PRIMER ON THE AUTONOMIC NERVOUS SYSTEM THIRD EDITION
PRIMER ON THE AUTONOMIC NERVOUS SYSTEM THIRD EDITION Editor In Chief
David Robertson Vanderbilt University
Editors
Italo Biaggioni Vanderbilt University
Geoffrey Burnstock
University College Medical School
Phillip A. Low
Mayo College of Medicine
Julian F.R. Paton University of Bristol
AMSTERDAM • BOSTON • HEIDELBERG • LONDON NEW YORK • OXFORD • PARIS • SAN DIEGO SAN FRANCISCO • SINGAPORE • SYDNEY • TOKYO Academic Press is an imprint of Elsevier
Academic Press is an imprint of Elsevier 32 Jamestown Road, London NW1 7BY, UK 225 Wyman Street, Waltham, MA 02451, USA 525 B Street, Suite 1800, San Diego, CA 92101-4495, USA First edition 1996 Second edition 2004 Third edition 2012 Copyright © 2012 Elsevier Inc. All rights reserved Except the figures of chapter 76 for which the author retains copyright Cover Image: The human autonomic nervous system, which in large part lies deep within the body, is readily accessible through biopsies of the skin. In the cover image, using the cholinergic marker, vasoactive intestinal peptide (shown in red), there is clear visualization of the sympathetic cholinergic innervation running between the endothelial and basal lamina layers of cutaneous blood vessels in a skin biopsy of the distal thigh. The blood vessels are visualized with the endothelial vascular marker CD31 (an endothelial vascular marker that highlights blood vessels – shown in green) and the vascular basal lamina with collagen type IV (a marker that highlights the basal lamina layer of the extracellular matrix – shown in blue). Image courtesy of Ningshan Wang, Christopher Gibbons and Roy Freeman. No part of this publication may be reproduced, stored in a retrieval system or transmitted in any form or by any means electronic, mechanical, photocopying, recording or otherwise without the prior written permission of the publisher. Permissions may be sought directly from Elsevier’s Science & Technology Rights Department in Oxford, UK: phone (44) (0) 1865 843830; fax (44) (0) 1865 853333; email:
[email protected]. Alternatively, visit the Science and Technology Books website at www.elsevierdirect.com/rights for further information 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 British Library Cataloguing-in-Publication Data A catalogue record for this book is available from the British Library Library of Congress Cataloging-in-Publication Data A catalog record for this book is available from the Library of Congress ISBN : 978-0-12-386525-0 For information on all Academic Press publications visit our website at elsevierdirect.com Typeset by MPS Limited, a Macmillan Company, Chennai, India www.macmillansolutions.com Printed and bound in United States of America 12
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Primer on the Autonomic Nervous System (Third Edition) Copyright © 2012 Elsevier Inc. All rights reserved ISBN: 978-0-12-386525-0 About this Book | Shortcut link to this Title Add to Favorites
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Table of Contents Front-matter, Pages i,iii Show preview |
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Copyright, Page iv Show preview |
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Preface, Page xix, David Robertson, Italo Biaggioni, Geoffrey Burnstock, Phillip A. Low, Julian F.R. Paton Show preview |
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List of Contributors, Pages xxi-xxv, Ana P.L. Abdala, David H. Adams, Marlies Alvarenga, Amy C. Arnold, Felicia B. Axelrod, Franca Barbic, Peter J. Barnes, Deborah Bauer, Christopher Bell, Eduardo E. Benarroch, Elizabeth M. Berry-Kravis, Luciano Bernardi, Italo Biaggioni, Lori Birder, Virginia L. Brooks, Joan Heller Brown, Geoffrey Burnstock, Michael Camilleri, J.Preston Campbell, Robert M. Carey, et al. Show preview |
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Part I: Introduction Part II: Biochemical and Pharmacological Mechanisms Part III: Autonomic Physiology Part IV: Stress Part V: Pathophysiological Mechanisms Part VI: Cardiovascular Disorders Part VII: Catecholamine Disorders Part VIII: Autonomic Synucleinopathies Part IX: Peripheral Autonomic Disorders Part X: Autonomic Disorders Part XI: Orthostatic Intolerance Part XII: Special Clinical Conditions Part XIII: Management of Autonomic Disorders Part XIV: Experimental Autonomic Neuroscience Index, Pages 693-703 Show preview |
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Primer on the Autonomic Nervous System (Third Edition) Copyright © 2012 Elsevier Inc. All rights reserved ISBN: 978-0-12-386525-0 About this Book | Shortcut link to this Title Add to Favorites
Font Size: = Full-text available
= Abstract only
Table of Contents Front-matter, Pages i,iii Show preview |
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Copyright, Page iv Show preview |
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Preface, Page xix, David Robertson, Italo Biaggioni, Geoffrey Burnstock, Phillip A. Low, Julian F.R. Paton Show preview |
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List of Contributors, Pages xxi-xxv, Ana P.L. Abdala, David H. Adams, Marlies Alvarenga, Amy C. Arnold, Felicia B. Axelrod, Franca Barbic, Peter J. Barnes, Deborah Bauer, Christopher Bell, Eduardo E. Benarroch, Elizabeth M. Berry-Kravis, Luciano Bernardi, Italo Biaggioni, Lori Birder, Virginia L. Brooks, Joan Heller Brown, Geoffrey Burnstock, Michael Camilleri, J.Preston Campbell, Robert M. Carey, et al. Show preview |
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Part I: Introduction Chapter 1 - Development and Differentiation of Autonomic Neurons, Pages 3-8, Chun-Hyung Kim, Kwang-Soo Kim Show preview |
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Chapter 2 - Central Autonomic Control, Pages 9-12, Eduardo E. Benarroch Show preview |
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Chapter 3 - Imaging of Brainstem Sites Involved in Cardiovascular Control, Pages 13-16, Vaughan G. Macefield, Luke A. Henderson Show preview |
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Chapter 4 - Peripheral Autonomic Nervous System, Pages 17-26, Robert W. Hamill, Robert E. Shapiro, Margaret A. Vizzard Show preview |
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Chapter 5 - Cotransmission, Pages 27-33, Geoffrey Burnstock Show preview |
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Part II: Biochemical and Pharmacological Mechanisms Chapter 6 - Noradrenergic Neurotransmission, Pages 37-43, David S. Goldstein Show preview |
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Chapter 7 - Tyrosine Hydroxylase, Pages 45-47, Kazuto Kobayashi, Toshiharu Nagatsu Show preview |
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Chapter 8 - Antidepressant-Sensitive Norepinephrine Transporters: Structure and Regulation, Pages 49-50, Maureen K. Hahn Show preview |
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Chapter 9 - α -Adrenergic Receptors, Pages 51-54, Marion C. Mohl, Robert M. Graham 1 Show preview |
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Chapter 10 - α -Adrenergic Receptors, Pages 55-58, Qin Wang 2 Show preview |
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Chapter 11 - β-Adrenergic Receptors, Pages 59-61, C.Michael Stein Show preview |
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Chapter 12 - Dopaminergic Neurotransmission, Pages 63-65, Graeme Eisenhofer, Heinz Reichmann Show preview |
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Chapter 13 - Dopamine Receptors, Pages 67-70, Sean M. Peterson, Nikhil Urs, Marc G. Caron Show preview |
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Chapter 14 - Cholinergic Neurotransmission, Pages 71-74, Brett A. English, Carrie K. Jones Show preview |
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Chapter 15 - Acetylcholine and Muscarinic Receptors, Pages 75-78, Joan Heller Brown, Nora Laiken Show preview |
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Chapter 16 - Nicotinic Receptors, Pages 79-82, Palmer Taylor Show preview |
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Chapter 17 - Serotonin Receptors and Neurotransmission, Pages 83-86, Elaine Sanders-Bush, Charles D. Nichols Show preview |
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Chapter 18 - Purinergic Neurotransmission and Nucleotide Receptors, Pages 87-93, Geoffrey Burnstock Show preview |
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Chapter 19 - Adenosine Receptors and Autonomic Regulation, Pages 95-97, Italo Biaggioni Show preview |
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Chapter 20 - Nitric Oxide and Autonomic Regulation, Pages 99-101, Alfredo Gamboa Show preview |
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Chapter 21 - Glutamatergic Neurotransmission, Pages 103-107, Deborah Bauer, Michael Robinson Show preview |
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Chapter 22 - GABAergic Neurotransmission, Pages 109-111, Andre H. Lagrange, Mark D. Grier Show preview |
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Chapter 23 - Renin-Angiotensin, Pages 113-116, Amy C. Arnold, Debra I. Diz Show preview |
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Chapter 24 - Aldosterone and the Mineralocorticoid Receptor, Pages 117-119, J. Howard Pratt Show preview |
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Chapter 25 - Vasopressin and Disorders of Water Homeostasis, Pages 121-125, Joseph G. Verbalis Show preview |
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Chapter 26 - Calcitonin Gene-Related Peptide and Adrenomedullin, Pages 127-129, Donald J. DiPette, Scott C. Supowit Show preview |
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Chapter 27 - Leptin Signaling and Energy Homeostasis, Pages 131-134, Kamal Rahmouni Show preview |
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Chapter 28 - The Endothelin System, Pages 135-139, Ernesto L. Schiffrin Show preview |
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Chapter 29 - Pharmacology of the Nucleous Tractus Solitarii, Pages 141-144, Ching-Jiunn Tseng, Pei-Wen Cheng, Che-Se Tung Show preview |
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Part III: Autonomic Physiology Chapter 30 - Entrainment of Sympathetic Rhythms, Pages 147-149, Michael P. Gilbey Show preview |
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Chapter 31 - Cross-talk Between Body Systems: Respiratory-Cardiovascular Coupling in Health and Disease, Pages 151-155, Julian F.R. Paton, Anthony E. Pickering Show preview |
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Chapter 32 - Circadian Rhythms and Autonomic Function, Pages 157-159, Diego A. Golombek Show preview |
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Chapter 33 - Baroreceptor Reflexes, Pages 161-165, Mark W. Chapleau Show preview |
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Chapter 34 - Genetic Determinants of Baroreflex Function, Pages 167-169, Italo Biaggioni Show preview |
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Chapter 35 - Cardiac and Other Visceral Afferents, Pages 171-176, John C. Longhurst, Liang-Wu Fu Show preview |
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Chapter 36 - Autonomic Control of the Heart, Pages 177-180, Rachel C. Drew, Lawrence I. Sinoway Show preview |
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Chapter 37 - Cardiac Vagal Ganglia, Pages 181-185, Javier G. Castillo, David H. Adams Show preview |
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Chapter 38 - Neural Control of Blood Vessels, Pages 187-191, Julian H. Lombard, Allen W. Cowley Jr. Show preview |
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Chapter 39 - Physiology of Upright Posture, Pages 193-195, Wouter Wieling, Jan T. Groothuis Show preview |
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Chapter 40 - Cerebral Circulation, Pages 197-200, Ronald Schondorf Show preview |
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Chapter 41 - Autonomic Control of the Lower Airways, Pages 201-204, Peter J. Barnes Show preview |
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Chapter 42 - Gastrointestinal Function, Pages 205-209, Michael Camilleri Show preview |
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Chapter 43 - The Splanchnic Circulation, Pages 211-213, Gregory D. Fink, John W. Osborn Show preview |
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Chapter 44 - Autonomic Control of the Kidney, Pages 215-220, Edwin K. Jackson Show preview |
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Chapter 45 - Dopamine Mechanisms in the Kidney, Pages 221-223, Robert M. Carey Show preview |
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Chapter 46 - Autonomic Control of the Lower Urinary Tract, Pages 225-228, Lori Birder, William C. de Groat Show preview |
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Chapter 47 - Bladder Function in Health and Disease, Pages 229-233, Marcus J. Drake, Brian A. Parsons Show preview |
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Chapter 48 - Physiology and Pathophysiology of Female Sexual Function, Pages 235-238, Max J. Hilz Show preview |
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Chapter 49 - Control of the Pupil, Pages 239-242, Karen M. Joos, Mark R. Melson Show preview |
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Chapter 50 - Central Thermoregulation, Pages 243-247, Shaun F. Morrison Show preview |
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Chapter 51 - Sweating, Pages 249-251, Phillip A. Low Show preview |
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Chapter 52 - Regulation of Metabolism, Pages 253-255, Christopher Bell Show preview |
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Chapter 53 - Autonomic Innervation of the Skeleton, Pages 257-259, Florent Elefteriou, J.Preston Campbell Show preview |
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Chapter 54 - Sex Differences in Autonomic Function, Pages 261-264, Emma C. Hart, Nisha Charkoudian, Michael J. Joyner Show preview |
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Chapter 55 - Autonomic Control During Pregnancy, Pages 265-268, Virginia L. Brooks, Belinda H. McCully, Priscila A. Cassaglia Show preview |
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Part IV: Stress Chapter 56 - Aging and the Autonomic Nervous System, Pages 271-273, Lewis A. Lipsitz, Vera Novak Show preview |
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Chapter 57 - Exercise, Pages 275-279, Qi Fu, Benjamin D. Levine Show preview |
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Chapter 58 - Effects of High Altitude, Pages 281-282, Luciano Bernardi Show preview |
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Chapter 59 - Space Physiology, Pages 283-285, Gilles Clément, Scott Wood Show preview |
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Chapter 60 - Hypothermia and Hyperthermia, Pages 287-289, Nisha Charkoudian Show preview |
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Chapter 61 - Psychological Stress and the Autonomic Nervous System, Pages 291-293, Michael G. Ziegler Show preview |
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Chapter 62 - Mind–Body Interactions, Pages 295-299, Calvin Carter, Daniel Tranel Show preview |
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Part V: Pathophysiological Mechanisms Chapter 63 - Alpha-Synuclein and Neurodegeneration, Pages 303-305, Kiren Ubhi, Leslie Crews, Eliezer Masliah Show preview |
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Chapter 64 - Insulin Resistance and the Autonomic Nervous System, Pages 307-312, Megan S. Johnson, Vincent G. DeMarco, Adam WhaleyConnell, James R. Sowers Show preview |
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Chapter 65 - Salt Sensitivity of Blood Pressure, Pages 313-318, Cheryl L. Laffer, Fernando Elijovich Show preview |
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Chapter 66 - Endothelial Dysfunction, Pages 319-324, Julian P.J. Halcox Show preview |
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Chapter 67 - Inflammation, Immunity and the Autonomic Nervous System, Pages 325-329, Paul J. Marvar, David G. Harrison Show preview |
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Chapter 68 - Oxygen Sensing, Pages 331-333, Nanduri R. Prabhakar Show preview |
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Chapter 69 - Reactive Oxygen Species and Oxidative Stress, Pages 335-338, Rhian M. Touyz Show preview |
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Part VI: Cardiovascular Disorders Chapter 70 - Neurally Mediated Syncope, Pages 341-343, Satish R. Raj Show preview |
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Chapter 71 - Sympatho-Vagal Imbalance in Hypertension, Pages 345-348, Guido Grassi, Gino Seravalle Show preview |
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Chapter 72 - Baroreflex Failure, Pages 349-353, Jens Jordan Show preview |
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Chapter 73 - Blood Pressure Variability, Pages 355-357, Stanley Fernandez, Sirisha Srikakarlapudi, Joseph L. Izzo Show preview |
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Chapter 74 - Obesity-Associated Hypertension, Pages 359-361, Cyndya Shibao Show preview |
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Chapter 75 - Orthostatic Hypertension, Pages 363-365, David Robertson Show preview |
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Chapter 76 - Heart Failure, Pages 367-370, John S. Floras Show preview |
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Chapter 77 - Stress Cardiomyopathy and Takotsubo Syndrome, Pages 371-375, David Robertson, Kyoko Sato Show preview |
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Chapter 78 - Clinical Evaluation of Autonomic Disorders, Pages 377-382, Paola Sandroni Show preview |
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Chapter 79 - Tilt Table Studies, Pages 383-387, Satish R. Raj Show preview |
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Chapter 80 - Sympathetic Microneurography, Pages 389-392, B. Gunnar Wallin Show preview |
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Chapter 81 - Clinical Applications of Microneurography, Pages 393-397, Tadaaki Mano Show preview |
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Chapter 82 - Clinical Sympathetic Imaging, Pages 399-403, David S. Goldstein Show preview |
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Chapter 83 - Assessment of the Autonomic Control of the Cardiovascular System by a Frequency Domain Approach, Pages 405-408, Raffaello Furlan, Franca Barbic Show preview |
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Chapter 84 - Assessment of Sudomotor Function, Pages 409-411, Ronald Schondorf Show preview |
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Chapter 85 - Cutaneous Autonomic Innervation: Assessment by Skin Biopsy, Pages 413-417, Christopher H. Gibbons, Roy Freeman Show preview |
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Part VII: Catecholamine Disorders Chapter 86 - Pheochromocytoma, Pages 421-425, Graeme Eisenhofer, Jacques W.M. Lenders, William M. Manger Show preview |
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Chapter 87 - Deficiencies of Tetrahydrobiopterin, Tyrosine Hydroxylase and Aromatic L-Amino Acid Decarboxylase, Pages 427-430, Keith Hyland, Lauren A. Hyland Show preview |
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Chapter 88 - Dopamine β-Hydroxylase Deficiency, Pages 431-434, Emily M. Garland Show preview |
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Chapter 89 - Menkes Disease and Other ATP7A-Related Phenotypes, Pages 435-437, Stephen G. Kaler Show preview |
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Chapter 90 - Norepinephrine Transporter Deficiency, Pages 439-442, Maureen K. Hahn Show preview |
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Chapter 91 - Monoamine Oxidase Deficiency, Pages 443-444, Jacques W.M. Lenders, Graeme Eisenhofer Show preview |
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Chapter 92 - Congenital Central Hypoventilation Syndrome (CCHS) and PHOX2B Mutations, Pages 445-449, Debra E. Weese-Mayer, Pallavi P. Patwari, Casey M. Rand, André Diedrich, Nancy L. Kuntz, Elizabeth M. Berry-Kravis Show preview |
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Part VIII: Autonomic Synucleinopathies Chapter 93 - Multiple System Atrophy, Pages 453-457, David Robertson, Sid Gilman Show preview |
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Chapter 94 - Parkinson’s Disease, Pages 459-461, John Y. Fang, Thomas L. Davis Show preview |
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Chapter 95 - Dementia with Lewy Bodies, Pages 463-466, Sylvia Stemberger, Michaela Stampfer, Gregor K. Wenning Show preview |
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Chapter 96 - Pure Autonomic Failure, Pages 467-469, Horacio Kaufmann, Irwin J. Schatz Show preview |
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Part IX: Peripheral Autonomic Disorders Chapter 97 - Diagnostic Workup of Peripheral Neuropathies with Dysautonomia, Pages 473-475, Amanda C. Peltier Show preview |
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Chapter 98 - Diabetic Autonomic Dysfunction, Pages 477-481, Amanda C. Peltier, Stephen N. Davis Show preview |
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Chapter 99 - Amyloidotic Autonomic Failure, Pages 483-487, Yadollah Harati, Cecile L. Phan Show preview |
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Chapter 100 - Autoimmune Autonomic Ganglionopathy, Pages 489-492, Steven Vernino, Phillip A. Low Show preview |
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Chapter 101 - Guillain–Barré Syndrome, Pages 493-494, Phillip A. Low, James G. McLeod Show preview |
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Chapter 102 - Hereditary Autonomic Neuropathies, Pages 495-498, Yadollah Harati, Shahram Izadyar Show preview |
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Chapter 103 - Familial Dysautonomia (Riley–Day Syndrome), Pages 499-502, Horacio Kaufmann, Lucy Norcliffe-Kaufmann, Felicia B. Axelrod Show preview |
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Part X: Autonomic Disorders Chapter 104 - Autonomic Disturbances in Spinal Cord Injuries, Pages 505-509, Christopher J. Mathias, David A. Low Show preview |
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Chapter 105 - Drug-Induced Autonomic Dysfunction, Pages 511-514, James M. Luther Show preview |
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Part XI: Orthostatic Intolerance Chapter 106 - Postural Tachycardia Syndrome (POTS), Pages 517-519, Phillip A. Low, Paola Sandroni Show preview |
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Chapter 107 - Mechanisms of Postural Tachycardia Syndrome, Pages 521-523, Satish R. Raj Show preview |
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Chapter 108 - Symptoms and Signs of Postural Tachycardia Syndrome (POTS), Pages 525-528, Julian Stewart Show preview |
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Chapter 109 - Delayed Orthostatic Hypotension, Pages 529-530, Christopher H. Gibbons, Roy Freeman Show preview |
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Chapter 110 - Chronic Fatigue Syndrome and the Autonomic Nervous System, Pages 531-534, Luis E. Okamoto, Satish R. Raj, Italo Biaggioni Show preview |
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Chapter 111 - Joint Hypermobility Syndrome and Dysautonomia, Pages 535-537, Giris Jacob, Blair P. Grubb Show preview |
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Part XII: Special Clinical Conditions Chapter 112 - Neuroleptic Malignant Syndrome, Pages 541-544, Fenna T. Phibbs, P. David Charles Show preview |
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Chapter 113 - Migraine and the Autonomic Nervous System, Pages 545-547, Pietro Cortelli Show preview |
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Chapter 114 - Epilepsy and Autonomic Regulation, Pages 549-552, Matthias Dütsch, Max J. Hilz Show preview |
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Chapter 115 - Disorders of Sweating, Pages 553-559, Robert D. Fealey Show preview |
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Chapter 116 - Male Erectile Dysfunction, Pages 561-564, Douglas F. Milam Show preview |
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Chapter 117 - Sleep Apnea, Pages 565-569, Tomas Konecny, Virend K. Somers Show preview |
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Chapter 118 - Altered Adrenal Function and the Autonomic Nervous System, Pages 571-574, Subbulaxmi Trikudanathan, Gordon H. Williams Show preview |
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Chapter 119 - Mastocytosis, Pages 575-576, L. Jackson Roberts II Show preview |
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Chapter 120 - Cocaine Overdose, Pages 577-581, Andrew Kontak, Wanpen Vongpatanasin, Ronald G. Victor Show preview |
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Chapter 121 - Complex Regional Pain Syndrome, Pages 583-587, Wilfrid Jänig Show preview |
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Chapter 122 - Carcinoid Tumors, Pages 589-591, Kenneth R. Hande Show preview |
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Chapter 123 - Paraneoplastic Autonomic Dysfunction, Pages 593-596, Ramesh K. Khurana Show preview |
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Chapter 124 - Abdominal Pain and Cyclic Vomiting, Pages 597-600, Gisela Chelimsky, Thomas Chelimsky Show preview |
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Chapter 125 - Fecal Incontinence, Pages 601-602, James F.X. Jones Show preview |
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Part XIII: Management of Autonomic Disorders Chapter 126 - Panic Disorder, Pages 605-608, Murray Esler, Marlies Alvarenga, David Kaye, Gavin Lambert, Jane Thompson, Jacqui Hastings, Rosemary Schwarz, Margaret Morris, Jeff Richards Show preview |
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Chapter 127 - Physical Measures, Pages 609-612, Wouter Wieling, Roland D. Thijs Show preview |
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Chapter 128 - Water and the Osmopressor Response, Pages 613-615, Jens Jordan Show preview |
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Chapter 129 - Droxidopa (L-DOPS), Pages 617-620, Horacio Kaufmann Show preview |
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Chapter 130 - Midodrine, Adrenergic Agonists and Antagonists, Pages 621-625, Janice L. Gilden Show preview |
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Chapter 131 - Agents Potentiating Sympathetic Tone, Pages 627-630, Cyndya Shibao, Luis Okamoto Show preview |
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Chapter 132 - Acetylcholinesterase and its Inhibitors, Pages 631-633, Brett A. English, Andrew A. Webster Show preview |
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Chapter 133 - Fludrocortisone, Pages 635-637, David Robertson, Rose Marie Robertson Show preview |
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Chapter 134 - Acarbose, Pages 639-641, Cyndya Shibao Show preview |
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Chapter 135 - Erythropoietin in Autonomic Failure, Pages 643-644, Italo Biaggioni Show preview |
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Chapter 136 - Somatostatin Agonists, Pages 645-648, Robert Hoeldtke Show preview |
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Chapter 137 - Harnessing the Autonomic Nervous System for Therapeutic Intervention, Pages 649-652, Murray Esler Show preview |
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Chapter 138 - Acupuncture Regulation of Cardiovascular Function, Pages 653-657, John C. Longhurst Show preview |
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Chapter 139 - Bionic Baroreflex, Pages 659-662, Takayuki Sato, André Diedrich, Kenji Sunagawa Show preview |
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Part XIV: Experimental Autonomic Neuroscience Chapter 140 - Anesthetic Management in Autonomic Disorders, Pages 665-668, Chih Cherng Lu, Shung Tai Ho, Che Se Tung Show preview |
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Chapter 141 - Evolution of the Cardiovascular Autonomic Nervous System in Vertebrates, Pages 669-673, Tobias Wang Show preview |
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Chapter 142 - Human Physiome, Pages 675-680, Peter Hunter Show preview |
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Chapter 143 - Modeling the Autonomic Nervous System, Pages 681-687, Ilya A. Rybak, Yaroslav I. Molkov, Julian F.R. Paton, Ana P.L. Abdala, Daniel B. Zoccal Show preview |
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Chapter 144 - Optogenetics, Pages 689-691, Sergey Kasparov Show preview |
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Index, Pages 693-703 Show preview |
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Preface
The Primer on the Autonomic Nervous System aims to provide a concise and accessible overview of autonomic neuroscience for students, scientists, and clinicians. In spite of its compact size, its 144 chapters draw on the expertise of more than 250 scientists and clinicians. We thank the American Autonomic Society for its continued interest and moral support of this project. We especially express appreciation to our contributors, who, along with the editors, prepared their chapters without compensation in order to keep the cost of the Primer within the reach of students and trainees. We are delighted with the enthusiastic reception of the first and second English editions, and the Japanese edition of the Primer, which has sold more copies than any previous text on autonomic neuroscience. With this edition we welcome Julian F.R. Paton as a new editor. The third edition of the Primer would not have been possible without Mrs. Sonja Campbell, whose efficiency
and wisdom, combined with her mastery of lucid English prose, facilitated the preparation of this substantially enlarged edition. We also thank Mica Haley and Melissa Turner at Academic Press, who kept all of us on track and on schedule. In earlier editions, readers were encouraged to email their criticisms and advice for improving the text. We thank the many of you who took time to do just that. Several new sections and a number of clarifications based on these suggestions have been implemented. If you have comments or advice for improving future editions please send them to
[email protected].
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David Robertson Italo Biaggioni Geoffrey Burnstock Phillip A. Low Julian F.R. Paton
List of Contributors
Ana P.L. Abdala School of Physiology and Pharmacology, Bristol Heart Institute, University of Bristol, Bristol, UK David H. Adams Guggenheim Pavillion, New York, NY, USA Marlies Alvarenga Baker IDI Heart and Diabetes Institute, Melbourne, Australia Amy C. Arnold Division of Clinical Pharmacology, Vanderbilt University School of Medicine, Nashville, TN, USA Felicia B. Axelrod Professor, Pediatrics and Neurology, New York University School of Medicine, New York, NY 10016, USA Franca Barbic Neuroscience Research Association, Bolognini Hospital, Seriate (Bg), Italy Peter J. Barnes Department of Thoracic Medicine, National Heart and Lung Institute, London, UK Deborah Bauer Departments of Pediatrics and Pharmacology, Children’s Hospital of Philadelphia, University of Pennsylvania, Philadelphia, PA 19104, USA Christopher Bell Department of Health and Exercise Science, Colorado State University, Fort Collins, CO, USA Eduardo E. Benarroch Department of Neurology, Mayo Clinic, Rochester, MN, USA Elizabeth M. Berry-Kravis Professor of Pediatrics, Neurology, and Biochemistry at Rush University Medical Center, Chicago, IL 60612, USA Luciano Bernardi Clinica Medica 2 – Dipartimento Medicina Interna, IRCCS S. Matteo, Universita’ di Pavia, 27100 Pavia, Italy Italo Biaggioni Professor of Medicine and Pharmacology, Vanderbilt University, Nashville, TN 37212, USA Lori Birder University of Pittsburgh School of Medicine, Departments of Medicine and Pharmacology, Pittsburgh PA 15261, USA Virginia L. Brooks Department of Physiology and Pharmacology, Oregon Health and Science University, Portland, OR 97239, USA Joan Heller Brown Department of Pharmacology, University of California, San Diego School of Medicine, La Jolla, CA, USA Geoffrey Burnstock Autonomic Neuroscience Centre, University College Medical School, London NW3 2PF, UK Michael Camilleri Mayo Clinic, Rochester, MN, USA J. Preston Campbell Vanderbilt University Medical Center, Nashville, TN 37232, USA Robert M. Carey Division of Endocrinology, University of Virginia Health Systems, Charlottesville, VA, USA Marc G. Caron Department of Cell Biology, Duke University Medical Center, Durham, NC 27710, USA Calvin Carter Department of Neurology, University of Iowa, College of Medicine, Iowa City, IA, USA Priscila A. Cassaglia Department of Physiology and Pharmacology, Oregon Health and Science University, Portland, OR 97239, USA Javier G. Castillo Resident Physician, Department of Cardiothoracic Surgery, The Mount Sinai School of Medicine, New York, NY, USA
Primer on the Autonomic Nervous System. DOI: 10.1016/B978-0-12-386525-0.00149-9
Mark W. Chapleau Departments of Internal Medicine, and Molecular Physiology and Biophysics, University of Iowa and Veterans Affairs Medical Center, Iowa City, IA, USA Nisha Charkoudian Department of Anesthesiology and Department of Physiology, and Biomedical Engineering, Mayo Clinic, Rochester, MN, USA P. David Charles Movement Disorders Clinic, Medical Center South, Vanderbilt University, Nashville, TN, USA Gisela Chelimsky Department of Pediatrics, Rainbow Babies and Children’s Hospital, and University Hospitals Case Medical Center, Cleveland, OH 44106, USA Thomas Chelimsky Department of Neurology, University Hospitals Case Medical Center, Cleveland, OH 44106, USA Pei-Wen Cheng Department of Medical Education and Research, Kaohsiung Veterans General Hospital, Kaohsiung, Taiwan, ROC Gilles Clément International Space University, Strasbourg, France Pietro Cortelli Department of Neurological Sciences, Alma Mater Studiorum, University of Bologna, 40123 Bologna, Italy Allen W. Cowley Department of Physiology, Medical College of Wisconsin, Milwaukee, WI 53226, USA Leslie Crews Department of Pathology, University of California, San Diego/La Jolla, CA, USA Stephen N. Davis Chair, Internal Medicine, University of Maryland, Baltimore, MD, USA Thomas L. Davis Clinical Research Center, Vanderbilt University, Nashville, TN, USA William C. de Groat University of Pittsburgh School of Medicine, Departments of Medicine and Pharmacology, Pittsburgh, PA 15261, USA Vincent G. DeMarco University of Missouri, Diabetes and Cardiovascular Center, and the Harry S. Truman VA Medical Center, Columbia, MO, USA André Diedrich Autonomic Dysfunction Center, Department of Medicine and Department of Biomedical Engineering, Vanderbilt University School of Medicine, Nashville, TN, USA Donald J. DiPette Departments of Medicine (DJD), and Cell Biology and Anatomy (SCS), University of South Carolina School of Medicine, Columbia, SC 29208, USA Debra I. Diz Professor and Director, Hypertension and Vascular Research Center, Wake Forest University School of Medicine, Winston-Salem, NC 27157-1032, USA Marcus J. Drake FRCS(Urol)Bristol Urological Institute, Bristol, UK Rachel C. Drew Heart and Vascular Institute, Penn State College of Medicine, Milton S. Hershey Medical Center, Hershey, PA, USA Matthias Dütsch Department of Neurology, University of Erlangen-Nuremberg, D-91054 Erlangen, Germany, and Department of Neurology, Rummelsberg Hospital, D-90592 Schwarzenbruck, Germany Graeme Eisenhofer Department of Medicine, and Institute of Clinical Chemistry and Laboratory Medicine, University Hospital Carl Gustav Carus, Dresden, Dresden, Germany
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© 2012 Elsevier Inc. All rights reserved.
xxii
LIst of ContrIbutors
Florent Elefteriou Assistant Professor and Director Elect, Vanderbilt Center for Bone Biology, Vanderbilt University Medical Center, Nashville, TN 37232, USA Fernando Elijovich Professor of Medicine, Texas A&M HSC, College of Medicine and Center for Neuroscience, USA Brett A. English Division of Allergy, Pulmonary and Critical Care Medicine, Drug Discovery, Vanderbilt University Medical Center, Nashville, TN, USA Murray Esler Baker IDI Heart and Diabetes Institute, Melbourne, Australia John Y. Fang Assistant Professor, Department of Neurology, Vanderbilt University, Nashville, TN, USA and Staff Physician, Neurology Service, Tennessee Valley Healthcare System, Nashville, TN, USA Robert D. Fealey Department of Neurology, Mayo Clinic, Rochester, MN, USA Stanley Fernandez Department of Medicine, State University of New York at Buffalo, Buffalo, NY 14215, USA Gregory D. Fink Michigan State University, Department of Pharmacology and Toxicology, East Lansing, MI 48840, USA John S. Floras University Health Network and Mount Sinai Hospital Department of Medicine, University of Toronto, Toronto, Ont., Canada Roy Freeman Center for Autonomic and Peripheral Nerve Disorders, Beth Israel Deaconess Medical Center, Boston, MA 02215, USA Qi Fu Institute for Exercise and Environmental Medicine, Texas Health Presbyterian Hospital Dallas, The University of Texas, Southwestern Medical Center at Dallas, Dallas, TX, USA Liang-Wu Fu Department of Medicine, School of Medicine, University of California, Irvine, Irvine, CA 92697-4075, USA Raffaello Furlan Internal Medicine, Bolognini Hospital, Seriate (Bg), University of Milan, Milan, Italy Alfredo Gamboa Autonomic Dysfunction Center, Vanderbilt University, Nashville, TN, USA Emily M. Garland Division of Clinical Pharmacology, Medical Center North, Vanderbilt University, Nashville, TN, USA Christopher H. Gibbons Center for Autonomic and Peripheral Nerve Disorders, Beth Israel Deaconess Medical Center, Boston MA 02215, USA Michael P. Gilbey Department of Physiology, University College London, London, UK Janice L. Gilden Professor of Medicine, Rosalind Franklin University of Medicine and Science, James A. Lovell Federal Health Care Center, North Chicago, and Saints Mary and Elizabeth Medical Center, Chicago, IL, USA Sid Gilman Department of Neurology, 300 N. Ingalls St. 3D15, Ann Arbor, MI, USA David S. Goldstein National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892, USA Diego A. Golombek Universidad Nacional de Quilmes/ CONICET, Buenos Aires, Argentina Robert M. Graham Victor Chang Cardiac Research Institute, Darlinghurst, Sydney, NSW 2010, Australia Guido Grassi Università Milano-Bicocca, Ospedale San Gerardo, Monza (Milan), Milan, Italy, andIstituto Auxologico Italiano, Milan, Italy
Mark D. Grier Department of Pharmacology, Vanderbilt University, Nashville, TN, USA Jan T. Groothuis Department of Physiology, Radboud University Nijmegen Medical Centre, 6500 HB Nijmegen, The Netherlands, and, Department of Rehabilitation, St Maartenskliniek, 6500 GM Nijmegen, The Netherlands Blair P. Grubb Recanati Autonomic Dysfunction Center, Tel Aviv University, Faculty of Medicine, Tel-Aviv 64239, Israel Maureen K. Hahn Department of Medicine and Pharmacology, Vanderbilt University School of Medicine, Nashville, TN 37232, USA Julian P.J. Halcox Professor of Cardiology, Cardiff University School of Medicine, Wales Heart Research Institute, Cardiff, CF14 4XN, UK Robert W. Hamill Department of Neurology, University of Vermont, College of Medicine, Burlington, VT, USA Kenneth R. Hande Division of Medical Oncology, Preston Research Building, Nashville, TN, USA Yadollah Harati Department of Neurology, Baylor College of Medicine, Houston, TX, USA David G. Harrison Department of Psychiatry, Vanderbilt University School of Medicine, Nashville, TN, USA Emma C. Hart Department of Anesthesiology, Mayo Clinic, Rochester, MN, USA Jacqui Hastings Baker IDI Heart and Diabetes Institute, Melbourne, Australia Luke A. Henderson Department of Anatomy and Histology, University of Sydney, Sydney, Australia Max J. Hilz Department of Neurology, University of ErlangenNuremberg, D-91054 Erlangen, Germany, and Departments of Neurology, Medicine, Psychiatry, New York University School of Medicine, New York, NY 10016, USA Robert Hoeldtke Division of Endocrinology, West Virginia University, Morgantown, WV, USA Shung Tai Ho Graduate Institute of Medical Science, National Defense Medical Center, Taipei, Taiwan, ROC Peter Hunter Auckland Bioengineering Institute, University of Auckland, New Zealand Keith Hyland Department of Neurochemistry, Medical Neurogenetics, Atlanta, GA, USA Lauren Hyland Department of Neurochemistry, Medical Neurogenetics, Atlanta, GA, USA Shahram Izadyar Department of Neurology, Baylor College of Medicine, Houston, TX, USA Joseph L. Izzo Department of Medicine, State University of New York at Buffalo, Buffalo, NY 14215, USA Edwin K. Jackson University of Pittsburgh School of Medicine, Department of Pharmacology and Chemical Biology, Pittsburgh, PA 15219, USA Giris Jacob Head of Medicine F, Recanati Autonomic Dysfunction Center, Tel Aviv (Sourasky) Medical Center, Tel Aviv University, Faculty of Medicine, Tel-Aviv 64239, Israel Wilfrid Jänig Physiologisches Institut, Christian-AlbrechtsUniversität zu Kiel, Kiel, Germany Megan S. Johnson University of Missouri, Diabetes and Cardiovascular Center, Columbia, MO, USA Carrie K. Jones Department of Pharmacology, and Center for Neuroscience Drug Discovery, Vanderbilt University Medical Center, Nashville, TN, USA James F.X. Jones School of Medicine and Medical Sciences, University College Dublin, Ireland
I. INTRODUCTION
LIst of ContrIbutors
Karen M. Joos Vanderbilt Eye Institute, Vanderbilt University Medical Center, Nashville, TN, USA Jens Jordan Institute of Clinical Pharmacology, Hannover Medical School, Hannover, Germany Jens Jordan Institute of Clinical Pharmacology, Hannover Medical School, 30625 Hannover, Germany Michael J. Joyner Department of Anesthesiology, Mayo Clinic, Rochester, MN, USA Stephen G. Kaler Program in Molecular Medicine, NICHD, Bethesda, Maryland 20892-1853, USA Sergey Kasparov Professor of Molecular Physiology, University of Bristol, Bristol, BS8 1TD, UK Horacio Kaufmann Professor, Neurology, Pediatrics and Medicine, New York University School of Medicine, New York, NY 10016, USA Horacio Kaufmann New York University School of Medicine, New York, NY 10016, USA David Kaye Baker IDI Heart and Diabetes Institute, Melbourne, Australia Ramesh K. Khurana Division of Neurology, Union Memorial Hospital, Baltimore, MD, USA Chun-Hyung Kim Department of Psychiatry, Harvard Medical School, Boston, MA, USA Kwang-Soo Kim Department of Psychiatry, Harvard Medical School, Boston, MA, USA Kazuto Kobayashi Department of Molecular Genetics, Institute of Biomedical Sciences, Fukushima Medical University School of Medicine, Fukushima 960-1295, Japan Nancy L. Kuntz Associate Professor of Pediatrics, Northwestern University Feinberg School of Medicine, Center for Autonomic Medicine in Pediatrics at CMH, Chicago, IL 60614, USA Tomas Konecny Assistant Professor of Medicine, Department of Cardiovascular Diseases and Internal Medicine, Mayo Clinic, Rochester, MN, USA, and ICRC – Department of Cardiovascular Diseases, St Anne’s University Hospital Brno, Brno, Czech Republic Andrew Kontak Division of Cardiology/Hypertension Section, University of Texas Southwestern Medical Center, Dallas, TX, USA Cheryl L. Laffer Associate Professor of Medicine, Texas A&M HSC College of Medicine, USA Andre H. Lagrange Assistant Professor of Neurology, Epilepsy Division, Vanderbilt University, Nashville, TN, USA Nora Laiken Department of Pharmacology, University of California, San Diego School of Medicine, La Jolla, CA, USA Gavin Lambert Baker IDI Heart and Diabetes Institute, Melbourne, Australia Jacques W.M. Lenders Department of Internal Medicine, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands, and Department of Medicine, University Hospital Carl Gustav Carus Dresden, Dresden, Germany Benjamin D. Levine Institute for Exercise and Environmental Medicine, Texas Health Presbyterian Hospital Dallas, The University of Texas, Southwestern Medical Center at Dallas, Dallas, TX, USA Lewis A. Lipsitz Institute for Aging Research, Hebrew Senior Life; Division of Gerontology, Beth Israel Deaconess Medical Center; Harvard Medical School, Boston, MA, USA Julian H. Lombard Department of Physiology, Medical College of Wisconsin, Milwaukee, WI 53226, USA
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John C. Longhurst Departments of Medicine, Physiology and Biophysics, Pharmacology and Biomedical Engineering, University of California, Irvine, Irvine, CA 92697-4075, USA David A. Low Autonomic and Neurovascular Medicine Unit, Faculty of Medicine, Imperial College London at St Mary’s Hospital London, WZ1NY, UK Phillip A. Low Department of Neurology, Mayo Foundation, Rochester, MN 55905, USA Chih Cherng Lu, MD,MS Department of Anaesthesiology, Departments of Tri-Service General Hospital/National Defense Medical Center, Taipei, Taiwan, ROC James M. Luther Division of Clinical Pharmacology, Departments of Medicine and Pharmacology, Vanderbilt University, Nashville, TN, USA Vaughan G. Macefield Professor of Integrative Physiology, School of Medicine, University of Western Sydney, NSW 1797, Australia Belinda H. McCully Department of Physiology and Pharmacology, Oregon Health and Science University, Portland, OR 97239, USA James G. McLeod Department of Medicine, University of Sydney, Sydney, Australia William M. Manger New York University Medical Center, and National Hypertension Association, New York, NY, USA Tadaaki Mano Tokai Central Hospital, Kakamigahara, Gifu, Japan Paul J. Marvar Department of Psychiatry, and Center of Behavioral Sciences, Vanderbilt University School of Medicine, Nashville, TN, USA Eliezer Masliah University of California-San Diego, La Jolla, CA 92093-0624, USA Christopher J. Mathias Autonomic and Neurovascular Medicine Unit, Faculty of Medicine, Imperial College London at St Mary’s Hospital London, WZ1NY, UK and Autonomic Unit, National Hospital for Neurology and Neurosurgery, Queen Square/Institute of Neurology, University College London, London, UK Mark R. Melson Vanderbilt Eye Institute, Vanderbilt University Medical Center, Nashville, TN, USA Douglas F. Milam Department of Urologic Surgery, Vanderbilt University, Nashville, TN, USA Marion C. Mohl Victor Chang Cardiac Research Institute, Darlinghurst, Sydney, NSW, 2010, Australia Yaroslav I. Molkov Department of Neurobiology and Anatomy, Drexel University College of Medicine, Philadelphia, PA, USA Margaret Morris Baker IDI Heart and Diabetes Institute, Melbourne, Australia Shaun F. Morrison Department of Neurological Surgery, Oregon Health and Science University, Portland, OR 97239, USA Toshiharu Nagatsu Department of Pharmacology, School of Medicine, Fujita Health University, Toyoake 470-1192, Japan Charles D. Nichols Department of Pharmacology, LSU Health Sciences Center, New Orleans, LA, USA Lucy Norcliffe-Kaufmann Instructor, Physiology and Neuroscience, New York University School of Medicine, New York, NY 10016, USA Vera Novak Division of Gerontology, Beth Israel Deaconess Medical Center;, Harvard Medical School, Boston, MA, USA Luis E. Okamoto Department of Medicine, Division of Clinical Pharmacology, and the Autonomic Dysfunction Center, Vanderbilt University School of Medicine, Nashville, TN, USA
I. INTRODUCTION
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LIst of ContrIbutors
John W. Osborn University of Minnesota, Department of Integrative Biology and Physiology, Minneapolis, MN 55455, USA Brian A. Parsons Bristol Urological Institute, Southmead Hospital, Bristol, UK Julian F.R. Paton School of Physiology and Pharmacology, Bristol Heart Institute, University of Bristol, Bristol, BS8 1TD, UK Pallavi P. Patwari Assistant Professor of Pediatrics, Northwestern University Feinberg School of Medicine, and Assistant Director, Center for Autonomic Medicine in Pediatrics at CMH, Chicago, IL 60614, USA Cecile L. Phan Department of Neurology, Baylor College of Medicine, Houston, TX, USA Fenna T. Phibbs Department of Neurology, Vanderbilt University Medical Center, Nashville, TN, USA Nanduri R. Prabhakar Institute for Integrative Physiology, and Center for Systems Biology of O2 Sensing, Biological Sciences Division, University of Chicago, IL, USA Amanda C. Peltier Department of Neurology, Division of Neuromuscular, Vanderbilt University, Nashville, TN, USA Sean M. Peterson Department of Cell Biology, Duke University Medical Center, Durham, NC 27710, USA Anthony E Pickering School of Physiology and Pharmacology, Bristol Heart Institute, University of Bristol, Bristol, BS8 1TD, UK J. Howard Pratt Department of Medicine, Indiana University School of Medicine, Indianapolis, IN, USA Kamal Rahmouni University of Iowa, Cardiovascular Center, Iowa City, IA, USA Satish R. Raj Autonomic Dysfunction Unit, Division of Clinical Pharmacology, Departments of Medicine and Pharmacology, Vanderbilt University, Nashville, TN, USA Casey M. Rand Center for Autonomic Medicine in Pediatrics at CMH, Chicago, IL 60614, USA Heinz Reichmann Department of Neurology, University Hospital Carl Gustav Carus Dresden, Dresden, Germany Jeff Richards Baker IDI Heart and Diabetes Institute, Melbourne, Australia L.Jackson Roberts Division of Clinical Pharmacology, Robinson Research Building, Vanderbilt University, Nashville, TN, USA David W. Robertson Vanderbilt University, Nashville, TN, USA Rose Marie Robertson Vanderbilt University, Nashville, TN, USA Michael Robinson Departments of Pediatrics and Pharmacology, Children’s Hospital of Philadelphia, University of Pennsylvania, Philadelphia, PA 19104, USA Ilya A. Rybak Department of Neurobiology and Anatomy, Drexel University College of Medicine, Philadelphia, PA, USA Elaine Sanders-Bush Department of Pharmacology, Vanderbilt University, Nashville, TN, USA Paola Sandroni Deptartment of Neurology, Mayo Clinic, Rochester, MN, USA Kyoko Sato Department of Cardiovascular Control, Kochi Medical School, Nankoku, Japan Takayuki Sato Department of Cardiovascular Control, Kochi Medical School, Japan Irwin J. Schatz John A. Burns School of Medicine, University of Hawaii at Manoa, Department of Medicine, Honolulu, HI, USA
Ernesto L. Schiffrin Department of Medicine, Sir Mortimer B. Davis-Jewish General Hospital, and Lady Davis Institute for Medical Research, McGill University, Montreal, Que., Canada. Ronald Schondorf Department of Neurology, Sir Mortimer B. Davis Jewish General Hospital, Montreal, QC, Canada Rosemary Schwarz Baker IDI Heart and Diabetes Institute, Melbourne, Australia Gino Seravalle Istituto Auxologico Italiano, Milan, Italy. Robert E. Shapiro Department of Neurology, University of Vermont College of Medicine, Burlington, VT, USA Cyndya Shibao Department of Medicine, Division of Clinical Pharmacology, and the Autonomic Dysfunction Center,Vanderbilt University School of Medicine, Nashville, TN, USA Virend Somers Professor of Medicine, Department of Cardiovascular Diseases and Internal Medicine, Mayo Clinic, Rochester, MN, USA Michaela Stampfer Movement Disorders Section, Department of Neurology, University Hospital, Innsbruck, Austria C.Michael Stein Division of Clinical Pharmacology, Vanderbilt University School of Medicine, Nashville, TN 37232, USA Sylvia Stemberger Division of Clinical Neurobiology, Innsbruck Medical University, Innsbruck, Austria Julian Stewart New York Medical College, Hawthorne, NY, USA Lawrence I. Sinoway Pennsylvania State University College of Medicine, Milton S. Hershey Medical Center, Hershey, PA, USA James R. Sowers University of Missouri, Diabetes and Cardiovascular Center, and the Harry S. Truman VA Medical Center, Columbia, MO, USA Sirisha Srikakarlapudi Department of Medicine, State University of New York at Buffalo, Buffalo, NY 14215, USA Kenji Sunagawa Department of Cardiovascular Medicine, Kyushu University Graduate School of Medical Sciences, Japan Scott C. Supowit Departments of Medicine (DJD), and Cell Biology and Anatomy (SCS), University of South Carolina School of Medicine, Columbia, SC 29208, USA Palmer Taylor Department of Pharmacology, University of California, La Jolla, CA, USA Jane Thompson Baker IDI Heart and Diabetes Institute, Melbourne, Australia Roland D. Thijs Department of Neurology and Clinical Neurophysiology, Leiden University Medical Centre, 2300 RC Leiden, The Netherlands and Department of Neurology, Dutch Epilepsy Clinics Foundation, 2300 RC Hoofddorp, the Netherlands Rhian M Touyz Kidney Research Centre, Ottawa Hospital Research Institute, University of Ottawa, Ottawa, Ont., Canada Daniel Tranel Department of Neurology, University of Iowa, College of Medicine, Iowa City, IA, USA Subbulaxmi Trikudanathan Endocrinology, Diabetes and Hypertension Division, Brigham and Women’s Hospital, and, Harvard Medical School, Boston, MA, USA Ching-Jiunn Tseng Department of Medical Education and Research, Kaohsiung Veterans’ General Hospital, Kaohsiung, Taiwan, ROC Che-Se Tung Department of Physiology, National Defense Medical Center, Taipei, Taiwan, ROC Kiren Ubhi Department of Neurosciences, University of California, San Diego/La Jolla, CA, USA
I. INTRODUCTION
LIst of ContrIbutors
Nikhil Urs Department of Cell Biology, Duke University, Durham, NC 27710, USA Joseph G. Verbalis Georgetown University, Washington, DC 20007, USA Steven Vernino Department of Neurology, UT Southwestern Medical Center, Dallas, TX 75390-9036, USA Ronald G. Victor Hypertension Center, The Heart Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA Margaret A. Vizzard University of Vermont College of Medicine, Burlington, VT, USA Wanpen Vongpatanasin Division of Cardiology/Hypertension Section, University of Texas Southwestern Medical Center, Dallas, TX, USA B. Gunnar Wallin Institute of Neuroscience and Physiology, Sahlgrenska Academy at Göteborg University, S-41345 Göteborg, Sweden Tobias Wang Zoophysiology, Department of Biological Sciences, Aarhus University, Denmark Qin Wang Department of Physiology and Biophysics, University of Alabama at Birmingham, Birmingham, AL, USA Andrew A. Webster Professor and Chair, Department of Pharmaceutical Sciences, Belmont University School of Pharmacy, Nashville, TN, USA
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Debra E. Weese-Mayer Professor of Pediatrics, Northwestern University Feinberg School of Medicine, and Director, Center for Autonomic Medicine in Pediatrics, at Children’s Memorial Hospital (CMH), Chicago, IL 60614, USA Gregor K. Wenning Movement Disorders Section, Department of Neurology, University Hospital, Innsbruck, Austria Adam Whaley-Connell University of Missouri, Diabetes and Cardiovascular Center, and the Harry S. Truman VA Medical Center, Columbia, MO, USA Wouter Wieling Department of Internal Medicine, Academic Medical Centre, 1105 AZ Amsterdam, The Netherlands Gordon H. Williams Endocrinology, Diabetes and Hypertension Division, Brigham and Women’s Hospital, and, Harvard Medical School, Boston, MA, USA Scott Wood Universities Space Research Association, Houston, TX, USA Michael G. Ziegler UCSD Medical Center, San Diego, CA, USA Daniel B. Zoccal Department of Physiological Sciences, Center of Biological Sciences, Federal University of Santa Catarina, Florianópolis, Santa Catarina, Brazil
I. INTRODUCTION
PA R T I
INTRODUCTION
Primer on the Autonomic Nervous System. DOI: 10.1016/B978-0-12-386525-0.00001-9
© 2012 Elsevier Inc. All rights reserved.
C H A P T E R
1 Development and Differentiation of Autonomic Neurons Chun-Hyung Kim, Kwang-Soo Kim increasing the sympathetic outflow to the heart and other viscera, the parasympathetic system is responsible for the basal autonomic functions such as heart rate and respiration under normal conditions. The enteric system regulates peristalsis of the gut wall and modulates the activity of the secretary glands. During the last decade, exciting progress has been made with regard to the molecular mechanisms underlying the development of the ANS. Among many different aspects, this review will focus primarily on the transcriptional regulatory code underlying the development and neurotransmitter identity determination of the ANS.
An intricate network of extracellular signals and nuclear transcription factors orchestrates the specification of numerous neuronal phenotypes during development of the vertebrate nervous system. During the last decade or so, impressive progress has been achieved in identifying the extracellular signaling molecules and key transcription factors that critically govern the development and fate determination of the autonomic nervous system (ANS). In particular, the so-called “transcriptional regulatory code” underlying the development and differentiation of the ANS has been elucidated; several key fatedetermining transcription factors such as Mash1, Phox2, AP2 and GATA3, have been identified to be responsible for development of the autonomic nervous system and the neurotransmitter identity specification. One important emerging feature is that those key transcription factors regulate not only development, but also final properties of differentiated neurons such as neurotransmitter identity. In line with this concept, those factors directly or indirectly regulate the expression of both cell type-specific markers as well as pan-neuronal markers. Second, these transcription factors function in an intricate regulatory cascade, starting from key signaling molecules such as bone morphogenic proteins. Finally, as evidenced by the study of dopamine β-hydroxylase gene regulation, multitudes of cell type-specific factors (e.g., Phox2a and 2b) and general transcription factors (e.g., CREB and Sp1) co-operatively regulate the expression of cell type-specific marker genes. This new molecular information will facilitate our understanding of the function of the autonomic nervous system in the normal, as well as in the diseased brain.
THE ANS IS DERIVED FROM NEURAL CREST CELLS During the early developmental period of vertebrate embryo, the neural tube and notochord are formed from the ectodermal and mesodermal layers, respectively. At this time, neural crest cells originate from the dorsolateral edge of the neural plate, and are generated at the junction of the neural tube and the ectoderm (Fig. 1.1). Interactions between the non-neural ectodermal layer and the neural plate critically influence the formation of neural crest cells at their interface [1]. Upon formation, neural crest cells migrate along specific routes to diverse destinations and differentiate into a variety of cell types that include all neurons and glial cells of the peripheral nervous system and the neurons of the gastric mucosal plexi. In addition, some other cell types such as smooth muscle cells, pigment cells, and chromatophores are known to arise from neural crest cells. Much progress has recently been achieved in the identification of signaling molecules and downstream transcription factors that control lineage determination and differentiation of neural crest cells [2,3].
INTRODUCTION The autonomic nervous system (ANS; also called the autonomic division or the autonomic motor system) is one of two major divisions of the peripheral nervous system. The ANS has three major subdivisions that are spatially segregated: the sympathetic, the parasympathetic, and the enteric nervous systems. While the sympathetic system controls the fight-or-flight reactions during emergencies by
Primer on the Autonomic Nervous System. DOI: 10.1016/B978-0-12-386525-0.00001-9
SIGNALING MOLECULES REGULATE THE DEVELOPMENTAL PROCESSES OF THE ANS Recent studies have demonstrated that various signaling molecules, e.g., members of the bone morphogenic
3
© 2012 Elsevier Inc. All rights reserved.
4
1. DEvElOPmENT AND DIffERENTIATION Of AUTONOmIC NEURONs
development, while its robust activation opposes, even in the presence of BMP-2, SA cell development and the expression of SA lineage-determining genes [9]. Finally, during the last decade, numerous studies demonstrated that different neurotrophic factors such as NGF, GDNF, NT3, and/or their receptor signaling, critically regulate the survival and development of all three divisions of the ANS [10,11].
Neural plate Ectodermis Mesoderm
TRANSCRIPTIONAL REGULATORY CODE UNDERLYING THE DEVELOPMENT AND PHENOTYPIC SPECIFICATION OF THE ANS Notochord
Neural crest
Neural tube
Somite Dorsal aorta
FIGURE 1.1 All cell types of the ANS are derived from neural crest cells. Neural crest cells are formed at the dorsal neural tube and migrate along diverse routes. Depending on their specific routes and interactions with the target tissues, they differentiate into a variety of cell types including pigment cells, different types of neurons and glia of the ANS, and parts of the adrenal gland.
protein (BMP) family, Wnt, sonic hedgehog, and fibroblast growth factor, play critical roles in the early formation of neural crest cells as well as for final determination of neuronal identity [1–5]. These signals are often provided from neighboring tissues during migration of neural crest cells. For instance, grafting and ablation experiments in chick embryos demonstrate that the notochord is necessary but not sufficient to induce adrenergic phenotypes of neural crest-derived sympathetic ganglia [6,7]. A possible candidate for notochord-derived molecule(s) is sonic hedgehog [7]. In addition, a series of elegant experiments established that BMP family members, expressed from the dorsal aorta, play a crucial role in the differentiation and fate determination of the sympathetic nervous system [8 and references therein]. It is of note that these extracellular signaling molecules seem to work in concert with intracellular signals such as cAMP. Consistent with this, using neural crest cell culture, induction of differentiation and neurotransmitter phenotypes by BMP is enhanced by cAMP-elevating agents [4,9]. Interestingly, it appears that cAMP signaling acts as a bimodal regulator of sympathoadrenal (SA) cell development in neural crest cultures because its moderate activation promotes SA cell
Various transcription factors are thought to trigger a regulatory cascade by inducing the expression of downstream transcription factors, which eventually activate or repress the final target genes [4,12]. The regulatory cascade controlling the ANS’s noradrenergic neurotransmitter phenotype has been extensively studied, leading to the identification and functional characterization of critical transcription factors (Fig. 1.2). For example, the basic helix-loop-helix (bHLH) factor, Mammalian achaete-scute homolog-1 (Mash1, and the chicken homolog Cash1) induced by BMPs is the first transcription factor shown to be essential for noradrenergic neuron development. Downstream of Mash1 lies the homeodomain transcription factor Phox2a which is a critical regulator of noradrenergic cell lineage development. A closely related transcription factor Phox2b is also induced by BMPs independently of Mash1 and is another essential regulator of noradrenergic neuron development. In addition, GATA2/3 and dHand play critical roles for noradrenergic neuron development. Recent work from our laboratory showed that AP2β may critically regulate NA neuron development in the ANS. Specific functional roles of these key transcription factors in the development of the ANS have been identified as shown below (Fig. 1.2).
Mash1 (also called Cash1) Mash1, a basic helix-loop-helix (bHLH) protein, is the first transcription factor shown to be essential for development of the ANS. In Mash1/ mice, virtually all noradrenaline (NA) neurons of the nervous system are affected, suggesting that Mash1 is a critical factor for determining the NA fate. Mash1 appears to relay BMP molecules’ signals for sympathetic development. Consistent with this idea, Mash1 expression was induced by BMPs in neural crest cultures and it was largely diminished in sympathetic ganglia following inhibition of BMPs function [13]. In Mash1-inactivated mouse embryos, neural crest cells migrated to the vicinity of the dorsal aorta, but did not develop into mature sympathetic neurons, as evidenced by the lack of expression of tyrosine hydroxylase (TH) and dopamine β-hydroxylase (DBH), as well as the absence of pan-neuronal markers [14]. In addition,
I. INTRODUCTION
TRANsCRIPTIONAl REgUlATORy CODE UNDERlyINg THE DEvElOPmENT AND PHENOTyPIC sPECIfICATION Of THE ANs
cAMP
whereas Phox2a expression is regulated by both Mash1 and Phox2b (Fig. 1.2). Recent promoter studies showed that Phox2a and 2b are able to directly activate the DBH promoter by interacting with multiple sequence motifs residing in the 5 flanking region (see below). Collectively, Phox2a and 2b appear to regulate both the development and neurotransmitter identity of sympathetic neurons and of other noradrenergic neurons.
BMPs
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FIGURE 1.2 Diagrams depicting the regulatory network of the NA phenotype determination and maintenance. The diagram shows the possible regulatory interactions in the cascade of development and NA phenotype expression of ANS neurons. Thick arrows indicate likely direct regulation and thin arrows indicate direct or indirect regulation. BMPs are secreted from the dorsal aorta and activate the expression of MASH1/CASH1 and Phox2b. Phox2b then activates the expression of Phox2a. Phox2a and/or Phox2b in turn activate neurotransmitterspecifying genes TH and DBH. Direct action of Phox2a/2b on DBH transcription has been demonstrated. The transcription factor CREB has been shown to interact with the 5 promoter and directly activates transcription of the TH and DBH genes. The cAMP signaling pathway appears to regulate NA phenotype determination in concert with Phox2a/2b. The zinc finger factor GATA3, presumably downstream of Phox2b, also appears to be required for expression of NA-specific genes. Phox2a and 2b also regulate the expression of pan-neuronal genes including the GDNF receptor c-Ret, which may relate to their role in formation and/or survival of ANS neurons.
Mash1 directly or indirectly affects the expression of Phox2a, another key transcription factor important for DBH gene expression in a noradrenergic neuron-specific manner [15–17]. Thus, Mash1 is the first transcription factor known to control both differentiation and maintenance of noradrenergic neurons [18].
Phox2 Genes Phox2a and Phox2b are two closely related homeodomain transcription factors that are expressed in virtually all neurons that transiently or permanently express the noradrenergic neurotransmitter phenotype [19]. Gene inactivation studies have demonstrated that Phox2a and/or 2b are essential for proper development of all three divisions of the ANS and some noradrenergic containing structures of the CNS. For instance, in both Phox2a/ and 2b/ mouse brain, the major noradrenergic population in the locus coeruleus does not form, strongly suggesting that both genes are required for its development [20,21]. In contrast, only Phox2b seems to be required for the development of sympathetic neurons. In Phox2a/ mice, sympathetic neuron development is largely normal. Interestingly, however, both genes are able to induce sympathetic neuron-like phenotype when ectopically expressed in chick embryos [22]. During sympathetic development, Phox2b expression is induced by BMP molecules independently of Mash1,
The zinc finger transcription factor GATA-3 is a master regulator of type 2 T helper cell development. Interestingly, in GATA-3/ mice, noradrenaline deficiency is a proximal cause of embryonic lethality suggesting that GATA-3 is involved in the specification of noradrenergic neurotransmitter phenotype during noradrenergic neuron development [23]. Forced expression of GATA-3 in primary neural crest stem cell (NCSC) culture and developing chick embryos demonstrated that GATA-3 is able to increase the number of sympathoadrenergic neurons among NCSC culture, and induce ectopic expression of noradrenergic marker genes (TH and DBH) in developing chick embryos [24]. Furthermore, both TH and DBH promoters are robustly transactivated by GATA-3 via specific upstream subdomains encompassing binding motifs for transcription factors CREB, Sp1, and AP4. Protein–protein interaction assays showed that GATA-3 is able to physically interact with these transcription factors in vitro as well as in vivo [25]. Taken together, it is likely that GATA3 plays a critical role for specification of the NA phenotype via novel and distinct protein-protein interactions in both CNS and ANS development.
AP2(Activator Protein 2)β AP2 is a retinoic acid-inducible and developmentally regulated transcription factor with the basic helix-span-helix domain recognizing the palindromic 5-GCCNNNGGC-3 motif or its related GC-rich sequences. AP-2 family has 5 members, AP-2α, AP-2β, AP-2γ, AP-2δ, and AP-2, which show different spatiotemporal expression patterns during development. Based on its expression pattern in the neural crest, it was assumed that AP-2α regulates differentiation of neural crest-derived cells. However, our recent works demonstrated that AP2β is expressed in sympathetic ganglia of developing chick and mouse embryos and facilitates sympathoadrenergic differentiation in neural crest stem cells, while AP2α dramatically increases melanocytes at the expense of sympathoadrenergic cells [26,27]. Lossof-function studies of AP2β/ mouse revealed that DBH expression was significantly reduced in sympathetic ganglia as well as LC, indicating distinctive roles in neural crest differentiation and noradrenergic neurotransmitter specification in both central and peripheral nervous systems. Furthermore, these studies showed that AP2β directly controls the epinephrine phenotype by activating the
I. INTRODUCTION
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1. DEvElOPmENT AND DIffERENTIATION Of AUTONOmIC NEURONs
phenylethanolamine-N-methyl-transferase (PNMT) gene expression (Fig. 1.2).
Other Transcription Factors Although the above transcription factors are the most promising candidates, additional factors are emerging as being important for the ANS’ development and phenotype specification. For instance, dHand is another bHLH transcription factor whose expression is induced by BMPs and is dependent on Mash1. Based on its specific expression in sympathetic neurons, dHand may directly contribute to the ANS development. However, analysis of dHand function was hampered because knockout mice die before sympathetic neuron development. It is worthwhile to note that transcriptional regulation of the ANS and phenotype identity may require the combinatorial action of cell type-specific factors (e.g., Phox2a and 2b) and general transcription factors. Such examples may include cAMP response element binding protein and Sp1, which are required for transcriptional activity of both the TH and DBH genes (see below).
NEUROTRANSMITTER PHENOTYPES OF THE ANS Among the various phenotypes of a particular neuron, neurotransmitter identity is an essential feature because it determines the nature of the chemical neurotransmission a given neuron will mediate, and influences its specific connectivity with target cells. For specification of neurotransmitter identity, given neurons should express relevant genes encoding the biosynthetic enzymes and cofactors, as well as the specific reuptake protein(s). In addition, expression of these genes needs to be matched with the appropriate receptors of the target tissues. Therefore, expression of particular neurotransmitter phenotypes should be coordinated with the differentiation and phenotype specification of the target tissues. Recently, molecular mechanisms underlying the specification of neurotransmitters in the nervous system have been investigated extensively and key signaling molecules and transcriptional factors have been identified. Among these, specification of the noradrenaline (NA) phenotype of the sympathetic nervous system and the CNS is well characterized. Therefore, we will focus our discussion on the molecular characterization of the NA phenotype determination and its phenotypic switch to the cholinergic phenotype.
NA Phenotype NA is a major neurotransmitter of the ANS, especially in sympathetic neurons, and fundamentally mediates the function of the ANS. Consistent with this, a rare human disease called the dopamine β-hydroxylase deficient disease, in which NA is undetectable, was identified to be associated with severe autonomic function failure [28].
NA is one of the catecholamine neurotransmitters that are synthesized from tyrosine by three consecutive enzymatic steps. While tyrosine hydroxylase is responsible for the first step of catecholamine biosynthesis, converting tyrosine to L-dopa, and is expressed in all catecholamine neurons, dopamine β-hydroxylase (DBH) is responsible for conversion of dopamine to NA and is specifically expressed in NA neurons. Thus, DBH is a hallmark protein of NA neurons and the control mechanism of its expression is an essential feature of the development of NA neurons.
Control Mechanism of DBH Gene Expression is Closely Related to the ANS Development Numerous investigators using both in vivo transgenic mouse approaches and in vitro cell culture systems have studied DBH gene regulation. As schematically summarized in Figure 1.3, the 5 1.1 kb region upstream of the DBH gene promoter has three functional domains that can drive reporter gene expression in a NA cell type-specific manner. More detailed deletional and sitedirected mutational analyses indicate that as little as 486 bp of the upstream sequence of the human DBH gene can direct expression of a reporter gene in a cell-specific manner [29]. While the distal region spanning 486 to 263 bp appears to have a cell-specific silencer function, the proximal part spanning 262 to 1 bp is essential for high-level and cell-specific DBH promoter activity. In this 262 bp proximal area, four protein-binding regions (domains I to IV), initially identified by DNase I footprinting analysis, were found to encompass functionally important, multiple cis-regulatory elements [29], including the cAMP response element (CRE), YY1, AP2, Sp1, and core motifs of homeodomain (HD) binding sites. Site-directed mutagenesis of each sequence motif has revealed that these multiple cis-acting elements synergistically and/ or co-operatively regulate the transcriptional activity of the DBH gene [16]. Among these, two ATTA-containing motifs in domain IV and another motif in domain II were identified to be NA-specific cis-acting motifs in that their mutation diminished the DBH promoter function only in NA cell lines. More recently, another NA-specific cisregulatory element was identified between domain II and III (Fig. 1.3). Interestingly, analysis of DNA-protein interactions on the DBH promoter demonstrated that all of these four NA-specific cis-regulatory elements are Phox2binding sites [15]. Taken together, this experimental evidence establishes that the DBH gene is an immediate downstream target of Phox2 proteins.
Mutations of DBH Gene are Closely Associated with the Autonomic Disorder, Orthostatic Hypotension DBH deficiency is a rare congenital disorder, first described in 1986 [28,30]. DBH deficiency is a severe autonomic disorder exhibiting sympathetic noradrenergic
I. INTRODUCTION
NEUROTRANsmITTER PHENOTyPEs Of THE ANs DBH deficiency
Normal
nucleus
nucleus
ER X
L-tyrosine
L-tyrosine
L-DOPA
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dopamine
dopamine
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FIGURE 1.3 Effects of pathogenic mutations on DBH synthesis and trafficking. In normal, DBH enzymes (circle) are translated in the ER, transported to the Golgi, and then packaged into the LDCVs. In LDCV, DBH converts dopamine (triangle) to noradrenaline (rectangle). Noradrenaline are released by exocytosis upon stimulation of the nerve terminal and readily detectable in plasma. In DBH deficiency, DBH proteins (S-shape) encoded by missense mutations are retained in the ER and fail to be targeted to the LDCV due to their misfolding. As the result, noradrenaline is not synthesized in LDCV, leading to absence of noradrenaline in plasma. Instead, dopamine is dramatically increased.
failure and adrenomedullary failure but intact vagal and sympathetic cholinergic function [31]. DBH deficient patients exhibit severe deficits in autonomic regulation of cardiovascular function predisposing them to orthostatic hypotension. These patients display characteristic perturbations in the level of catecholamines: undetectable noradrenaline and its metabolites, and highly elevated dopamine and its metabolites. Given the fundamental role of noradrenaline in the nervous system, the report of adult patients with undetectable noradrenaline is both surprising and interesting. The report of frequent miscarriages and spontaneous abortions in mothers of known DBH deficiency cases suggests the interesting possibility that there could be many more undiagnosed fetal and neonatal deaths resulting from DBH deficiency and that those adult patients are lucky survivors [30]. In line with this, a DBH knock out mouse study showed less than 5% live births [32]. Mortality appeared to be due to cardiovascular failure caused by DBH deficiency in utero, which is reminiscent of tyrosine hydroxylase null mice. We, and others, have recently reported a mutation in the splice donor site of the first exon-intron junction and several missense mutations associated with the DBH deficiency syndrome in the DBH gene of these patients [33–35]. The mutation in the splice donor site (IVS1 2T→C) of DBH resulted in abnormal mRNA splicing and generated a transcript containing a premature stop codon as well as
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a normal transcript. Interestingly, all missense mutations so far identified in DBH deficient patients are subtle amino acid substitutions resulting in defective protein trafficking and mislocation, probably due to protein misfolding (Fig. 1.3) [35]. One of the well-known chemical chaperones, glycerol, could partially rescue defective secretion of DBH mutant proteins, suggesting the possibility that DBH deficiency disease could be more fundamentally treated with pharmacological chaperones [35].
Cholinergic Phenotype and the Switch of Neurotransmitter Phenotypes by Target Cell Interactions Another major neurotransmitter of the ANS is acetylcholine, and neurons generating this neurotransmitter are designated cholinergic. Among sympathetic neurons, the number of cholinergic neurons is much less than NA neurons. While differentiation and cholinergic specification are extensively investigated in central motor neurons [4], development of cholinergic ANS neurons is not well characterized. Therefore, it is of great interest to understand if key transcription factors such as HB9 and MNR2, likewise play key roles in determining the cholinergic phenotype during development of the ANS. Interestingly, it is well described that upon contacting developing sweat glands, the NA phenotype of sympathetic axons switches to the cholinergic phenotype [10]. The putative cholinergic-inducing factor secreted from sweat glands remains to be defined although leukemia inhibitory factor and ciliary neurotrophic factor are candidates. Consistent with the observation that TH and DBH expression remains even after neurotransmitter switch from the NA to the cholinergic phenotype, a recent study reported that levels of the TH cofactor, tetrahydrobiopterin (BH4), dropped significantly during the switch [36]. Immunoreactivity for the BH4-synthesizing GTP cyclohydrolase became undetectable in sweat gland neurons during this phenotypic switch, suggesting that suppression of cofactor expression underlies the neurotransmitter switch during development.
Acknowledgements This work was supported by NIH grants (MH048866, MH087903, and NS070577).
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[4] Edlund T, Jessell TM. Progression from extrinsic to intrinsic signaling in cell fate specification: a view from the nervous system. Cell 1999;96:211–24. [5] Wilson SI, Rydstrom A, Trimborn T, Willert K, Nusse R, et al. The status of Wnt signalling regulates neural and epidermal fates in the chick embryo. Nature 2001;411:325–30. [6] Stern CD, Artinger KB, Bronner-Fraser M. Tissue interactions affecting the migration and differentiation of neural crest cells in the chick embryo. Development 1991;113:207–16. [7] Ernsberger U, Rohrer H. The development of the noradrenergic transmitter phenotype in postganglionic sympathetic neurons. Neurochem Res 1996;21:823–9. [8] Schneider C, Wicht H, Enderich J, Wegner M, Rohrer H. Bone morphogenetic proteins are required in vivo for the generation of sympathetic neurons. Neuron 1999;24:861–70. [9] Bilodeau ML, Boulineau T, Hullinger RL, Andrisani OM. Cyclic AMP signaling functions as a bimodal switch in sympathoadrenal cell development in cultured primary neural crest cells. Mol Cell Biol 2000;20:3004–14. [10] Francis NJ, Landis SC. Cellular and molecular determinants of sympathetic neuron development. Annu Rev Neurosci 1999;22:541–66. [11] Taraviras S, Pachnis V. Development of the mammalian enteric nervous system. Curr Opin Genet Dev 1999;9:321–7. [12] Goridis C, Brunet JF. Transcriptional control of neurotransmitter phenotype. Curr Opin Neurobiol 1999;9:47–53. [13] Goridis C, Rohrer H. Specification of catecholaminergic and serotonergic neurons. Nat Rev Neurosci 2002;3:531–41. [14] Guillemot F, Lo LC, Johnson JE, Auerbach A, Anderson DJ, et al. Mammalian achaete-scute homolog 1 is required for the early development of olfactory and autonomic neurons. Cell 1993;75:463–76. [15] Seo H, Hong SJ, Guo S, Kim HS, Kim CH, et al. A direct role of the homeodomain proteins Phox2a/2b in noradrenaline neurotransmitter identity determination. J Neurochem 2002;80:905–16. [16] Kim HS, Seo H, Yang C, Brunet JF, Kim KS. Noradrenergic-specific transcription of the dopamine beta-hydroxylase gene requires synergy of multiple cis-acting elements including at least two Phox2abinding sites. J Neurosci 1998;18:8247–60. [17] Yang C, Kim HS, Seo H, Kim CH, Brunet JF, et al. Paired-like homeodomain proteins, Phox2a and Phox2b, are responsible for noradrenergic cell-specific transcription of the dopamine betahydroxylase gene. J Neurochem 1998;71:1813–26. [18] Hirsch MR, Tiveron MC, Guillemot F, Brunet JF, Goridis C. Control of noradrenergic differentiation and Phox2a expression by MASH1 in the central and peripheral nervous system. Development 1998;125:599–608. [19] Brunet JF, Pattyn A. Phox2 genes - from patterning to connectivity. Curr Opin Genet Dev 2002;12:435–40. [20] Morin X, Cremer H, Hirsch MR, Kapur RP, Goridis C, et al. Defects in sensory and autonomic ganglia and absence of locus coeruleus in mice deficient for the homeobox gene Phox2a. Neuron 1997;18:411–23. [21] Pattyn A, Goridis C, Brunet JF. Specification of the central noradrenergic phenotype by the homeobox gene Phox2b. Mol Cell Neurosci 2000;15:235–43.
[22] Stanke M, Junghans D, Geissen M, Goridis C, Ernsberger U, et al. The Phox2 homeodomain proteins are sufficient to promote the development of sympathetic neurons. Development 1999;126:4087–94. [23] Lim KC, Lakshmanan G, Crawford SE, Gu Y, Grosveld F, et al. Gata3 loss leads to embryonic lethality due to noradrenaline deficiency of the sympathetic nervous system. Nat Genet 2000;25:209–12. [24] Hong SJ, Huh Y, Chae H, Hong S, Lardaro T, et al. GATA-3 regulates the transcriptional activity of tyrosine hydroxylase by interacting with CREB. J Neurochem 2006;98:773–81. [25] Hong SJ, Choi HJ, Hong S, Huh Y, Chae H, et al. Transcription factor GATA-3 regulates the transcriptional activity of dopamine betahydroxylase by interacting with Sp1 and AP4. Neurochem Res 2008;33:1821–31. [26] Hong SJ, Lardaro T, Oh MS, Huh Y, Ding Y, et al. Regulation of the noradrenaline neurotransmitter phenotype by the transcription factor AP-2beta. J Biol Chem 2008;283:16860–16867. [27] Hong SJ, Huh YH, Leung A, Choi HJ, Ding Y, et al. Transcription factor AP-2b regulates the neurotransmitter phenotype and maturation of chromaffin cells. Mol Cell Neurosci 2011;46:245–51. [28] Robertson D, Goldberg MR, Onrot J, Hollister AS, Wiley R, et al. Isolated failure of autonomic noradrenergic neurotransmission. Evidence for impaired beta-hydroxylation of dopamine. N Engl J Med 1986;314:1494–7. [29] Seo H, Yang C, Kim HS, Kim KS. Multiple protein factors interact with the cis-regulatory elements of the proximal promoter in a cellspecific manner and regulate transcription of the dopamine betahydroxylase gene. J Neurosci 1996;16:4102–12. [30] Man in’t Veld AJ,, Boomsma F, Moleman P, Schalekamp MA. Congenital dopamine-beta-hydroxylase deficiency. A novel orthostatic syndrome. Lancet 1987;1:183–8. [31] Biaggioni I, Goldstein DS, Atkinson T, Robertson D. Dopaminebeta-hydroxylase deficiency in humans. Neurology 1990;40:370–3. [32] Thomas SA, Matsumoto AM, Palmiter RD. Noradrenaline is essential for mouse fetal development. Nature 1995;374:643–6. [33] Kim CH, Zabetian CP, Cubells JF, Cho S, Biaggioni I, et al. Mutations in the dopamine beta-hydroxylase gene are associated with human norepinephrine deficiency. Am J Med Genet 2002;108:140–7. [34] Deinum J, Steenbergen-Spanjers GC, Jansen M, Boomsma F, Lenders JW, et al. DBH gene variants that cause low plasma dopamine beta hydroxylase with or without a severe orthostatic syndrome. J Med Genet 2004;41:e38. [35] Kim CH, Leung A, Huh YH, Yang E, Kim DJ, et al. Norepinephrine deficiency is caused by combined abnormal mRNA processing and defective protein trafficking of dopamine b-hydroxylase. J Biol Chem 2011;286:9196–9204. [36] Habecker BA, Klein MG, Sundgren NC, Li W, Woodward WR. Developmental regulation of neurotransmitter phenotype through tetrahydrobiopterin. J Neurosci 2002;22:9445–52.
I. INTRODUCTION
C H A P T E R
2 Central Autonomic Control Eduardo E. Benarroch Central control of the sympathetic and parasympathetic outputs involves several interconnected areas distributed throughout the neuraxis. This central autonomic network has a critical role in moment-to-moment control of visceral function, homeostasis, and adaptation to internal or external challenges. The functions of the central autonomic network are organized in four hierarchical levels that are closely interconnected: spinal, bulbopontine, pontomesencephalic and forebrain levels (Fig. 2.1). The spinal level mediates segmental sympathetic or sacral parasympathetic reflexes and is engaged in stimulus-specific patterned responses under the influence of the other levels. The bulbopontine (lower brainstem) level is involved in reflex control of circulation, respiration, gastrointestinal function, and micturition. The pontomesencephalic (upper brainstem) level integrates autonomic control with pain modulation and integrated behavioral responses to stress. The forebrain level includes the hypothalamus, which is involved in integrated control of autonomic and endocrine responses for homeostasis and adaptation, and components of the anterior limbic circuit, including the insula, anterior cingulate cortex, and amygdala, which are involved in integration of bodily sensation with emotional and goal-related autonomic responses.
sympathetic and parasympathetic outputs, primarily via a relay in the lateral hypothalamus [4,5].
Anterior Cingulate Cortex The anterior cingulate cortex is interconnected with the anterior insula and is subdivided into ventral (affective) and dorsal (cognitive) regions [6]. The ventral anterior cingulate is part of the brain “default mode network” whereas the dorsal anterior cingulate is a component of the frontoparietal attention networks. The ventral anterior cingulate cortex includes subcallosal and precallosal portions that have extensive connections with the insula, prefrontal cortex, amygdala, hypothalamus, and brain stem. Via these projections, the anterior cingulate cortex controls sympathetic and parasympathetic functions [7].
Amygdala The amygdala provides affective or emotional value to incoming sensory information [8] and has multiple downstream targets that participate in the autonomic and neuroendocrine response to stress [9]. The central nucleus of the amygdala (CeA), both directly and via the bed nucleus of the stria terminalis, has a major role in integration of the stress responses, particularly fear responses, via its widespread connections with the hypothalamus and brainstem, particularly the periaqueductal gray and the medullary reticular formation [10].
FOREBRAIN COMPONENTS The forebrain regions involved in the control of autonomic functions include the insular cortex, anterior cingulate cortex, amygdala, and several areas of the hypothalamus.
Hypothalamus The hypothalamus integrates autonomic and endocrine responses necessary for homeostasis and adaptation. It acts as a visceromotor pattern generator that initiates specific patterns of autonomic and endocrine responses according to the stimulus, such as hypoglycemia, changes in blood temperature or osmolarity, or external stressors [2,11]. The preoptic-hypothalamic area is functionally subdivided into three functional zones, periventricular, medial, and lateral [11]: The periventricular zone includes the suprachiasmatic nucleus (the circadian pacemaker), and several areas involved in neuroendocrine control via the pituitary gland. The medial zone includes the medial
Insular Cortex The insular cortex is the primary interoceptive cortex and integrates visceral, pain and temperature sensations [1,2]. The dorsal insula has a viscerotropic organization [3] and receives inputs from gustatory, visceral, muscle, and skin receptors via the thalamus. The dorsal insula projects to the right anterior insula, which, via its connections with neocortical association and limbic areas, integrates these interoceptive inputs with emotional and cognitive processing to conveys the conscious experience of bodily sensation [1]. The insula is also a visceromotor area controlling both the
Primer on the Autonomic Nervous System. DOI: 10.1016/B978-0-12-386525-0.00002-0
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© 2012 Elsevier Inc. All rights reserved.
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2. CEnTRAl AuTonomIC ConTRol
FIGURE 2.1 Central autonomic control areas and levels of interaction of autonomic control.
preoptic area, paraventricular nucleus (PVN) and dorsomedial nucleus (DMH), which orchestrate coordinated autonomic and endocrine outputs for thermoregulation, osmoregulation, and stress responses [11–14]. The lateral zone includes nuclei that control sleep, arousal and motivated behavior [2]. The main autonomic outputs of the hypothalamus originate from the PVN, DMH, and lateral hypothalamic area [2]. The PVN contains different neuronal populations that are differentially activated during stress responses [12]. They include magnocellular neurons that release arginine-vasopressin (AVP) to the general circulation; neurons that release corticotropin releasing hormone and activate the adrenocortical axis, and neurons that project to autonomic nuclei of the brainstem and spinal cord [12]. Via these outputs, the PVN modulates stress responses, food and sodium intake, glucose metabolism, and cardiovascular, renal, gastrointestinal, and respiratory functions. The DMH participates in stress responses [13]; thermoregulation [14,15] and cardiovascular control [16].
Hypocretin/orexin neurons of the posterior lateral hypothalamus contribute to control autonomic output in the setting of arousal, feeding and reward driven behaviors [2].
BRAINSTEM COMPONENTS The brainstem areas controlling autonomic output include the periaqueductal gray matter of the midbrain (PAG), the parabrachial nucleus (PBN) and several medullary regions, including the nucleus of the solitary tract (NTS), ventrolateral reticular formation of the medulla, and medullary raphe (Fig. 2.1).
Periaqueductal Gray The PAG is the interface between the forebrain and the lower brain stem and has a major role in integrated autonomic and somatic responses to stress, pain modulation,
I. INTRODUCTION
AuTonomIC ouTPuT of THE CEnTRAl nERvous sysTEm
and other adaptive functions. It consists of different longitudinal columns that, via their different spinal, brainstem, and cortical connections, participate in cardiovascular responses associated with pain modulation [17]; coordination of the micturition reflex [18]; and control of respiration.
Parabrachial Complex and Adjacent Regions of the Pons The PBN is a major relay center that receives converging visceral, nociceptive and thermoreceptive inputs from the spinal cord and conveys this information to the hypothalamus, amygdala, and thalamus [2]. The PBN also participates in the control of respiratory, cardiovascular, and gastrointestinal functions. The dorsal pontine tegmentum also contains the pontine micturition center (PMC), also referred to as Barrington nucleus or M- (for medial) region, which is critical for the coordination of the micturition reflex and participates in the control of the function of the lower gastrointestinal tract and sexual organs [18].
Nucleus of the Solitary Tract The NTS is the first relay station of taste and visceral afferent information and includes several subnuclei with a viscerotropic organization. The rostral portion of the NTS receives taste inputs; the intermediate portion receives gastrointestinal afferents; and the caudal portion receives baroreceptor, cardiac, chemoreceptor, and pulmonary afferents [19]. The NTS relays this information, either directly or via the PBN, to rostral brainstem and forebrain areas [2,3]. The NTS is also the first central relay for all medullary reflexes controlling cardiovascular function (baroreflex and cardiac reflexes) [20], respiration (carotid chemoreflex and pulmonary mechanoreflexes), and gastrointestinal motility [21].
Rostral Ventrolateral Medulla The rostral ventrolateral medulla (RVLM), including the C1 group of epinephrine-containing neurons, is a key area for regulation of arterial blood pressure [20,21]. Glutamatergic neurons of the RVLM project directly and provide tonic excitation to sympathetic preganglionic neurons controlling cardiac output and total peripheral resistance [15]. The RVLM mediates all reflexes controlling arterial blood pressure, including the baroreflex, cardiopulmonary reflexes, and chemoreflexes [20,22]. The sympathoexcitatory RVLM neurons receive and integrate a large variety of inputs from the brainstem and forebrain [22]. These include inhibitory signals from baroreceptorsensitive neurons of the NTS and mediated via inhibitory gamma-aminobutyric acid (GABA) ergic neurons of the caudal ventrolateral medulla [22]. The RVLM also receives several inputs from the hypothalamus, including the PVN.
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Caudal Ventrolateral Medulla The caudal ventrolateral medulla contains GABAergic neurons that maintain a tonic inhibitory control on the RVLM and relay the inhibitory inputs from the NTS mediating the sympathoinhibitory component of the arterial baroreflex. Electrical stimulation studies indicate that the caudal medulla also contains pressor regions [23]. The caudal ventrolateral medulla also contains the A1 group of neurons that provide noradrenergic innervation to the hypothalamus and are a component of a reflex pathway that triggers AVP release in response to hypovolemia or hypotension [24].
Ventromedial Medulla and Caudal Raphe The rostral ventromedial medulla including the caudal raphe nuclei, has an important role in thermoregulation [15] pain modulation [17], and control of automatic ventilation [25]. One group of medullary raphe neurons initiate sympathetic responses to cold via input to preganglionic sympathetic neurons that activate skin vasoconstriction and non-shivering thermogenesis in the brown adipose tissue [26].
AUTONOMIC OUTPUT OF THE CENTRAL NERVOUS SYSTEM Sympathetic Preganglionic Units The sympathetic output is critical for maintenance of arterial pressure, thermoregulation, and redistribution of regional blood flow during stress and exercise. The sympathetic output originates from sympathetic preganglionic neurons located in the thoracolumbar spinal cord at the T1 to -L2 segments, primarily in the intermediolateral cell column. These neurons are organized into functionally separate units that innervate selective subpopulations of sympathetic ganglion neurons and receive distinct segmental afferent inputs triggering segmental somato- and viscerosympathetic reflexes [27]. Different preganglionic sympathetic units are recruited in a coordinated fashion by premotor neurons in the brainstem and hypothalamus to initiate different patterns of responses to specific internal or external stressors, such as postural changes, exercise, hypoglycemia, dehydration, exposure to heat or cold, or stress [2]. The main sources of premotor sympathetic innervation are the RVLM, medullary raphe, A5 noradrenergic group of the pons; PVN, and lateral hypothalamic area [4,28].
Parasympathetic Outputs In contrast to the sympathetic system, which mediates stimulus-specific patterns of responses affecting multiple effectors; the parasympathetic system mediates reflexes activated in an organ-specific fashion.
I. INTRODUCTION
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2. CEnTRAl AuTonomIC ConTRol
Vagal Output The vagal output originates from preganglionic neurons located in the dorsal motor nucleus of the vagus (DMV) and in the ventrolateral portion of the nucleus ambiguus (NAmb) in the medulla. The DMV contains most of the vagal preganglionic parasympathetic neurons that are organized in a viscerotropic fashion [29] and innervate the local ganglia in the respiratory tract, enteric nervous system (ENS), liver and pancreas. The DMV receives inputs from the NTS and mediates all vago-vagal reflexes controlling gastrointestinal motility and secretion [21]. Vagal preganglionic neurons located in the ventrolateral portion of the NAmb provide the primary control of the heart via the cardiac ganglia [30]. These cardiovagal outputs inhibit the automatism of the sinoatrial node exerting a beat-to-beat control of the heart rate. The cardiovagal NAMb neurons are activated by the NTS during the baroreflex and are inhibited during inspiration. Sacral Parasympathetic Output The sacral preganglionic output originates in neurons located in the lateral gray matter at the S2-S4 segments of the sacral spinal cord [31]. These neurons are critical for normal micturition, defecation, and sexual organs; this involves their coordinated interactions with both lumbar sympathetic neurons located at T12-L2 levels and somatic motor neurons of the Onuf nucleus at the S2-S4 levels innervating the external urinary sphincter and pelvic floor.
References [1] Craig AD. Interoception: the sense of the physiological condition of the body. Curr Opin Neurobiol 2003;13:500–5. [2] Saper CB. The central autonomic nervous system: conscious visceral perception and autonomic pattern generation. Annu Rev Neurosci 2002;25:433–69. [3] Cechetto DF. Central representation of visceral function. Fed Proc 1987;46:17–23. [4] Loewy AD. Descending pathways to the sympathetic preganglionic neurons. Prog Brain Res 1982;57:267–77. [5] Westerhaus MJ, Loewy AD. Central representation of the sympathetic nervous system. 2001 [6] Vogt BA, Vogt L, Farber NB, Bash E, et al. Architecture and neurocytology of monkey cingulate gyrus. J Comp Neurol 2005;485:218–39. [7] Verberne AJ, Owens NC. Cortical modulation of the cardiovascular system. Prog Neurobiol 1998;54:149–68. [8] LeDoux J. The amygdala. Curr Biol 2007;17:R868–874. [9] Ulrich-Lai YM, Herman JP. Neural regulation of endocrine and autonomic stress responses. Nat Rev Neurosci 2009;10:397–409. [10] Davis M. The role of the amygdala in fear and anxiety. Annu Rev Neurosci 1992;15:353–75. [11] Thompson RH, Swanson LW. Structural characterization of a hypothalamic visceromotor pattern generator network. Brain Res Brain Res Rev 2003;41:153–202.
[12] Sawchenko PE, Li HY, Ericsson A. Circuits and mechanisms governing hypothalamic responses to stress: a tale of two paradigms. Prog Brain Res 2000;122:61–78. [13] Dimicco JA, Zaretsky DV. The dorsomedial hypothalamus: a new player in thermoregulation. Am. J Physiol Regul Integr Comp Physiol 2007;292:R47–63. [14] Yoshida K, Li X, Cano G, et al. Parallel preoptic pathways for thermoregulation. J Neurosci 2009;29:11954–11964. [15] Morrison SF. RVLM and raphe differentially regulate sympathetic outflows to splanchnic and brown adipose tissue. Am J Physiol 1999;276:R962–973. [16] Dampney RA, Horiuchi J, McDowall LM. Hypothalamic mechanisms coordinating cardiorespiratory function during exercise and defensive behavior. Auton Neurosci 2008. [17] Bandler R, Keay KA, Floyd N, et al. Central circuits mediating patterned autonomic activity during active vs. passive emotional coping. Brain Res Bull 2000;53:95–104. [18] Holstege G. Micturition and the soul. J Comp Neurol 2005;493:15–20. [19] Jean A. The nucleus tractus solitarius: neuroanatomic, neurochemical and functional aspects. Arch Int Physiol Biochim Biophys 1991;99:A3–52. [20] Dampney RA, Horiuchi J. Functional organisation of central cardiovascular pathways: studies using c-fos gene expression. Prog Neurobiol 2003;71:359–84. [21] Travagli RA, Hermann GE, Browning KN, Rogers C, et al. Brainstem circuits regulating gastric function. Annu Rev Physiol 2006;68:279–305. [22] Guyenet PG. The sympathetic control of blood pressure. Nat Rev Neurosci 2006;7:335–46. [23] Goodchild AK, Moon EA. Maps of cardiovascular and respiratory regions of rat ventral medulla: focus on the caudal medulla. J Chem Neuroanat 2009;38:209–21. [24] Lightman SL, Todd K, Everitt BJ. Ascending noradrenergic projections from the brainstem: evidence for a major role in the regulation of blood pressure and vasopressin secretion. Exp Brain Res 1984;55:145–51. [25] Corcoran AE, Hodges MR, Wu Y, Wang W, Wylie CJ, Deneris ES, Richerson S, et al. Medullary serotonin neurons and central CO2 chemoreception. Respir. Physiol Neurobiol 2009;168:49–58. [26] Morrison SF, Nakamura K, Madden CJ. Central control of thermogenesis in mammals. Exp Physiol 2008;93:773–97. [27] Janig W, Habler HJ. Neurophysiological analysis of target-related sympathetic pathways – from animal to human: similarities and differences. Acta Physiol Scand 2003;177:255–74. [28] Strack AM, Sawyer WB, Hughes JH, Platt KB, Lavey AD, et al. A general pattern of CNS innervation of the sympathetic outflow demonstrated by transneuronal pseudorabies viral infections. Brain Res. 1989;491:156–62. [29] Huang XF, Tork I, Paxinos G. Dorsal motor nucleus of the vagus nerve: a cyto- and chemoarchitectonic study in the human. J Comp Neurol 1993;330:158–82. [30] Hopkins DA, Armour JA. Brainstem cells of origin of physiologically identified cardiopulmonary nerves in the rhesus monkey (Macaca mulatta). J Auton Nerv Syst 1998;68:21–32. [31] Birder L, de Groat W, Mills I, Morrison J, Thor K, Drake M, et al. Neural control of the lower urinary tract: peripheral and spinal mechanisms. Neurourol Urodyn 29:128–39.
I. INTRODUCTION
C H A P T E R
3 Imaging of Brainstem Sites Involved in Cardiovascular Control Vaughan G. Macefield, Luke A. Henderson The medulla is phylogenetically the oldest structure of the brain, containing dense clusters of neurons (nuclei) that coordinate many homeostatically critical functions, such as respiration, heart rate and blood pressure. Much of what we know of the functions of the medulla we have learnt from experiments in anesthetized or decerebrate animals. And, although its small size makes it difficult to study its function in awake humans, it is possible to use non-invasive neuroimaging approaches to delineate some of its nuclei. We shall limit our discussion to the control of arterial pressure, in which most of the work has been carried out. The maintenance of blood pressure within a relatively narrow physiological range is essential to ensure adequate perfusion of vital organs such as the brain. A primary determinant of arterial pressure is the level of sympathetically-mediated vasoconstriction within skeletal muscle. Muscle sympathetic nerve activity (MSNA) occurs as pulse-synchronous bursts, the incidence and magnitude of which are inversely correlated to diastolic pressure. The beat-to-beat control of arterial pressure is governed by the baroreflex – a classic negative-feedback loop in which increases in blood pressure, detected by the arterial baroreceptors (located in the carotid sinus and aortic arch), are corrected by withdrawal of muscle vasoconstrictor drive as well as decreases in heart rate and stroke volume. This short-term regulation of blood pressure survives removal of structures rostral to the medulla yet is abolished by transection of the spinal cord immediately below the medulla, indicating that the medulla contains structures critical for the generation and maintenance of vasomotor tone.
produce increases in activity in cutaneous sympathetic neurons yet no increase in blood pressure [1]. It is known from intracellular recordings from RVLM neurons that they exhibit an irregular tonic firing that decreases with increases in blood pressure and increases with decreases in blood pressure; it is also known that this tonic activity is modified by excitatory and inhibitory inputs, but that in the absence of such inputs this tonic activity continues [2]. The current understanding of the baroreflex circuitry defined primarily in anesthetized animal preparations – is that primary afferent axons from the baroreceptors project to the caudal region of the nucleus tractus solitarius (NTS), where they synapse onto second-order neurons, which in turn send excitatory (glutamatergic) projections onto GABAregic neurons within the region of the caudal ventrolateral medulla (CVLM). These CVLM GABAergic neurons synapse directly onto excitatory neurons within the RVLM and serve to inhibit the spontaneous activity of RVLM premotor sympathetic neurons. Nucleus ambiguus and the dorsal motor nucleus of the vagus also receive glutamatergic projections from NTS [3], activating vagal cardiac efferents and slowing the heart. In addition to these components of the basic baroreflex arc, it is known that other brainstem regions, such as the caudal pressor area (CPA), located in the most caudal part of the ventrolateral medulla, can also influence baroreflex activity by altering the activity in these baroreflex medullary nuclei [2]. Studies in conscious animals, using c-fos expression as a marker of neuronal activation, have confirmed the operation of the NTS-CVLM-RVLM serial pathway during maneuvers that increase or decrease arterial pressure [4,5].
IDENTIFICATION OF MEDULLARY CARDIOVASCULAR NUCLEI IN EXPERIMENTAL ANIMALS
IDENTIFICATION OF MEDULLARY CARDIOVASCULAR NUCLEI IN HUMANS
The circuitry responsible for the baroreflex has been examined in detail in anesthetized experimental animals. Early work had shown that excitation within discrete regions of the rostral ventrolateral medulla (RVLM) could activate muscle vasoconstrictor neurons and increase blood pressure, while activation within other areas could
Non-invasive neuroimaging has become a powerful tool in defining the functions of various regions in the human brain, but relatively little work has been done in cardiovascular control (for review see [6]). Most of the recent studies in this area use functional magnetic resonance imaging (fMRI), in which changes in blood-oxygen
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FIGURE 3.1 Significant BOLD signal intensity changes in the medulla and cerebellum, obtained from the brainstem-specific scans (n 15) overlaid onto an average T2-weighted anatomical image set. Ventral is at the base of each image. The hot and cool color scales (coded for t-value) indicate regional signal increases and decreases, respectively. Slice positions (MNI space) are indicted in the top right of each image. To the right are three graphs showing the mean (SEM) percent changes in signal intensity (SI) over time for three significant clusters. Vertical grey boxes indicate each of the three inspiratory-capacity apnea periods. From Macefield et al. (2006) [8].
level dependent (BOLD) signal intensity are used as a proxy marker of neuronal activity: increases in signal intensity reflect increases in neuronal activity, while decreases reflect deactivations. Such approaches have been used in the anesthetized cat to identify changes in signal intensity within the medullary regions described above [7], but relatively few studies have applied fMRI to investigate the role of the brainstem in human cardiovascular control. One of the first investigations to do so used the Valsalva maneuver – a forced expiratory effort which evokes a stereotypical pattern of autonomic changes. The virtue in using this maneuver is that the changes in heart rate and arterial pressure are well known, with the increase in arterial pressure being brought about by an increase in muscle sympathetic nerve activity (MSNA). Significant changes in BOLD signal intensity occurred in the amygdala, hippocampus, insular and lateral frontal cortices, as well as in the dorsal pons, dorsal medulla, lentiform nucleus, and fastigial and dentate nuclei of the cerebellum [7]. This was one of the first studies to have attempted to identify the functional roles of the human brainstem in autonomic control, but the fact that the Valsalva maneuver is a complex, volitionally generated task makes it difficult to tease out elements related to motor planning, execution, sensory feedback and autonomic changes. A simpler maneuver, the inspiratory-capacity apnea – a maximal inspiratory
FIGURE 3.2 Left panel, axial sections of the brainstem during a series of inspiratory-capacity apneas, showing bilateral activation of the dorsolateral medulla. Data from Macefield et al. (2006) [8]. Right panel, axial sections of the human brainstem showing a high density of AngII binding in RVLM. Data reproduced with permission from Allen et al. (1988) [9]. See color plate at back of the book.
breath-hold – evokes a sustained increase in MSNA that is believed to be due primarily to unloading of the low-pressure baroreceptors. During the static phase of the maneuver, in which the inspiratory pump muscles are quiescent and only the laryngeal constrictors are active, intrathoracic pressure changes because of the elastic recoil of the lungs and chest wall against the closed glottis. This is different to the Valsalva maneuver, in which the diaphragm, abdominal and intercostal muscles are co-activated in a sustained effort that increases intra-abdominal and intrathoracic pressures. Like the Valsalva maneuver,
I. INTRODUCTION
IdEnTIfICATIon of mEdullARy CARdIovASCulAR nuClEI In HumAnS
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FIGURE 3.3 Significant increases (warm color scale) and decreases (cool color scale) in BOL1D signal intensity within the brainstem correlated with MSNA total burst activity in the resting state; raw fMRI data from seven experiments. Equivalent histological sections are shown on the right. Figure from Macefield and Henderson (2010) [12].
the inspiratory-capacity apnea evokes discrete changes in BOLD signal intensity over multiple brain regions. Significant increases in BOLD signal intensity occur bilaterally in the lateral prefrontal cortex, anterior insular cortex, anterior cingulate cortex, dorsomedial hypothalamus and deep cerebellar nuclei; decreases in signal intensity occur in the hippocampus, posterior cingulate cortex and the cerebellar cortex [8]. As shown in the sagital and axial sections of the human brainstem in Figure 3.1, bilateral increases in activity also occur in the rostral lateral medulla, with decreases occurring in the dorsomedial and caudal lateral medulla. We believe the increases in the rostral lateral medulla reflect increases in activity of the RVLM. In humans, the RVLM and CVLM are displaced dorsally by the large inferior olivary nuclei [9]. The functional and anatomical localization of the human RVLM is illustrated in Figure 3.2: the left panel shows a bilateral increase in signal intensity during a maximal inspiratory breath-hold; the right panel shows the anatomical identification of the human RVLM, based on histochemical identification [9]. While McAllen and colleagues have functionally identified the medullary raphé nucleus during whole-body cooling [10], until recently no human fMRI studies had functionally identified NTS. As indicated in the right panel of Figure 3.2, the solitary tract nucleus is located dorsal and medial to the RVLM. We believe the decreases in signal intensity in the dorsomedial medulla reflect decreases in NTS, with the decreases in the caudal lateral medulla reflecting
decreases in neuronal activity in the CVLM. These responses can be explained by (i) the reduction of baroreceptor inputs to the NTS; (ii) a consequent reduction in activity of CVLM; and hence (iii) a reduction in inhibitory drive to the RVLM. The withdrawal of inhibitory drive to RVLM then allows this nucleus to increase its activity and thereby bring about an increase in MSNA. Sustained increases in MSNA can also be induced by static handgrip exercise and post-exercise ischemia: accumulation of the metabolites of contraction activates metaboreceptors within the muscle and induces a reflex increase in MSNA and arterial pressure. It is known that metaboreceptors project to the NTS, which sends excitatory projections to the RVLM without an intervening inhibitory synapse: increases in BOLD signal intensity occurred in discrete regions of the human medulla corresponding to the NTS and RVLM, but did not include CVLM [11]. A recent development has been concurrent microneurography and fMRI. By recording spontaneous bursts of MSNA and correlating these to spontaneous fluctuations in BOLD signal intensity it has been possible to functionally identify regions of the brainstem involved in the generation of spontaneous MSNA [12]. Analysis of the temporal coupling between BOLD signal intensity and nerve signal intensity revealed sites in which the two signals covaried, but these sites were limited to the medulla. The advantage of this approach is that maneuvers, with all of the associated confounds, need not be performed. As shown in Figure 3.3, increases in MSNA were associated
I. INTRODUCTION
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3. ImAgIng of BRAInSTEm SITES InvolvEd In CARdIovASCulAR ConTRol
with bilateral increases in signal intensity in the rostral lateral medulla that corresponds to the human equivalent of the RVLM. There was also a unilateral (left) increase in activity in the area that corresponds to the caudal pressor area (CPA). Reciprocal decreases in signal intensity occurred in the dorsomedial region of NTS and in CVLM, though on average the latter appeared to be limited to the right side. Although not illustrated here, increases in signal intensity also occurred in the medullary raphé and in the region that includes the dorsal motor nucleus of the vagus. The use of this approach promises to increase our understanding of the functional organization of the medulla and changes in sympathetic outflow that are associated with many pathophysiological states.
References [1] McAllen RM, May CN, Shafton AD. Functional anatomy of sympathetic premotor cell groups in the medulla. Clin Exp Hypertens 1995;17:209–21. [2] Dampney RA, Polson JW, Potts PD, Hirooka Y, Horiuchi J. Functional organization of brain pathways subserving the baroreceptor reflex: studies in conscious animals using immediate early gene expression. Cell Mol Neurobiol 2003;23:597–616. [3] Wang J, Irnaten M, Neff RA, Venkatesan P, Evans C, Loewy AD, et al. Synaptic and neurotransmitter activation of cardiac vagal neurons in the nucleus ambiguus. Ann N Y Acad Sci 2001;940:237–46. [4] Minson JB, Llewellyn-Smith IJ, Arnolda LF, Pilowsky PM, Chalmers JP. C-fos expression in central neurons mediating the arterial baroreceptor reflex. Clin Exp Hypertens 1997;19:631–43.
[5] Horiuchi J, Killinger S, Dampney RA. Contribution to sympathetic vasomotor tone of tonic glutamatergic inputs to neurons in the RVLM. Am J Physiol 2004;287:R1335–43. [6] Critchley HD, Nagai Y, Gray MA, Mathias CJ. Dissecting axes of autonomic control in humans: insights from neuroimaging. Auton Neurosci. 2011;161:34–42. [7] Henderson LA, Richard CA, Macey PM, Runquist ML, Yu PL, Galons JP, et al. Functional magnetic resonance signal changes in neural structures to baroreceptor reflex activation. J Appl Physiol 2004;96:693–703. [8] Macefield VG, Gandevia SC, Henderson LA. Neural sites involved in the sustained increase in muscle sympathetic nerve activity induced by inspiratory-capacity apnea – a fMRI study. J Appl Physiol 2006;100:266–73. [9] Allen AM, Moeller I, Jenkins TA, Zhuo J, Aldred GP, Chai SY, Mendelsohn FA. Angiotensin receptors in the nervous system. Brain Res Bull 1998;47:17–28. [10] McAllen RM, Farrell M, Johnson JM, Trevaks D, Cole L, McKinley MJ, et al. Human medullary responses to cooling and rewarming the skin: a functional MRI study. Proc Nat Acad Sci USA 2006;103:809–13. [11] Sander M, Macefield VG, Henderson LA. Cortical and brainstem changes in neural activity during static handgrip and post-exercise ischemia in humans. J Appl Physiol 2010;108:1691–700. [12] Macefield VG, Henderson LA. Real-time imaging of the medullary circuitry involved in the generation of spontaneous muscle sympathetic nerve activity in awake subjects. Human Brain Mapp 2010;31:539–59.
I. INTRODUCTION
C H A P T E R
4 Peripheral Autonomic Nervous System Robert W. Hamill, Robert E. Shapiro, Margaret A. Vizzard are paired structures that are located bilaterally along the vertebral column. They extend from the superior cervical ganglia (SCG), located rostrally at the bifurcation of the internal carotid arteries, to ganglia located in the sacral region. All told, there are three cervical ganglia (the SCG, middle cervical ganglion, and inferior cervical ganglion, which is usually termed the cervicothoracic or stellate ganglion because it is a fused structure combining the inferior cervical and first thoracic paravertebral ganglia), eleven thoracic ganglia, four lumbar ganglia, and four to five sacral ganglia. More caudally, two paravertebral ganglia join to become the ganglion impar. Prevertebral ganglia are midline structures located anterior to the aorta and vertebral column, and are represented by the celiac ganglia, aortico-renal ganglia, and the superior and inferior mesenteric ganglia. Previsceral, or terminal ganglia, are small collections of sympathetic ganglia located close to target structures; they are also referred to as short noradrenergic neurons since their axons cover limited distances. Generally, the preganglionic fibers are relatively short and the postganglionic fibers are quite long in the SNS. The axons of these postsynaptic neurons are generally unmyelinated and of small diameter (5 μm). The target organs of sympathetic neurons include smooth muscle and cardiac muscle, glandular structures, and parenchymal organs (e.g., liver, kidney, bladder, reproductive organs, muscles, etc. (see Fig. 4.1)) as well as other cutaneous structures. The spinal cells of origin for the presynaptic input to sympathetic peripheral ganglia are located from the first thoracic to the second lumbar level of the cord, although minor variations exist. The principal neurons generally have been viewed as located in the lateral horn of the spinal gray matter (intermediolateral cell column-IML), but four major groups of autonomic neurons exist: intermediolateralis pars principalis (ILP), intermediolateralis pars funicularis (ILF), nucleus intercalatus spinalis (IC) and the central autonomic nucleus (CAN) or dorsal commissural nucleus (DCN) (anatomical nomenclature is nucleus intercalatus pars paraependymalis (ICPE)). For paravertebral ganglia, 85–90% of the presynaptic fibers originate from cell bodies in ILP or ILF. Prevertebral ganglia and terminal ganglia receive a larger proportion of preganglionic terminals from the CAN/DCN. The nucleus intercalatus also contributes preganglionic fibers, but the exact
The autonomic nervous system (ANS) is structurally and functionally positioned to interface between the internal and external milieu, coordinating bodily functions to ensure homeostasis (cardiovascular and respiratory control, thermal regulation, gastrointestinal motility, urinary and bowel excretory functions, reproduction, and metabolic and endocrine physiology), and adaptive responses to stress (flight or fight response). Thus, the ANS has the daunting task of ensuring the survival as well as the procreation of the species. These complex roles require complex responses, and depend upon the integration of behavioral and physiological responses that are coordinated centrally and peripherally. In 1898, Langley, a Cambridge University physiologist coined the term “autonomic nervous system” and identified three separate components (sympathetic, parasympathetic, and enteric). The following section of the Primer will focus on the first two aspects of the peripheral ANS: sympathetic nervous system (SNS) including the adrenal medulla; and parasympathetic nervous system (PNS). The following précis will address the neuroanatomy of the SNS, adrenal medulla, and PNS, and then present a more detailed, albeit brief, review of the functional neuroanatomy, physiology and pharmacology of the peripheral autonomic nervous system. Importantly, the ANS’s role at multiple interfaces in normal and abnormal physiology is emerging as a key mediator of pathophysiology in a range of complex disorders (anxiety and panic, chronic fatigue syndrome, regional pain syndromes, autonomic failure) and a critical substrate underpinning the field of neurocardiology. The following information will serve as a framework from which to view the complexity of the ANS as revealed in the more detailed descriptions that follow.
SYMPATHETIC NERVOUS SYSTEM (SEE FIG. 4.1) The SNS is organized at a spinal and peripheral level such that cell bodies within the thoracolumbar segments of the spinal cord provide preganglionic efferent innervation to sympathetic neurons that reside in ganglia dispersed in three arrangements: paravertebral, prevertebral, and previsceral or terminal ganglia. Paravertebral ganglia
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4. PERIPHERAl AuToNomIC NERvouS SySTEm
Parasympathetic Division
Brainstem & Spinal Cord
Sympathetic Division
Target Organs
Trunk
Trunk
Target Organs
Oliary Ganglion
III
Nucleus Ambigours Superior Cervical Ganglion
Parotid Gland
Middle Cervical Ganglion Stellate
Heart
Ganglion
Respiratory Tract & Lungs
Small Intestine Adrenal Medulla Small Intestine
Celiac Ganglion
Greater Splanchnic Nerve Lesser Splanchnic Nerve Superior Mesenteric Ganglion
Colon Pelvin Colon & Rectum Genitourinary Tract
Interior Mesenteric Ganglion
C1 C2 C3 C4 C5 C6 C7 C8 T1 T2 T3 T4 T5 T6 T7 T8 T9 T10 T11 T12 L1 L2 L3 L4 L5 S1 S2 S3 S4 S5
Submandibular Ganglion
Sweat Glands, Hair Follicles, Blood Vessels
Lacrimal & Submandibular Glands
Stomach
VII IX X X
Edinger-Westphal Nucleus Superior Salivatory Nucleus Inferior Salivatory Nucleus Dorsal Motor Nucleus
Eye
Pterygopalatine Ganglion
Otic Ganglion
Eye Lacrimal & Palatine Glands Submandibular & Sublingual Glands Parotid Gland
Respiratory Tract & Lungs Gastrointestinal Tract, Liver & Pancreas Heart Nasopharynx Esophagus
Pelvic Colon & Rectum Pelvic Nerve
Genitourinary Tract
Hypogastric Ganglion
FIGURE 4.1 Schematic diagram of the sympathetic and parasympathetic divisions of the peripheral autonomic nervous system. The paravertebral chain of the sympathetic division is illustrated on both sides of the spinal outflow in order to demonstrate the full range of target structures innervated. Although the innervation pattern is diagrammatically illustrated to be direct connects between preganglionic outflow and postganglionic neurons, there is overlap of innervation such that more than one spinal segment provides innervation to neurons within the ganglia.
extent of these is not fully understood and is probably limited. These spinal autonomic nuclei receive substantial supraspinal input from multiple transmitter systems located at multiple levels of the neuraxis; diencephalon (hypothalamus) and brainstem (raphe, locus coeruleus, reticular formation and ventral lateral medulla) provide the largest input and the pattern of innervation viewed in horizontal sections reveals a ladder like arrangement of the distribution of nerve terminals [1]. Without detailing the source or course of specific systems, it is important to point out that the following different neurotransmitter systems impinge on preganglionic neurons within this ladder like structure: monoamines – epinephrine, norepinephrine (NE), serotonin; neuropeptides – substance P, thyrotropin-release hormone (TRH), met-enkephalin, vasopressin, oxytocin, and neuropeptide Y (NPY); amino acids – glutamate, GABA, and glycine. Undoubtedly, others exist and more will be found. It is apparent that dysfunction of these supraspinal systems, or alterations of these
neurotransmitters by disease or pharmacological agents will alter the spinal control of peripheral ganglia and result in clinical dysfunction. The outflow from the spinal cord to peripheral ganglia is segmentally organized with some overlap. Retrograde tracing studies indicate that there is a rostral-caudal gradient: SCG receives innervation from spinal segments T1–T3; stellate ganglia – T1–T6; adrenal gland – T5–T11; celiac and superior mesenteric ganglia – T5–T12; inferior mesenteric and hypogastric ganglion from L1–L2. These presynaptic fibers, which are small in diameter (2–5 μm) and thinly myelinated, exit the ventral roots via the white rami communicantes to join the paravertebral chain either directly innervating their respective ganglion at the same level or traveling along the chain to innervate a target ganglion many levels away (Fig. 4.2). The distribution of postsynaptic fibers also follow a regional pattern with the head, face and neck receiving innervation from the cervical ganglia (spinal segments T1–4), the upper limb and
I. INTRODUCTION
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SymPATHETIC NERvouS SySTEm
Parasympathetic Nervous System
Sympathetic Nervous System Thoracolumbar Spinal Cord
Sacral Spinal Cord
Spinal ganglion Afferent autonomic fiber Vasomotor Sudomotor Pilomotor fibers
Preganglionic fiber Postganglionic fiber
Gray communicating ramus (post ganglionic) White communicating ramus (preganglionic)
Paravertebral ganglion
Splanchnic nerve
Descending colon Rectum Urinary Bladder Sexual organs
Pelvic splanchnic nerve Prevertebral ganglion Pelvic ganglion
Postganglionic visceral nerves to smooth muscle of inner organs & visceral blood vessels
FIGURE 4.2 Schematic illustration of the segmental spinal arrangement of the sympathetic and parasympathetic nervous system. Although segmental interactions exist, they are polysynaptic operating via interneurons; the primary input to spinal preganglionic neurons is supraspinal originating from brainstem structures (not shown).
thorax from the stellate and upper thoracic ganglia (spinal segments T1–8); the lower trunk and abdomen from lower thoracic ganglia (spinal segments T4–12), and the pelvic region and lower limbs from lumbar and sacral ganglia (spinal segments T10–L2). More recently, with the introduction of trans-neuronal tracing techniques, using pseudorabies virus (PRV), it has been possible to inject ganglia in the periphery and examine the trans-synaptic passage of PRV. Thus, supraspinal neurons projecting to the specific sets of preganglionic neurons that innervate the peripheral ganglia injected may be examined. Interestingly, a surprisingly common set of central pathways influencing the thoracolumbar sympathetic outflow were labeled. For instance, following injections in either the SCG, stellate or celiac ganglia, or the adrenal gland, the following five brain areas are labeled: ventromedial and rostral ventrolateral medulla; caudal raphe nuclei; A5 noradrenergic cell group; and the paraventricular nucleus of the hypothalamus [2]. Apparently, these central loci must share regulatory functions that are coordinated through similar pathways of thoracolumbar outflow. These same studies indicate that other brain areas are only labeled from specific ganglia; thus, site specific central control exists as well. Of additional interest is that numerous, small interneurons in Rexed laminae VII and X of the spinal cord were labeled providing structural support
for the observation that spinal intersegmental and intrasegmental autonomic interactions (including autonomic reflexes) exist. It is apparent that the structural organizational of the sympathetic nervous system permits the integration and dissemination of responses depending on demand. Multiple supraspinal descending pathways provide a dense innervation of all four major autonomic cell groups in the spinal cord, but clearly specific topographic responses exist as well. In turn, each preganglionic neuron innervates anywhere from 4 to 20 postganglionic sites, and each spinal outflow level may reach multiple peripheral ganglia which in turn supply multiple targets, permitting additional dispersion of sympathetic responses when indicated. At each thoracic level there are an estimated 5000 preganglionic neurons (these counts have generally been limited to the cells located in the ILP). Since preganglionic output to prevertebral ganglia originates from more medially placed cell bodies, it is conceivable that a greater number of neurons at certain segmental levels contribute to the output. Thus, a given spinal segment has a powerful base to influence greater than 100,000 postganglionic neurons. Although original thinking suggested that responses were “all-or-none and widespread”, anatomical studies have continued to reveal subtleties of structural arrangements that indicate that the system is not only poised for
I. INTRODUCTION
20
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generalized activation of the peripheral sympathetic nervous system, but is also able to exert control of relatively specific sites and functions. The postganglionic fibers in the SNS travel quite lengthy paths to arrive at target organs. For instance, fibers from the SCG traverse the extracranial and intracranial vasculature to reach such targets as the lacrimal glands, parotid glands, pineal gland, and pupils. Fibers from the stellate ganglia course through the brachial plexus to reach vascular and cutaneous targets in the upper limb and hand. Within the abdomen, axons originating from the paravertebral ganglia supply the viscera as well as the mesenteric vasculature. Lumbar and sacral paravertebral ganglia course distally along peripheral nerves and blood vessels to reach the distal vasculature and cutaneous structures in the feet. In humans, the innervation to the leg requires a sympathetic axon to be 50 cm long and with an estimated overall diameter of 1.2 μm the axonal volume is approximately 565,000 μm3. This axonal cytoskeleton and its metabolic requirements are supported by a perikaryon of about 30 μm with a somal volume of 14,000 μm3. With this structural architecture to maintain, these neurons are vulnerable to various metabolic and structural insults. Although most preganglionic fibers have a relatively short course to their ganglion targets, the upper thoracic preganglionic fibers travel relatively longer distances to reach the stellate and SCG, and preganglionic fibers to the adrenal medulla and prevertebral ganglia course through the paravertebral chain reaching these visceral targets as the splanchnic nerves. Along the course, fiber systems may be interrupted, resulting in local autonomic dysfunction. For example, the Horner’s syndrome results from lesion of either preganglionic fibers to the SCG or the postganglionic axons which leave the SCG to innervate Müller’s muscle of the upper eyelid, pupillodilator muscles, facial vasculature, and sudomotor structures of the face (see Fig. 4.1). The autonomic neuroeffector junction is generally a poorly defined synaptic structure lacking the pre- and postjunctional specializations that are observed in the central nervous system or skeletal muscle motor end plates. The unmyelinated, highly branched postganglionic fibers become beaded with varicosities as they approach their targets. The varicosities are not static; they move along as structures with a diameter of 0.5 to 2 μm, and a length of approximately 1.0 μm. The number of varicosities varies from 10,000/mm3 to over 2 million per mm3 depending on the target being innervated. The varicosities are packed with mitochondria and vesicles containing various transmitters, and are at varying distances from their target organs. For instance, for smooth muscle targets, this distance varies from 20 nm in the vas deferens to 1–2 μm in large arteries. In a sense the release of transmitter is accomplished en passage as the impulse travels along an autonomic axon. The lack of a restrictive synaptic arrangement permits the released NT to diffuse various distances along a target organ and activate multiple receptors,
again expanding the overall effect of sympathetic activation. Between 100 and 1000 vesicles exist in each varicosity in noradrenergic fibers. Traditional teaching suggests that vesicle characteristics indicate the transmitter system: small granular vesicles are noradrenergic; small agranular vesicles are cholinergic; large granular vesicles are peptidergic. However, exceptions to these correlations exist. The principal neuronal phenotype in peripheral sympathetic ganglia is the noradrenergic neuron which is generally multipolar in character with synapses mainly located more on dendrites than somata. Depending on which ganglia are examined, studies indicate that from 80–95% of ganglion cells will stain positively for tyrosine hydroxylase, the rate-limiting enzyme in catecholamine biosynthesis, or have positive catecholamine fluorescence. The remaining cells have a mixture of transmitters, or are postganglionic cholinergic cells (the sudomotor and periosteal components of sympathetic function). Within sympathetic ganglia there is a small group of small intensely fluorescent (SIF) neurons. The transmitters identified in SIF cells include dopamine, epinephrine, or serotonin. As will be described later, the original concept that preganglionic neurons in the SNS are cholinergic and postganglionic neurons are noradrenergic has given way to new information that a whole array of molecules (cholinergic, catecholaminergic, monoaminergic, peptidergic, “non-cholinergic, non-adrenergic”, and gaseous) appear to be involved in neurotransmission either as agents themselves or as neuromodulators (vide infra).
SYMPATHOADRENAL AXIS AND THE ADRENAL GLAND Interactions between the adrenal cortex and adrenal medulla constitute a critical link between the autonomic and endocrine systems. The adrenal cortex is largely regulated by the hypothalamic-pituitary-adrenocortical axis, whereas the adrenal medulla is primarily under neural control. Both adrenal cortex and medulla, respond to stress and metabolic aberrations. The coordinated response of elevated plasma cortisol and catecholamines during stress indicate that central limbic and hypothalamic centers exert combined influences to ensure the needed neurohumoral adaptations. The interdependence of these two components of the adrenal gland arise early in development: migrating sympathoblasts destined for the adrenal medulla require the presence of the cortical tissue to change their developmental fate from neurons to that of chromaffin cells. These cells, named because they exhibit brown color when treated with “chrome salts”, do not develop neural processes but instead serve an endocrine function by releasing their neurohumors (epinephrine, norepinephrine, and neuropeptides) into the blood stream. During adulthood, the presence of the cortex is critical for maintaining the levels of epinephrine since the induction of the enzyme
I. INTRODUCTION
PARASymPATHETIC NERvouS SySTEm
phenylethanolamine-n-methyltransferase is dependent on local levels of cortisol. Although traditional teaching emphasizes the preganglionic cholinergic splanchnic innervation of the adrenal medulla, there is also evidence that postganglionic sympathetic fibers, vagal afferents, and other sensory afferents are present. Tracing studies indicate that dye placed within the adrenal medulla is transported retrogradely within spinal preganglionic sympathetic neurons in a somewhat bell shaped distribution from approximately T2–L1 with the predominant innervation originating from T7–T10. Neuronal cell bodies are primarily within the nucleus intermediolateralis pars principalis (ILP) with the pars funicularis and pars intercalatus providing a relatively small portion of the innervation. The exiting nerve roots pass through the sympathetic chain, join to form the greater splanchnic nerve, and distribute themselves beneath the adrenal capsule and within the medulla. A small number of nerve cells are labeled in ganglia within the sympathetic chain suggesting that postganglionic sympathetic fibers innervate the gland. Whether these terminals are labeled as they pass along blood vessels within the gland or whether they innervate medullary or cortical cells is not fully resolved. Also, at least in the guinea pig, tracing studies indicate that the parasympathetic system may contribute a small efferent innervation to the gland since neurons in the dorsal motor nucleus of the vagus are labeled after injections in the medulla. Also, cell bodies within the dorsal root ganglia and vagal sensory ganglia (nodose) are also labeled after tracer studies of the adrenal medulla indicating an afferent innervation as well. Lastly, although not a prominent innervation pattern, there appears to be an intrinsic innervation that arises from ganglion cells sparsely populating the subcapsular, cortical and medullary regions of the gland. The innervation pattern of the adrenal medulla is thus more complex than the traditionally listed thoracolumbar preganglionic cholinergic outflow, although the major adaptive responses depend on the preganglionic cholinergic innervation since surgical section of these nerves, or pharmacological blockade with cholinergic antagonists preclude the induction of tyrosine hydroxylase and appropriate release of catecholamines following various stress paradigms. Morphological studies of the adrenal medulla have revealed the presence of two basic types of granules in chromaffin cells. A diffuse spherical granule contains the predominant monoamine secreted by medullary cells, epinephrine, whereas eccentrically located dense core granules contain norepinephrine. As indicated above for ganglion neurons, chromaffin cells of the adrenal medulla also cocontain other molecules. For instance, the opioid molecules are well represented: enkephalin is co-contained in vesicles with the monoamines. The signaling cascade responsible for enhancing the synthesis and release of these neurohormonal agents is complicated and includes preganglionic innervation, steroid hormones (e.g., glucocorticoids), and growth factors (e.g., nerve growth factor, NGF).
21
PARASYMPATHETIC NERVOUS SYSTEM (SEE FIG. 4.1) The craniosacral outflow is the source of central neuronal pathways providing the efferent innervation of peripheral ganglia of the parasympathetic nervous system (PNS). The cranial nerves involved include cranial nerves III, VII, IX, and X, and the sacral outflow is largely restricted to sacral cord levels 2, 3, and 4. As indicated for the SNS, the preganglionic innervation is largely cholinergic with these terminals releasing acetylcholine (ACh) at the ganglion synapses. In contrast to the SNS, the major transmitter postsynaptically is also ACh. These cholinergic neurons also co-contain other transmitter substances: preganglionic neurons contain enkephalins, and ganglionic cholinergic neurons frequently contain vasoactive intestinal peptide (VIP) and/or NPY. The parasympathetic fibers in cranial nerve III originate in the Edinger–Westphal nuclei of the midbrain and travel in the periphery of the nerve (where they are subject to dysfunction secondary to nerve compression), exiting along with the nerve to the inferior oblique to supply the ciliary ganglion. Second order postganglionic fibers exit in the ciliary nerves and supply the pupiloconstrictor fibers of the iris and the ciliary muscle where their combined action permits the near response, including accommodation. The salivatory nuclei, located near the pontomedullary junction, provide the preganglionic parasympathetic innervation for cranial nerves VII and IX. The superior salivatory nucleus sends preganglionic fibers, which leave the facial nerve at the level of the geniculate ganglion (non-parasympathetic sensory ganglion), to form the greater superficial petrosal nerve to the pterygopalatine (sphenopalatine) ganglia that provides postganglionic secretomotor and vasodilator fibers to the lacrimal glands via the maxillary nerve. Other preganglionic fibers in the facial nerve continue and subsequently leave via the chorda tympani to join the lingual nerve, eventually synapsing in the submandibular ganglion. Postsynaptic cholinergic fibers supply the sublingual and submandibular glands. Postganglionic fibers from the pterygopalatine and submandibular ganglia also supply glands and vasculature in the mucosa of the sinuses, palate, and nasopharynx. The inferior salivatory nucleus sends preganglionic fibers via the glossopharyngeal nerve (cranial nerve IX) to the otic ganglion that in turn relays postganglionic fibers to the parotid gland via the auriculotemporal nerve. The preganglionic fibers in cranial nerve IX branch from the nerve at the jugular foramen and contribute to the tympanic plexus and form the lesser superficial petrosal nerve. This nerve exits the intracranial compartment via the foramen ovale along with the third division of the trigeminal nerve to reach the otic ganglion. The most caudal cranial nerve participating in the preganglionic parasympathetic system is the vagus nerve (cranial nerve X). The dorsal motor nucleus of the vagus is located in the medulla and sends preganglionic fibers to innervate essentially all organ systems within the chest
I. INTRODUCTION
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4. PERIPHERAl AuToNomIC NERvouS SySTEm
and abdomen including the gastrointestinal tract as far as the left colonic flexure (splenic flexure). Also, the nucleus ambiguus supplies preganglionic fibers to the vagus and these fibers are believed to be involved mostly with regulating visceral smooth muscle whereas the dorsal motor vagus neurons may be secretomotor in nature. The glossopharyngeal and vagus nerves also contain a substantial number of afferent fibers (in the vagus, afferent fibers may exceed the efferent fiber system by a ratio of 9 to 1) so that a sensory component related to autonomic control exists within cranial nerve IX and X. These afferents provide a critical component of the baroreceptor reflex arc relaying information regarding the systemic blood pressure to central cardiovascular areas in the nucleus tractus solitarii and other medullary centers involved in blood pressure and heart rate control. The parasympathetic cell bodies in the spinal cord are located in the sacral parasympathetic nucleus of second, third, and fourth sacral segments (see Fig. 4.2). These neurons send preganglionic nerve fibers via the pelvic nerve to ganglia located close to or within the pelvic viscera. Postganglionic fibers are relatively short, in contradistinction to their length in the SNS, and supply cholinergic terminals to structures involved in excretory (bladder and bowel) and reproductive (fallopian tubes and uterus, prostate, seminal vesicles, vas deferens, and erectile tissue) functions. Of interest, the pelvic ganglia involved in some of these functions appear to be mixed ganglia (especially in rodents) where sympathetic and parasympathetic neurons are components of the same pelvic ganglion. They appear to receive their traditional preganglionic input, but may have local interconnections that are not fully revealed by current studies. As indicated below, there is clear evidence that the cholinergic postganglionic neurons in the pelvic ganglion in the rodent co-contain vasoactive intestinal peptide and nitric oxide as two other neuroactive compounds. These neurons are believed to be integrally involved in sexual functions in the male, permitting the development and maintenance of potency. The exact regulatory factors controlling the synthesis and release of these transmitter molecules, and the specific receptor systems involved remain to be fully explored.
THE CONCEPT OF PLURICHEMICAL TRANSMISSION AND CHEMICAL CODING The notion of the presence of multiple transmitters and a chemical coding system of autonomic neurons is now firmly established. Originally it was posited that principal neurons were only noradrenergic (contained NE), but over the last two decades it has become clear that within a single neuron multiple transmitter systems may exist, and that within a given ganglion the variety and pattern of neurotransmitters may be quite extensive (see Table 4.1). Also, the composition of neurotransmitters (NT) may change depending on the location of the ganglia: paravertebral
TABLE 4.1 Neurotransmitter Phenotypes in Autonomic Neurons Autonomic Neurons Sympathetic neurons Paravertebral ganglia Prevertebral ganglia Terminal ganglia (previsceral ganglia) Parasympathetic neurons Major parasympathetic ganglia Ciliary Sphenopalatine Otic Submandibular/sublingual Pelvic ganglia Terminal parasympathetic ganglia (previsceral ganglia) Enteric neurons Myenteric plexus (Auerbach’s) Submucosal plexus (Meisner’s)
Transmitter Characteristics (not all inclusive) NE, CCK, somatostatin, SP, Enk, Ach VIP, 5-HT, NPY, DYN1-8, DYN1-17
ACh, VIP, SP, CAs-SIF, NPY, NO
GABA, ACh, VIP, 5-HT SP, Enk, SRIF, motilinlike peptide, bombesinlike peptide
Enteric ganglia Chromaffin cells of adrenal medulla Paraganglia-chromaffin
E, NE, Enk, NPY, APUD
SIF cells, ganglia
ganglia tend to have fewer transmitters whereas prevertebral and terminal ganglia may have various NT, although as noted for the guinea pig SGC (Fig. 4.3), some paravertebral ganglia have a broad array of transmitters. The exact co-location and functions of these multiple transmitters are not fully understood, but some general principles exist. Neuropeptide NPY is probably the most prominent peptide in sympathetic ganglia and is highly co-localized with NE. The sudomotor component of ganglia is dependent upon a population of cells, which are cholinergic in character [contain ACh as NT], and the most frequent peptide colocalized with ACh is vasoactive intestinal peptide (VIP). The distribution of these cholinergic cells varies: in paravertebral ganglia they may represent 10–15% of the neuronal population whereas they represent 1% of the neurons in prevertebral ganglia. NE NPY, and ACh VIP are believed to be released together, but some degree of activity associated-chemical coding exists. That is, at lower levels of activation NE is preferentially released, whereas higher levels of stimulation result in NPY being released. Both agents have vasoconstrictor properties and are integral in cardiovascular control, especially in the maintenance of blood pressure. Of course, the eventual action and effect of a transmitter rests with the receptor system that is activated (vide infra). Purinergic neurotransmission expands the co-transmission motif. Presynaptic and postsynaptic mechanisms exist: the purine nucleotide adenosine triphosphate (ATP) is in high concentration in sympathetic synaptic vesicles and following release ATP is catabolized to adenosine
I. INTRODUCTION
vISCERAl AffERENT NEuRoNS ANd AuToNomIC NERvouS SySTEm
23
FIGURE 4.3 Chemical coding and target organization. Chemical coding of sympathetic neurons projecting from the superior cervical ganglion to various targets in the head of guinea-pigs. Each population of neurons has a specific combination of neuropeptides. Note that all neurons containing a form of dynorphin A (DYN1-8 or DYN1-17) also contain dynorphin B and neo-endorphin. No neuropeptides have been found in neurons projecting to secretory tissue in the salivary or lacrimal glands. Neurons with similar peptide combinations also occur in other paravertebral ganglia of guinea-pigs, except that the salivary secretomotor neurons are absent. Conversely, the paravertebral ganglia have many non-noradrenergic vasodilatory neurons containing prodynorphin-derived peptides, VIP and NPY. AVAs, arterio-venous anastomoses; NA, noradrenaline; NPY, neuropeptide Y; ACh, acetylcholine; CGRP, calcitonin gene-related peptide; SP, substance P; VIP, vasoactive intestinal polypeptide (see Elfvin, Lindh and Hokfelt, 1993 [11]; Jänig, 2006 [12]).
moieties. There are at least eight receptors (four purinergic and four adenosinergic) that serve to translate purinergic and adenosinergic effects (vasoconstriction and vasodilatation) to vascular beds via endothelium-dependent and endothelium-independent mechanisms. Chemical coding also reveals that ganglion neurons with specific transmitter molecules innervate specific targets or receive specific afferent inputs. Apparently, anterograde and retrograde transsynaptic information appears to determine the transmitter phenotype of the neuron. Thus, studies of neuronal circuitry indicate that pathwayspecific combinations determine the presence and combinations of specific peptides within autonomic neurons. This is particularly so in the prevertebral ganglia, but studies in the guinea pig SCG demonstrate that the transmitter molecules will vary depending on the target organ supplied (see Fig. 4.3). Although all principal cells portrayed are noradrenergic in character (as indicated by NA), the neuropeptides co-contained in neurons vary depending on whether the targets are secretory (salivary and lacrimal glands), vascular (small vs. large arteries, arterioles vs. arterio-venous anastomoses), pupil or skin. Detailed pictures of these chemically coded circuits are beginning to emerge from studies of paravertebral (SCG), prevertebral (superior mesenteric), and previsceral (pelvic) ganglia. This phenomenon pertains to both the SNS and PNS. Preganglionic sympathetic neurons in the spinal cord have traditionally been viewed as cholinergic neurons.
More recently, it has been recognized that neuronal cell bodies in the cat ILP may contain a variety of transmitters including enkephalin, neurotensin, somatostatin, and substance P. In rodents, VIP and calcitonin gene-related pepitde (CGRP) containing neurons have also been localized to the ILP by immunocytochemistry. Also, preganglionic fibers in the sacral parasympathetic outflow co-contain enkephalin. It is apparent that neurotransmission is plurichemical in both preganglionic and postganglionic-fiber systems.
VISCERAL AFFERENT NEURONS AND AUTONOMIC NERVOUS SYSTEM Visceral afferent neurons are polymodal and are excited by physical (distention, contraction), chemical and thermal events. These stimuli are transmitted to the spinal cord and brainstem neurons resulting in target organ regulation, reflexes and sensation. In rats, vagal afferent neurons arising in the stomach may terminate within the medullary nucleus tractus solitarius in proximity to dendrites from dorsal motor nucleus efferent neurons sending axons back to the stomach [3]. Spinal primary afferent neurons that innervate viscera have multiple functions (afferent, efferent and trophic functions) [4] and contain a diverse assortment of neuropeptides including calcitonin generelated peptide (CGRP), substance P, vasoactive intestinal
I. INTRODUCTION
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4. PERIPHERAl AuToNomIC NERvouS SySTEm
polypeptide (VIP) and pituitary adenylate cyclase activating polypeptide (PACAP) [5]. For example, bladder afferent neurons travel in the hypogastric and pelvic nerves, and their cell bodies are located in dorsal root ganglia (DRG) at spinal segments T11–L2 and S2–S4 in humans and L1–L2 and L6–S1 in rats [5,6]. Bladder afferent fibers consist of lightly myelinated Aδ fibers and unmyelinated C-fibers. Sensation of bladder filling is conveyed by Aδ fibers, the most important mechanoreceptors of the bladder. C-fibers are normally “silent”, but they do respond to chemical or noxious stimuli, including extreme bladder pressure [5,6].
FUNCTIONAL NEUROANATOMY AND BIOCHEMICAL PHARMACOLOGY The peripheral ANS is well structured to provide the physiological responses critical for homeostasis and acute adaptations to stressful, perhaps life-threatening, circumstances. As outlined in Figure 4.1 and Table 4.2, multiple organ systems respond to neurotransmitters released from autonomic endings, and circulating catecholamines released from the adrenal medulla. Traditional teaching is that the effects of activation of the SNS and PNS are generally antagonistic; this is still largely the case. However, viewed more specifically, the relationships between these two major components of the ANS are far from simple. For instance, not all organs receive an equal number of both sets of fibers, and in some situations, both SNS and PNS effects are similar. It is important to remember that receptor systems, including the signal transduction components, on the target organs are the critical molecular proteins that determine the actual effects of ligand-receptor interactions on the cell membrane. Thus, when the SNS is stimulated with its capability to produce a widespread response, a host of receptor systems are activated to effect the necessary and desired change. An example of these responses includes the following aspects of SNS activation: dilatation of the pupil; slight increase in glandular secretions; bronchodilatation; increased heart rate and force of contraction; decreased gastrointestinal tract motility; decreased function of the reproductive organs; and mobilization of energy substrates to meet demands. The receptor systems mediating these responses include α1A, α1B,, α1D,, α2A, α2B, α2C, β1, β2 and β3 receptors. α1 receptors have subtypeselective distributions, second messenger systems and functions. Activation of these receptors occurs following interaction with NE and variously results in contraction of smooth muscle in the vasculature and iris, and relaxation of smooth muscle in the gut. α1 receptors exert a limited positive inotropic effect on the heart, as well as mediate salivary gland secretion and contraction of the prostate gland. α2 receptors also have discrete subtype-specific localizations and functions in brain, peripheral nerve, and target tissues. α2 receptors serve as autoreceptors on sympathetic nerve terminals and inhibit the release of NE as
TABLE 4.2 Autonomic Nervous System functions Organ
Sympathetic Nervous System
Parasympathetic Nervous System
Eye Pupil Ciliary muscle
Dilatation Relax (far vision)
Constriction Constrict (near vision)
Lacrimal gland
Slight secretion
Secretion
Parotid gland
Slight secretion
Secretion
Submandibular gland
Slight secretion
Secretion
Heart
Increased rate Positive inotropism
Slowed rate Negative inotropism
Lungs
Bronchodilation
Bronchodilation
Gastrointestinal tract
Decreased motility
Increased motility
Kidney
Decreased output
None
Bladder
Relax detrusor Contract sphincter
Contract detrusor Relax sphincter
Penis
Ejaculation
Erection
Sweat glands
Secretion
Palmar sweating
Piloerection muscles
Contraction
None
Blood vessels Arterioles
Constriction
None
Constriction or dilatation Glycogenolysis
None
Muscle Arterioles Metabolism
None
part of a negative feed back loop. α2 receptors also can act as constrictors of both arterial and venous vascular smooth muscle. Furthermore, these receptors play important roles in nociception and also mediate metabolic and endocrine changes such as inhibition of lipolysis in adipose tissue and reduction of insulin release from the pancreas. β receptors (β1) provide positive inotropic and chronotropic effects on the heart and stimulate renin release from the kidney. β2 receptors relax smooth muscle of the bronchi and pelvic organs as well as the vascular structures of the gut and skeletal muscle. β2 receptors located in liver and skeletal muscle elicit activation of glycogenolysis and gluconeogenesis. This receptor system is particularly activated by epinephrine rather than norepinephrine. The parasympathetic nervous system is poised for more focal responses, but some effects may be quite broad, particularly with the wide-ranging innervation of the vagus nerve. Activation of parasympathetic pathways lead to pupillary constriction, substantial secretion from lacrimal and salivary glands, slowed cardiac rate and negative inotropism, bronchoconstriction, enhanced gastrointestinal motility and contraction of the detrusor muscle of the bladder. In contrast to the SNS, the PNS does not appear to influence metabolic or endocrine processes in any major way. However, recent evidence indicates that preganglionic vagal fibers originating in the dorsal motor nucleus innervate postganglionic parasympathetic ganglia in the
I. INTRODUCTION
STRESS ANd AuToNomIC dySfuNCTIoN
pancreas, and appear to influence exocrine and endocrine function. Thus, as new data emerge, the integrated roles of the SNS and PNS will continue to expand. An understanding of the receptor systems mediating the responses to PNS activation is incomplete. Preganglionic cholinergic receptors, which exist in the SNS as well as PNS, are nicotinic in character whereas postganglionic cholinergic receptors are muscarinic. Recently, molecular cloning studies have revealed multiple subtypes of both sets of receptors. The subtypes of muscarinic receptors (mAChRs), M(1)-M(5), are more fully understood (at least for the first three subtypes): M1 receptors are excitatory to neurons in ganglia and lead to noradrenaline release in sympathetic neurons; M2 receptors mediate the bradycardia and decreased contractility of the heart following vagal activation; M3 stimulation leads to contraction of smooth muscle and enhanced secretion from glandular tissues. Nicotinic acetylcholine receptor subtypes (nAChRs) are widely expressed in the mammalian CNS and PNS, playing a central role in autonomic transmission. Neuronal nicotinic acetylcholine receptors (nAChR) are composed of 12 subunits (α2–α10, β2–β4) but very little was known, until recently, about their physiological roles. The repertoire of nicotinic subunits in autonomic ganglia includes α3, α5, α7, β2 and β4 subunits. In the periphery, nicotinic receptors mediate vital excitatory fast synaptic cholinergic transmission at both the neuromuscular junction and ganglia. However, there is only a limited understanding of subunit actions in the presynaptic and postsynaptic components of the peripheral ANS. Functional deletions of subunit by gene knockout in animals are beginning to overcome these limitations.
STRESS AND AUTONOMIC DYSFUNCTION A prominent role for stress in the pathophysiology of cardiovascular disease and presentation of clinical pain states, including functional gastrointestinal disorders have been well documented. In addition, anxiety and stress may generate and worsen urinary symptoms and functional urinary disorders [7], such as interstitial cystitis (IC)/bladder pain syndrome (BPS). The majority of IC/BPS patients report symptom exacerbation by stress, and clinical studies have shown that acute stress increases bladder pain and urgency in IC/BPS patients [7,8]. Clinical populations afflicted with bladder disorders have a greater incidence of comorbid anxiety disorders than populations without bladder dysfunction. Both anxiety and bladder dysfunction can be caused and/or exacerbated by exposure to environmental stressors in human clinical populations and animal models. A number of ongoing studies from various laboratories are evaluating whether autonomic nervous system pathology and stress/anxiety share overlapping neuronal circuitry. The complexity of autonomic control and the range of mechanisms available to peripheral sympathetic and
25
parasympathetic neurons and their targets are expanded by presynaptic gaseous molecules (nitric oxide [NO]) and postsynaptic endothelium released peptides. Also, central nervous system centers involved in autonomic control contain nitric oxide synthase and evidence suggests that NO may mediate sympatho-inhibition or sympathoexcitation depending on the nuclear groups involved. Peripherally, NO exerts tonic vasodilation and mediates acetylcholine-induced vasodilation, as well as mediating catecholamine release and action. Endothelins, released abluminally by endothelial cells, bind to endothelial and adrenoceptors on vascular smooth muscle and endothelial cells and appear to regulate sympathetic terminals as well. The recent discoveries that a number of neurotrophic factors (neurotrophins) and their receptors are part and parcel of the development and integrity of the SNS and PNS expand the horizons regarding how anatomical pathways are established and maintained, and adapt to intrinsic and extrinsic demands. Because of its relatively simple anatomical architecture, the peripheral ANS continues to serve as a model system to understand neuronal development, structural and functional linkages among neurons and their targets, and the integrative role(s) these “little brains” (6000–30,000 neurons) serve. More recently, observations of the clinical phenotype and neuropathology of Parkinson Disease (PD) suggest that the peripheral ANS may serve as a model to study human neurodegenerative disease since peripheral and preganglionic, including medullary preganglionic vagal (DMV) neurons, may be involved at the earliest stages of the disease [9], before the onset of the well-known motor system dysfunctions related to the basal ganglia. A neuropathological cascade that originates in peripheral autonomic nerves may gradually and progressively ‘spread’ to involve central nervous system structures with the eventual involvement of the classically described neurons of the locus, coeruleus, substantia nigra and more rostral structures. Recent investigations in animal models of PD have taken advantage of the relative simplicity of the peripheral ANS to explore pathophysiological mechanism of how α-synuclein might initiate the premotor clinical dysfunction and presumed underlying alteration is neurotransmitter biochemistry and neurophysiology of peripheral autonomic neurons [10]. As the structure-function relationships and molecular pharmacology of the peripheral ANS are clarified, and more understandings accrue regarding their involvement in disease processes, new approaches to understanding ANS functions in health and disease and treatments of its maladies will undoubtedly emerge. The following sections of this Primer will expand on these issues.
References [1] Romagnano MA, Hamill RW. Spinal sympathetic pathway: an enkephalin ladder. Science 1984;225:737–9. [2] Strack AM, Sawyer WG, Hughes JH, Platt KB, Loewy AD. A general pattern of CNS innervation of the sympathetic outflow
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[3] [4]
[5]
[6] [7]
[8] [9] [10]
[11] [12]
4. PERIPHERAl AuToNomIC NERvouS SySTEm
demonstrated by transneuronal pseudorabies viral infections. Brain Res 1989;491:156–62. Shapiro RE, Miselis RR. The central organization of the vagus nerve innervating the stomach of the rat. J Comp Neurol 1985;238:473–88. Jänig W, Habler HJ. Specificity in the organization of the autonomic nervous system: a basis for precise neural regulation of homeostatic and protective body functions. Prog Brain Res 2000;122:351–67. Arms L, Vizzard MA. Neuropeptides in lower urinary tract function. In: Urinary tract, handbook of experimental pharmacology 202. Berlin Heidelberg: Springer-Verlag; 2011. Fowler CJ, Griffiths D, de Groat WC. The neural control of micturition. Nat Rev Neurosci 2008;9(6):453–66. Baldoni F, Ercolani M, Baldaro B, Trombini G. Stressful events and psychological symptoms in patients with functional urinary disorders. Percept Mot Skills 1995;80:605–6. Koziol JA, Clark DC, Gittes RF, Tan EM. The natural history of interstitial cystitis: a survey of 374 patients. J Urol 1993;149:465–9. Braak H, Del Tredici K. Invited Article: Nervous system pathology in sporadic Parkinson disease. Neurology 2008;70:1916–25. Hamill RW, Girard B, Tompkins JD, Galli JR, Parsons RL, Kershen RT, et al. Synucleinopathy model: Autonomic plasticity in the major pelvic ganglion (MPG) in mice with human alpha-synuclein overexpression. Developmental Neurobiol, in revision. Elfvin L-G, Lindh B, Hökfelt TJ. The chemical neuroanatomy of sympathetic ganglia. Ann Rev Neurosci 1993;16:471–507. Jänig W. The Integrative Action of the Autonomic Nervous System Neurobiology of homeostasis. Cambridge: Cambridge University Press; 2006.
Further Reading Baloh RH, Enomoto H, Johnson Jr. EM, Milbrandt J. The GDNF family ligands and receptors-implications for neural development. Curr Opin Neurobiol 2000;10:103–10. Burnstock G, Milner P. Structural and chemical organization of the autonomic nervous system with special reference to non-adrenergic, non-cholinergic transmission. In: Banister R, Mathias CJ, editors. Autonomic failure (4th edn.). New York: Oxford University Press; 1999. p. 63. Chowdhary S, Townend JN. Role of nitric oxide in the regulation of cardiovascular autonomic control. Clin Sci (Lond) 1999;97(July):5–17. Dinner DS, editor. The autonomic nervous system. (Review articles) J Clin Neurophysiol, 10; 1993 1–82 Gibbins I. Chemical neuroanatomy of sympathetic ganglia. In: McLachlan EM, editor. Autonomic ganglia. Luxembourg: Harwood Academic Publishers; 1995. p. 73–121. Goldstein DS. The autonomic nervous system in health and disease. New York: Marcel Dekker, Inc; 2001. 23–135 Schober A, Unsicker K. Growth and neurotrophic factors regulating development and maintenance of sympathetic preganglionic neurons. Int Rev Cytol 2001;205:37–76. Zansinger J. Role of nitric oxide in the neural control of cardiovascular function. Cardiovasc Res 1999;43:639–49.
I. INTRODUCTION
C H A P T E R
5 Cotransmission Geoffrey Burnstock
EARLY STUDIES
TABLE 5.1 Cotransmitters in the Peripheral and Central Nervous System
For many years, understanding of neurotransmission incorporated the concept that one neuron releases only a single transmitter, known as “Dale’s Principle”. This idea arose from a widely adopted misinterpretation of Dale’s suggestion in 1935 that the same neurotransmitter was stored in and released from all terminals of a single neuron, a suggestion which did not specifically preclude the possibility that more than one transmitter may be associated with the same neuron. Early hints that nerves might release more than one transmitter began in the 1950s with evidence for the involvement of both noradrenaline (NA) and acetylcholine (ACh) in sympathetic transmission. Koelle identified acetylcholinesterase in some adrenergic neurons in 1955, while Burn and Rand introduced the concept of a “cholinergic” link in adrenergic transmission in 1959. Another line of evidence provided by Hillarp concerned the coexistence of adenosine 5-triphosphate (ATP) with catecholamines, first in adrenal chromaffin cells and later in sympathetic nerves. Inconsistencies in the single transmitter hypothesis provided by these and other studies, including those concerned with invertebrate neurotransmission, from the early literature were rationalized in an article by Burnstock in 1976 [1] with the provocative title: “Do some nerve cells release more than one transmitter?” Today, it is widely accepted that cotransmission is an integral feature of neurotransmission. A role for ATP as a cotransmitter in sympathetic, parasympathetic, sensory-motor and enteric non-adrenergic, non-cholinergic (NANC) inhibitory nerves was supported by research from Burnstock and colleagues, while Hökfelt and colleagues focused on the colocalization, vesicular storage and release of peptides from both peripheral and central nerves (see [2–4]). Furness and Costa introduced the concept of “chemical coding” to describe the combination of potential neurotransmitters found in enteric nerves and this concept has since been applied to other nerve types, in both peripheral and central nervous systems (CNS) [5]. Colocalized substances are not necessarily cotransmitters, they can (especially peptides) act as pre- and/or postjunctional neuromodulators of the release and actions of the principal cotransmitters. The proportions of cotransmitters vary considerably between species and organs, and show
Primer on the Autonomic Nervous System. DOI: 10.1016/B978-0-12-386525-0.00005-6
PERIPHERAL NERVOUS SYSTEM Sympathetic nerves
ATP NA NPY
Parasympathetic nerves
ATP ACh VIP
Sensory-motor
ATP CGRP SP
NANC enteric nerves
ATP NO VIP
Motor nerves (in early development)
ATP Ach
CENTRAL NERVOUS SYSTEM Cortex, caudate nucleus
ATP Ach
Hypothalamus, locus ceruleus
ATP NA
Hypothalamus, dorsal horn, retina
ATP GABA
Mesolimbic system
ATP DA
Hippocampus, dorsal horn
ATP glutamate
Compiled from [4]. ACh, acetylcholine; ATP, adenosine 5-triphosphate; CGRP, calcitonin gene-related peptide; DA, dopamine; GABA, γ-amino butyric acid; NA, noradrenaline; NO, nitric oxide; NPY, neuropeptide Y; SP, substance P; VIP, vasoactive intestinal peptide.
plasticity of expression during development and in pathological conditions. In general, classical transmitters are contained in small synaptic vesicles, whereas peptides are stored in large granular (dense-cored) vesicles (LGVs), although small molecule transmitters are sometimes stored together with peptides in LGVs. Pharmacological studies of pre- and postjunctional neuromodulation provide evidence, which is complementary to the concept of cotransmission. Evidence for ATP being a cotransmitter with established neurotransmitters in the CNS as well as in the periphery has been reported (see Table 5.1).
SYMPATHETIC NERVES There is substantial evidence to show that NA, ATP and neuropeptide Y (NPY) are cotransmitters in sympathetic nerves, having differentially important roles as transmitters and neuromodulators depending on the tissue, the species, and on the parameters of stimulation.
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© 2012 Elsevier Inc. All rights reserved.
28
5. CoTRANSmISSIoN
The first indication that ATP might be released from sympathetic nerves was the demonstration that stimulation of sympathetic nerves by Su et al. in 1971 [6] led to release of tritium from taenia coli preincubated in [3H]adenosine (which is taken up and converted to [3H]ATP). Later Sol Langer and colleagues suggested that the substantial residual NANC response of the cat nictitating membrane observed after depletion of NA by reserpine was due to the release of ATP remaining in the sympathetic nerves. Most of the early studies establishing the model of cotransmission of NA and ATP were made by Dave Westfall and colleagues on the vas deferens, a tissue with a high density of sympathetic nerves. In retrospect, there was a good indication that the excitatory junction potentials (EJPs) recorded in the guinea pig vas deferens when the electrophysiology of sympathetic nerve smooth muscle transmission was first described by Burnstock and Holman in 1960, were due to ATP released as a cotransmitter from sympathetic nerves, rather than to NA. It was puzzling at the time that adrenoceptor antagonists failed to block the EJPs, although guanethidine, a drug that prevents the release of sympathetic transmitters, was effective. It was over 20 years later that NANC EJPs were shown to be blocked by desensitization of the ATP (P2) receptors by α,β-methylene ATP (α,β-meATP) and mimicked by ATP [7]. After destruction of sympathetic nerves with 6-hydroxydopamine, purinergic nerve-mediated responses were abolished. ATP is co-stored with NA in small and large vesicles. Differential prejunctional modulation of the release of NA and ATP by various agents has been shown in the vas deferens, perhaps indicating that NA and ATP are stored in different vesicles. Cotransmission of NA and ATP in perivascular sympathetic nerves supplying the rabbit aorta, portal vein and saphenous, pulmonary and mesenteric arteries, and the dog basilar artery has been demonstrated (see [8]). Electrophysiological studies have shown that in a number of vessels the electrical response to stimulation of perivascular sympathetic nerves is biphasic; an initial fast, transient depolarization or EJP of the vascular smooth muscle is followed by a slow, prolonged depolarization. The EJP and slow depolarization are mimicked by the effects of ATP and NA, respectively. Considerable variation exists in the proportions of NA and ATP utilized by sympathetic nerves. For example, in guinea pig submucosal arterioles both vasoconstriction and EJPs, evoked in response to electrical stimulation of sympathetic nerves, are mediated exclusively by ATP, with NA assuming the role of a neuromodulator, by acting through prejunctional α2-adrenoceptors to depress transmitter release. At the other extreme, in rat renal arteries the purinergic component is relatively small. It has also been noted that the purinergic component is optimal with short bursts of low frequency stimulation, whereas longer durations of higher frequency favor adrenergic transmission. NPY has been found to be present in LGV in most sympathetic nerves. The release of NPY, as well as NA and ATP, in response to electrical stimulation of sympathetic nerve terminals is prevented by guanethidine. The major role of
FIGURE 5.1 Schematic of sympathetic cotransmission. ATP and NA released from small granular vesicles (SGV) act on P2X and α1 receptors on smooth muscle, respectively. ATP acting on inotropic P2X receptors evokes excitatory junction potentials (EJPs), increase in intracellular calcium ([Ca2]i) and fast contraction; while occupation of metabotropic α1 adrenoceptors leads to production of inositol triphosphate (InsP3), increase in [Ca2]i and slow contraction. Neuropeptide Y (NPY) stored in large granular vesicles (LGV) acts on release both as a prejunctional inhibitory modulator of release of ATP and NA and as a postjunctional modulatory potentiator of the actions of ATP and NA. Nucleotidases are released from nerve varicosities, and are also present as ectonucleotidases. (Reproduced from [14] with permission from Elsevier.)
NPY in the vasculature, and in the vas deferens, appears to be that of a pre- and/or postjunctional modulator of sympathetic transmission, since it has little direct postjunctional action or causes contraction only at high concentrations (see Fig. 5.1). Direct vasoconstrictor actions of NPY have, however, been demonstrated in some vessels. At the prejunctional level, NPY has potent inhibitory effects, reducing the release of NA and ATP from sympathetic nerves. Postjunctionally, NPY generally acts to enhance the actions of sympathetic nerve stimulation, NA and ATP. Although 5-hydroxytryptamine (5-HT) immunofluorescent nerves have been localized in a number of vessels, for the most part 5-HT is not synthesized and stored in separate nerves, but is taken up, stored in, and released as a “false transmitter” from sympathetic nerves. Enkephalins have been shown to coexist with NA in cell bodies and fibers of some postganglionic sympathetic neurons. The functional significance of sympathetic coexistence of opioids is likely to be related to their prejunctional inhibitory effects on sympathetic transmission.
PARASYMPATHETIC NERVES The classical evidence for cotransmission of ACh and vasoactive intestinal polypeptide (VIP) in certain
I. INTRODUCTION
ENTERIC ANd CARdIAC NERvES
postganglionic parasympathetic neurons comes from pharmacological studies performed by Lundberg in 1981 on cat salivary glands (see [9]). ACh and VIP are released from the same parasympathetic nerve terminals in response to transmural nerve stimulation. During low frequency stimulation ACh is released to cause an increase in salivary secretion from acinar cells and also to elicit some minor dilatation of blood vessels in the gland. VIP is preferentially released at high frequencies to cause marked vasodilatation of blood vessels and, while it has no direct effect on acinar cells, it acts as a neuromodulator to enhance both the postjunctional effect of ACh on acinar cell secretion and the release of ACh from nerve varicosities via prejunctional receptors. Vasodilator nerves to the uterine arteries in the guinea pig contain immunoreactivity to VIP, which coexists with dynorphin, NPY and somatostatin. NPY-like immunoreactivity has been reported in some of the choline acetyltransferase-/VIP-containing neurons of the parasympathetic ciliary, sphenopalatine, otic and pterygopalatine ganglia with targets including the iris and cerebral vessels. Autonomic control of penile erection, involving relaxation of the smooth muscle of the corpus cavernosum as well as dilatation of other penile vascular beds, has traditionally been attributed to the vasodilator effects of ACh and VIP released from parasympathetic nerves. More recently, nitric oxide (NO) released from nerves arising from nerves in the pelvic ganglia, have been claimed to play a role in smooth muscle relaxation leading to penile erection. NO synthase (NOS)-containing fibers, shown by lesion studies to arise from parasympathetic cell bodies in the sphenopalatine ganglia, have been localized in the adventitia of cerebral arteries and many of these also contain VIP. A functional role for perivascular neuronal NO in cerebral arteries has been identified in studies showing that stimulation of adventitial nerve fibers causes vascular relaxation, which is attenuated by inhibitors of NOS. Parasympathetic nerves supplying the urinary bladder utilize ACh and ATP as cotransmitters, in variable proportions in different species, and by analogy with sympathetic nerves, ATP again acts through P2X ionotropic receptors to produce EJPs and fast contraction, while the slow component of the response is mediated by a metabotropic receptor, in this case muscarinic (see [10]). There is also evidence for parasympathetic, purinergic cotransmission to resistance vessels in the heart and airways.
SENSORY-MOTOR NERVES The neuropeptides substance P (SP) and calcitonin gene-related peptide (CGRP) are the principal transmitters of primary afferent nerves and have been shown to coexist in the same terminals. Furthermore, with the use of colloidal gold particles of different sizes, they have been shown to coexist in the same large granular vesicles. The motor (efferent) function of sensory nerves has been
29
demonstrated in rat mesenteric arteries where evidence exists for a role for CGRP as the mediator of vasodilatation following release from sensory motor nerves. In contrast, SP is not co-released with CGRP by electrical stimulation and SP has little or no vasodilator action on rat mesenteric arteries. While it is possible that SP released from nerves supplying the microvasculature could produce vasodilatation via SP receptors on endothelial cells, it is most unlikely to reach the endothelium without degradation in larger blood vessels. It may be that the role of the coexisting SP is either trophic or sensory (and not motor). Other peptide and non-peptide substances including neurokinin A, somatostatin, VIP and ATP have been described in capsaicin-sensitive sensory neurons. Unmyelinated sensory neurons containing cholecystokinin (CCK)/CGRP/dynorphin/SP have been shown to project to cutaneous arterioles in guinea pig skin. Neurons from the same ganglia which contain CCK/CGRP/SP, innovate arterioles of skeletal muscle, CGRP/dynorphin/ SP nerve fibers mostly supply the pelvic viscera, and CGRP/SP fibers run mainly to the heart, large arteries, and veins. There is also evidence for a sensory role for ATP and it has been proposed that ATP may coexist in sensory nerve terminals with SP and CGRP (Fig. 5.2).
ENTERIC AND CARDIAC NERVES Intrinsic neurons exist in most of the major organs of the body. Many of these are part of the parasympathetic nervous system, but certainly in the gut and perhaps also in the heart and airways, some of these intrinsic neurons are derived from neural crest tissue, which differs from that which forms the sympathetic and parasympathetic systems and appear to participate in local reflex actions independent of the CNS. The enteric nervous system contains several hundred million neurons located in the myenteric plexus between muscle coats and the submucous plexus. The chemical coding of these nerves has been examined in detail. A subpopulation of these intramural enteric nerves provides NANC inhibitory innervation of the gastrointestinal smooth muscle. It seems likely that three major cotransmitters are released from these nerves. ATP produces fast inhibitory junction potentials, NO also produces inhibitory potentials but with a slower time course, while VIP produces slow tonic relaxations. The proportions of these three transmitters varies considerably in different regions of the gut and in different species; for example, in some sphincters the NANC inhibitory nerves utilize largely VIP, in others largely NO, while in non-sphincteric regions of the intestine ATP is more prominent. In recent papers, evidence has suggested that ACh and ATP are fast excitatory cotransmitters to myenteric neurons and that there may be colocalization of ACh, ATP and 5-HT in enteric Dogiel Type I/S neurons. Detailed studies have allowed a very complete mapping of the complex neuronal markers and
I. INTRODUCTION
30
5. CoTRANSmISSIoN
FIGURE 5.2 Schematic hypotheses of the neurogenic basis of reflex vasodilatation of skin vessels. One suggestion is that substance P (a putative transmitter in sensory nerve endings in the spinal cord) is released from sensory nerve collaterals in the skin; another that ATP is the transmitter released from these collaterals. Both substances are powerful vasodilators and can release histamine from mast cells. ATP is also a potent inducer of prostaglandin synthesis. Another alternative, although less likely, is that a peripherally placed purinergic neuron is interposed between the sensory nerve collateral and the effector system. (This hypothesis incorporates early histologic reports of neurons in the skin and provides an alternative or additional explanation for the initiation of the vasodilator reflex by nicotine and its block by hexamethonium.) (Reproduced from [15], with permission.)
projections of enteric neurons. Several peptidergic substances, including NPY, VIP, enkephalin, somatostatin, peptide histidine isoleucine, galanin, SP and CGRP have been identified in enteric neurons, often coexisting (up to five peptides in the same neuron) with the neurotransmitters NA, ACh, 5-HT, NO and ATP (see Table 5.2). Studies of intrinsic cardiac neurons in culture have shown that subpopulations of intrinsic nerves in the atrial and intra-atrial septum contain and/or release cotransmitters, including ATP, NO, NPY, ACh and 5-HT. Many of these nerves project to the coronary microvasculature and produce potent vasomotor actions. NO together with ATP have been shown to be the mediators of NANC vasodilatation of the rabbit portal vein.
PHYSIOLOGICAL SIGNIFICANCE OF COTRANSMISSION In general, cotransmission offers greater physiological events by peripheral mechanisms rather than the all-ornone control by messages coming from the CNS, that has been the dominant view for many years (see [11]).
Cotransmitters with Different Firing Patterns Although single presynaptic action potentials release small molecule neurotransmitters, trains of impulses are
needed to release neuropeptides. For sympathetic and parasympathetic cotransmission, release of ATP is favored at low frequency stimulation, whereas NA and ACh are released at higher frequencies. There are instances where more than one fast cotransmitter is released (e.g. glutamate and ATP) together with one or more peptides.
Different Cotransmitters act on Different Postjunctional Cells Neurons using multiple transmitters may project to two or more targets. For example, ACh released at low frequency stimulation from parasympathetic nerves supplying salivary glands acts on acinar cells to produce secretion and a minor dilatation of vessels, whereas, at higher frequency stimulation, its cotransmitter VIP causes powerful vasodilatation of vessels in the glands and postjunctional enhancement of ACh-induced saliva secretion.
Neuromodulation A cotransmitter can feed back on presynaptic receptors that increase or decrease its own release or that of its cotransmitter(s). For example, ATP released as a cotransmitter with glutamate from primary afferent fibers in lamina II of the spinal cord can act on prejunctional P2X3 receptors to facilitate the release of its cotransmitter, glutamate,
I. INTRODUCTION
31
PHySIologICAl SIgNIfICANCE of CoTRANSmISSIoN
TABLE 5.2 Types of Neurons in the Enteric Nervous System Proportion
Chemical Coding
Function/Comments
Excitatory circular muscle motor neurons
12%
Short: ChAT/TK/ENK/GABA Long: ChAT/TK/ENK/NFP
To all regions, primary transmitter ACh, cotransmitter TK
Inhibitory circular muscle motor neurons
16%
Short: NOS/VIP/PACAP/ENK/ NPY/GABA Long: NOS/VIP/PACAP/ Dynorphin/BN/NFP
Several cotransmitters with varying prominence: NO, ATP, VIP, PACAP
Excitatory longitudinal muscle motor neurons
25%
ChAT/Calretinin/TK
Primary transmitter ACh, cotransmitter TK
Inhibitory longitudinal muscle motor neurons
~2%
NOS/VIP/GABA
Several cotransmitters with varying prominence: NO, ATP, VIP, PACAP
Ascending interneurons (local reflex)
5%
ChAT/Calretinin/TK
Primary transmitter ACh
Descending interneurons (local reflex)
5%
ChAT/NOS/VIP BN NPY
Primary transmitter ACh, ATP may be a cotransmitter
Descending interneurons (secretomotor reflex)
2%
ChAT/5-HT
Primary transmitter ACh, 5-HT (at NK3 receptors)
Descending interneurons (migrating myoelectric complex)
4%
ChAT/SOM
Primary transmitter ACh
Myenteric intrinsic primary afferent (primary sensory) neurons
26%
ChAT/Calbindin/TK/NK3 receptor
Primary transmitter TK
Intestinofugal neurons
1%
ChAT/BN/VIP/CCK/ENK
Primary transmitter ACh
Motor neurons to gut endocrine cells
N/A
N/A
For example, myenteric neurons innervating gastrin cells. Neurons of this type may be in submucosal ganglia
Non-cholinergic secretomotor/vasodilator neurons
45%
VIP/GAL
Primary transmitter VIP. A small proportion of these have cell bodies in myenteric ganglia
Cholinergic secretomotor/vasodilator neurons
15%
ChAT/Calretinin/Dynorphin
Primary transmitter ACh
MYENTERIC NEURONS
SUBMUCOSAL NEURONS
*Also listed are three types of motor neuron that are found in other parts of the tubular digestive tract, marked by asterisks. Reproduced from [13], with permission from Elsevier. ACh, acetylcholine; ATP, adenosine 5-triphosphate; BN, bombesin; CCK, cholecystokinin; CGRP, calcitonin gene-related peptide; ChAT, choline acetyltransferase; DA, dopamine; ENK, enkephalin; GABA, γ-amino butyric acid; GAL, galanin; 5-HT, 5-hydroxytryptamine; NA, noradrenaline; NFP, neurofilament protein; NK, neurokinin; NOS, nitric oxide synthase; NPY, neuropeptide Y; PACAP, pituitary adenylyl cyclase activating peptide; SOM, somatostatin; SP, substance P; TK, tachykinin; VIP, vasoactive intestinal peptide.
whereas adenosine resulting from ectoenzymatic breakdown of ATP acts on presynaptic P1 receptors to inhibit glutamate release. Both NA and ATP can prejunctionally modulate sympathetic transmission, NA via prejunctional α2-adrenoceptors and ATP via P1 receptors following breakdown to adenosine. Modulation of cotransmitter release and presynaptic action by other agents also occurs and might provide a new level of synaptic flexibility, in which individual neurons utilize more than one transmitter but retain independent control over their synaptic activity.
Synergism There are an increasing number of reports of the synergistic actions of cotransmitters. ATP and NA released from sympathetic nerves have synergistic actions on
smooth muscle of vas deferens and blood vessels, and ATP released with ACh from motoneurons facilitates the nicotinic actions of ACh at the skeletal neuromuscular junction. Co-operativity between receptors for ATP and N-methyl-D-aspartate (NMDA) in induction of long-term potentiation in hippocampal CA1 neurons has also been demonstrated. Thyrotropin-releasing hormone and 5-HT have been reported to have synergistic actions in spinal cord neurons. The mechanisms underlying cotransmitter synergism are not well understood. However, it has been suggested that postjunctional synergism between the responses of vas deferens to NA and ATP is caused by the ability of NA to potentiate the contractile responses to ATP by sensitizing smooth muscle cells to Ca2 via an inhibitory action on myosin light chain phosphatase,
