteromedial amygdalopiriform transition area (See Section 5.2.3.). Anterior amygdaloid area. Considering the definition of the anterior amygdaloid area in this and many other publications (Section 5.2.3.), it appears reasonable, as suggested by Stephan (1975) and de Olmos (1990), that the superficial part of the anterior amygdaloid area is the recipient of olfactory bulb input (K1-B 8) as in other primates and macrosmatic mammals such as the rat (e.g. Heimer 1978). How far medially the olfactory tract fibers reach into the superficial part of the human AAA and beyond is difficult to say. Olfactory bulb projections to the lateral part of the horizontal limb of the diagonal band do seem to exist in the monkey (Carmichael et al. 1994, Fig. 1G and H). A subpial glia zone in this area in the human, however, does not necessarily indicate an olfactory bulb projection area (Sanides and Sas 1970). The cortical amygdaloid nuclei. The region that was originally referred to as the cortical nucleus in the human (Johnston 1923; Hilpert 1928; Crosby and Humphrey 1941) occupies most of the superficial part of the amygdala located in the semilunar gyrus (SLG, K1-B 10). Most of this region in the monkey receives direct input from the olfactory bulb (Turner et al. 1978; Carmichael et al. 1994). The situation is likely to be similar in the human (K1-B 8-10). Judging from diminution of the distinct subpial glia zone this input becomes less pronounced in more ventral and caudal parts of the semilunar gyrus. The presence of olfactory bulb projection fibers is especially prominent in the region of the anterior cortical nucleus (K1-B 8-10). This nucleus is located in the fundus and lower lip of the endorhinal sulcus, just behind the primary olfactory cortex. A nearby region, which occupies most of the semilunar gyrus ventral to the anterior cortical nucleus, is referred to as the ventral cortical nucleus. Most of this region in the 154


Ch. H

monkey (Turner et al. 1978; Carmichael et al. 1994), and probably in the human, (K1B 8-10; see also Price 1990) receives olfactory bulb projection fibers. As discussed in Section 5.2.3., it is unlikely that an olfactory-related posterior cortical nucleus can be identified in the human. 4.4. OLFACTORY ENTORHINAL FIELD The question of whether the entorhinal cortex, which serves as an important gateway to the hippocampus, receives direct projections from the bulb, was long a matter of debate. It was only with the aid of more sensitive silver methods that this question could be affirmatively answered in the rat (White 1965; Heimer 1968) and the rabbit (Scalia 1966). Olfactory bulb projections to the entorhinal area have now been confirmed in a number of species including the monkey (Turner et al. 1978; Amaral et al. 1987; Price 1990; Carmichael et al. 1994). Such projections reach a major part of the entorhinal cortex in macrosmatic mammals (e.g. Kosel et al. 1981; Room et al. 1984), but their distribution is more restricted in the monkey (Turner et al. 1978; Carmichael et al. 1994). In the absence of a reliable method for labeling olfactory bulb projection fibers in the human, no hard data are available. Estimates can, however, be made by extrapolation from the monkey, and from the distribution of olfactory tract fibers and concomitant subpial glial zone in Klfiver-Barrera sections from human brains. Based on earlier studies, especially those by Price (1990) and Insausti et al. (1995), the olfactory bulb projections to the human entorhinal cortex would seem to be limited primarily to what they, and others (Amaral et al. 1987), have referred to as the olfactory field (OE in K1-B 6-7). The olfactory part of the entorhinal area includes the superficial part of the region named ambiens gyrus (AG in K1-B, 8 and 10) which forms a more or less pronounced prominence below the semiannular sulcus. The ambiens gyrus is usually demarcated ventrally by an indentation (inferior rhinal sulcus of Retzius 1896; intrarhinal sulcus of Amaral and Insausti 1990). This 'sulcus' is barely apparent in the brain we have used for the introductory series of KltiverBarrera-stained coronal sections, or in the brain shown in Fig. 47A, but is pronounced in Fig. 47B, taken from another brain. The reason for this variation, according to Van Hoesen and his colleagues (Arnold et al. 1991; Van Hoesen 1997) is that the 'sulcus' is artificial in the sense that it represents the impression made by the edge of the tentorium. This indentation provides for a more or less prominent 'landmark' on the ventral surface of the parahippocampal gyrus in about 70% of human brains (Corsellis 1958). Pathology related to this abnormality is clearly evident in the brain displayed in Fig. 48. When this indentation is exaggerated for whatever reason (e.g. increased intracranial pressure, head injury, etc.) it might, according to Van Hoesen (1997), lead to cytoarchitectural abnormalities (see inset in Fig. 48) with subsequent neuropsychological symptoms. This abnormality appears in the anteromedial 'uncal' part of the entorhinal area, which is that part of the hippocampal formation most closely related to the two major functional-anatomical systems discussed earlier in this chapter, i.e. the ventral striatopallidal system and extended amygdala (see Heimer et al. 1997b for further discussion of the relation between the anterior hippocampal formation and the mediobasal forebrain and its importance in the context of neuropsychiatric disorders).

155

Ch. H

L. Heimer et al.

Fig. 47: The 'intrarhinal sulcus' (arrows) is an artifact (see text) produced by the impression of the edge of the tentorium. It is barely visible in the brain illustrated in A, but quite pronounced in the brain shown in B.

5. S U P E R F I C I A L AMYGDALA AND T H E L A T E R O B A S A L C O M P L E X 5.1. G E N E R A L S T R U C T U R E OF T H E A M Y G D A L A Major subdivisions. Humphrey (1936) and Crosby and Humphrey (1941) divided the amygdaloid complex into a superficial corticomedial and a deeply located basolateral group of nuclei. This approach was based primarily on J.B. Johnston's (1923) subdivision into a phylogenetically 'older' corticomedial group (including also the central nucleus) and a 'younger' basolateral group of nuclei 8. With minor variations Johnston's subdivision is generally adhered to by most contemporary scientists (e.g. Aggleton 1985; Price et al. 1987; Amaral et al. 1992; Kordower et al. 1992; McDonald et al. 1995; Sorvari et al. 1995; Stefanacci et al. 1996; Emre et al. 1993). J.B. Johnston's pioneering comparative and developmental studies of different species, including the human, also resulted in an additional, and as it now appears, fundamental insight regarding forebrain anatomical organization, i.e. that the developmentally distinct central and medial amygdaloid nuclei extend into the medial part

8Although Johnston (1923) expresses this view on the basis of origin and age of the amygdaloid nuclei (p. 456 in his paper), he notes (pp. 472-473) that the morphological evolution of the amygdaloid complex suggests that the medial and the central nuclei constitute an old part to which the basolateral and cortical nuclei are newly added (see Koikegami 1963; Stephan 1975, for further discussion of this subject).

156


Ch.//

Fig. 48: The pathology including deformed neurons and subpial gliosis in the region of the 'intrarhinal sulcus' is clearly evident in this coronal Kliiver-Barrera stained section through the uncal part of the entorhinal area. The asterisk in the inset points to a zone of gliosis characterized primarily by oligodendroglia proliferation.

of the basal forebrain to form what we have referred to as the extended amygdala (Figs. 1 and 2C and D; also K1-B 6-12 in chapter I). This important discovery points to a dichotomy between the centromedial group (including to some extent the anterior amygdaloid area) and a cortical-basolateral group of nuclei in a manner alluded to in earlier studies by V61sch (1906, 1910). Many others since V61sch and Johnston (e.g. Hilpert 1928; Brockhaus 1940; Macchi 1951; Stephan 1975; Stephan and Andy 1977; Stephan et al. 1987; ten Donkelaar et al. 1979) have emphasized a subdivision between 157

Ch. H

L. Heimer et al.

the centromedial and the cortical-basolateral group of nuclei. Hilpert (1928), for instance, suggested that the small-celled centromedial part belonged to the substantia innominata, which in his opinion was clearly demarcated from what he considered to be the amygdaloid body. Brockhaus (1938), in his classic study of the human amygdala, also makes a special point of this fundamental subdivision by referring to the centromedial complex and the anterior amygdaloid area as the supraamygdaloid division ('Supraamygdaleum') in order to separate it from what he considered to be the amygdaloid nucleus in the strict sense ('Amygdaleum proprium'), i.e. the corticalbasolateral subdivision. Although our preferred terminology is different from that of Brockhaus, we endorse his and Hilpert's fundamental subdivision by including the centromedial amygdaloid complex in the extended amygdala. The concept of the extended amygdala, incidentally, is clearly foreshadowed in the descriptions of the human brain by these pioneering neuroanatomists. [The boundary between the extended amygdala, represented by the centromedial nuclear group, and the amygdaloid body in this more restricted, classical sense is indicated by a dashed line in Figs. 53-55.] Rotations of the amygdala in primate evolution. Some of the difficulties that confront the study of the primate amygdala in a comparative-anatomical context relate to the marked expansion of the temporal neocortex in the course of primate evolution, and the concomitant displacements and rotations within the temporal lobe (Figs. 49 and 50). These rotational changes (e.g. Johnston 1923; Macchi 1951; Spatz 1966; Humphrey 1968; Sidman and Rakic 1982; Gloor 1997) can, for didactic purposes, be imagined to occur in two directions. Rotation and displacement of the ventral part of the temporal lobe in a medial and upward direction explains why the amygdaloid body, which is located on the ventral temporal surface in the rat (Fig. 49), is located in the medial and dorsal part of the temporal lobe in the human (Fig. 50, see also K1-B 11). The other rotation, which takes place more or less around a transverse axis, explains why the entorhinal area, which is located behind the amygdaloid body in the rat (Fig. 49A), has shifted to a more rostral and medial position in the human (Fig. 50). Although analogous amygdaloid nuclei are generally present in all mammals, their positions in the primate, especially in the human, are significantly changed when compared to macrosmatic species (Johnston 1923). One example is provided by the medial, basomedial, basolateral and lateral amygdaloid nuclei, which, in the rat, are located from ventromedial to dorsolateral (Fig. 49B), but which, in the human, are rotated 90 ~ to place the medial nucleus dorsomedially and the lateral nucleus ventrolaterally (Fig. 50B). This rotation also explains why, in human and other primates, the anterior cortical nucleus is located deep to the endorhinal sulcus (hemispheric sulcus) but rostral to the medial amygdaloid nucleus, whereas in the rat it is located on the ventral surface and lies lateral and anterior to the medial nucleus. Despite rotation the relative positions between the individual nuclei are retained in the human (Johnston 1923). An unfortunate consequence of this rotation is that in the human a literal interpretation of the names of the amygdaloid nuclei can sometimes be misleading; for example, the medial nucleus is no longer the most medial part of the amygdala, nor is the anterior amygdaloid area the most anterior part of the human amygdala (e.g. see Fig. 51). This latter situation seems to have been the occasion for some confusion in identification of this area (see section 5.2.3.). The recognition of the effects of developmental rotation in primates is important in identifying homologous amygdaloid nuclei among species of the amygdala. Incidentally, it is also important in understand-

158


Ch. H

Fig 49: The general arrangement of the various amygdaloid nuclei in the rat is depicted in B, which represents a coronal section through the amygdala. The approximate level for the coronal section is indicated by the bar superimposed on the schematic sagittal section of the rat brain depicted in A. The arrow in B may be compared with a similar axis shown in Fig. 50B for the human brain.

159

Ch. H

160

L. Heimer et al.


Ch. H

The Primate Nervous System, Part III

The Enteric Nervous System

The Nervous System

The Nervous System

The Enteric Nervous System

The Human Central Nervous System

Erythropoietin and the Nervous System

Disorders of the Nervous System

Mobilisation of the Nervous System

Cytoskeleton of the Nervous System

Erythropoietin and the Nervous System

Central Nervous System Diseases

The Primate Visual System: A Comparative Approach

Sympathetic Nervous System Research Developments

Nicotinic Receptors in the Nervous System

Neurogerontology: Aging and The Nervous System

Infections of the Central Nervous System

Neurogerontology: Aging and the Nervous System

Intercellular Communication in the Nervous System

Primer on the Autonomic Nervous System

The Karate Kid Part III

Matrix Metalloproteinases in the Central Nervous System

Nicotinic Receptors in the Nervous System

Cells of the Nervous System (Gray Matter)

The Human Nervous System, Second Edition

Degeneration and Regeneration in the Nervous System

How to Examine the Nervous System

The Central Nervous System: Structure and Function

Intercellular Communication in the Nervous System

The Rat Nervous System, Third Edition (Paxinos, The Rat Nervous System)

Wolf's Obsession Part III

The Primate Nervous System, Part III

The Enteric Nervous System

The Nervous System

The Nervous System

The Enteric Nervous System

The Human Central Nervous System

Erythropoietin and the Nervous System

Disorders of the Nervous System

Mobilisation of the Nervous System

Cytoskeleton of the Nervous System

Erythropoietin and the Nervous System

Central Nervous System Diseases

The Primate Visual System: A Comparative Approach

Sympathetic Nervous System Research Developments

Nicotinic Receptors in the Nervous System

Neurogerontology: Aging and The Nervous System

Infections of the Central Nervous System

Neurogerontology: Aging and the Nervous System

Intercellular Communication in the Nervous System

Primer on the Autonomic Nervous System

The Karate Kid Part III

Matrix Metalloproteinases in the Central Nervous System

Nicotinic Receptors in the Nervous System

Cells of the Nervous System (Gray Matter)

The Human Nervous System, Second Edition

Degeneration and Regeneration in the Nervous System

How to Examine the Nervous System

The Central Nervous System: Structure and Function

Intercellular Communication in the Nervous System

The Rat Nervous System, Third Edition (Paxinos, The Rat Nervous System)

Wolf's Obsession Part III

Recommend Documents