Primer on the Autonomic Nervous System
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- Greatly amplified and updated from previous edition including the latest developments in the field of autonomic cardiovascular regulation and neuroscience
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- Discusses stress and how its effects on the body are mediated
- Compiles contributions by over 140 experts on the autonomic nervous system
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Primer on the Autonomic Nervous System - Phillip A. Low
Table of Contents
Cover image
Front-matter
Copyright
Preface
List of Contributors
Chapter 1. Development and Differentiation of Autonomic Neurons
Chapter 2. Central Autonomic Control
Chapter 3. Imaging of Brainstem Sites Involved in Cardiovascular Control
Chapter 4. Peripheral Autonomic Nervous System
Chapter 5. Cotransmission
Chapter 6. Noradrenergic Neurotransmission
Chapter 7. Tyrosine Hydroxylase
Chapter 8. Antidepressant-Sensitive Norepinephrine Transporters
Chapter 9. α1-Adrenergic Receptors
Chapter 10. α2-Adrenergic Receptors
Chapter 11. β-Adrenergic Receptors
Chapter 12. Dopaminergic Neurotransmission
Chapter 13. Dopamine Receptors
Chapter 14. Cholinergic Neurotransmission
Chapter 15. Acetylcholine and Muscarinic Receptors
Chapter 16. Nicotinic Receptors
Chapter 17. Serotonin Receptors and Neurotransmission
Chapter 18. Purinergic Neurotransmission and Nucleotide Receptors
Chapter 19. Adenosine Receptors and Autonomic Regulation
Chapter 20. Nitric Oxide and Autonomic Regulation
Chapter 21. Glutamatergic Neurotransmission
Chapter 22. GABAergic Neurotransmission
Chapter 23. Renin-Angiotensin
Chapter 24. Aldosterone and the Mineralocorticoid Receptor
Chapter 25. Vasopressin and Disorders of Water Homeostasis
Chapter 26. Calcitonin Gene-Related Peptide and Adrenomedullin
Chapter 27. Leptin Signaling and Energy Homeostasis
Chapter 28. The Endothelin System
Chapter 29. Pharmacology of the Nucleous Tractus Solitarii
Chapter 30. Entrainment of Sympathetic Rhythms
Chapter 31. Cross-talk Between Body Systems
Chapter 32. Circadian Rhythms and Autonomic Function
Chapter 33. Baroreceptor Reflexes
Chapter 34. Genetic Determinants of Baroreflex Function
Chapter 35. Cardiac and Other Visceral Afferents
Chapter 36. Autonomic Control of the Heart
Chapter 37. Cardiac Vagal Ganglia
Chapter 38. Neural Control of Blood Vessels
Chapter 39. Physiology of Upright Posture
Chapter 40. Cerebral Circulation
Chapter 41. Autonomic Control of the Lower Airways
Chapter 42. Gastrointestinal Function
Chapter 43. The Splanchnic Circulation
Chapter 44. Autonomic Control of the Kidney
Chapter 45. Dopamine Mechanisms in the Kidney
Chapter 46. Autonomic Control of the Lower Urinary Tract
Chapter 47. Bladder Function in Health and Disease
Chapter 48. Physiology and Pathophysiology of Female Sexual Function
Chapter 49. Control of the Pupil
Chapter 50. Central Thermoregulation
Chapter 51. Sweating
Chapter 52. Regulation of Metabolism
Chapter 53. Autonomic Innervation of the Skeleton
Chapter 54. Sex Differences in Autonomic Function
Chapter 55. Autonomic Control During Pregnancy
Chapter 56. Aging and the Autonomic Nervous System
Chapter 57. Exercise
Chapter 58. Effects of High Altitude
Chapter 59. Space Physiology
Chapter 60. Hypothermia and Hyperthermia
Chapter 61. Psychological Stress and the Autonomic Nervous System
Chapter 62. Mind–Body Interactions
Chapter 63. Alpha-Synuclein and Neurodegeneration
Chapter 64. Insulin Resistance and the Autonomic Nervous System
Chapter 65. Salt Sensitivity of Blood Pressure
Chapter 66. Endothelial Dysfunction
Chapter 67. Inflammation, Immunity and the Autonomic Nervous System
Chapter 68. Oxygen Sensing
Chapter 69. Reactive Oxygen Species and Oxidative Stress
Chapter 70. Neurally Mediated Syncope
Chapter 71. Sympatho-Vagal Imbalance in Hypertension
Chapter 72. Baroreflex Failure
Chapter 73. Blood Pressure Variability
Chapter 74. Obesity-Associated Hypertension
Chapter 75. Orthostatic Hypertension
Chapter 76. Heart Failure
Chapter 77. Stress Cardiomyopathy and Takotsubo Syndrome
Chapter 78. Clinical Evaluation of Autonomic Disorders
Chapter 79. Tilt Table Studies
10. Questions About Head-Up Tilt Table Testing
Chapter 80. Sympathetic Microneurography
Chapter 81. Clinical Applications of Microneurography
Chapter 82. Clinical Sympathetic Imaging
Chapter 83. Assessment of the Autonomic Control of the Cardiovascular System by a Frequency Domain Approach
Chapter 84. Assessment of Sudomotor Function
Chapter 85. Cutaneous Autonomic Innervation
Chapter 86. Pheochromocytoma
Chapter 87. Deficiencies of Tetrahydrobiopterin, Tyrosine Hydroxylase and Aromatic L-Amino Acid Decarboxylase
Chapter 88. Dopamine β-Hydroxylase Deficiency
Chapter 89. Menkes Disease and Other ATP7A-Related Phenotypes
Chapter 90. Norepinephrine Transporter Deficiency
Chapter 91. Monoamine Oxidase Deficiency
Chapter 92. Congenital Central Hypoventilation Syndrome (CCHS) and PHOX2B Mutations
Chapter 93. Multiple System Atrophy
Chapter 94. Parkinson’s Disease
Chapter 95. Dementia with Lewy Bodies
Chapter 96. Pure Autonomic Failure
Chapter 97. Diagnostic Workup of Peripheral Neuropathies with Dysautonomia
Chapter 98. Diabetic Autonomic Dysfunction
Chapter 99. Amyloidotic Autonomic Failure
Chapter 100. Autoimmune Autonomic Ganglionopathy
Chapter 101. Guillain–Barré Syndrome
Chapter 102. Hereditary Autonomic Neuropathies
Chapter 103. Familial Dysautonomia (Riley–Day Syndrome)
Chapter 104. Autonomic Disturbances in Spinal Cord Injuries
Chapter 105. Drug-Induced Autonomic Dysfunction
Chapter 106. Postural Tachycardia Syndrome (POTS)
Chapter 107. Mechanisms of Postural Tachycardia Syndrome
Chapter 108. Symptoms and Signs of Postural Tachycardia Syndrome (POTS)
Chapter 109. Delayed Orthostatic Hypotension
Chapter 110. Chronic Fatigue Syndrome and the Autonomic Nervous System
Chapter 111. Joint Hypermobility Syndrome and Dysautonomia
Chapter 112. Neuroleptic Malignant Syndrome
Chapter 113. Migraine and the Autonomic Nervous System*
Chapter 114. Epilepsy and Autonomic Regulation
Chapter 115. Disorders of Sweating
Chapter 116. Male Erectile Dysfunction
Chapter 117. Sleep Apnea
Chapter 118. Altered Adrenal Function and the Autonomic Nervous System
Chapter 119. Mastocytosis
Chapter 120. Cocaine Overdose
Chapter 121. Complex Regional Pain Syndrome
Chapter 122. Carcinoid Tumors
Chapter 123. Paraneoplastic Autonomic Dysfunction
Chapter 124. Abdominal Pain and Cyclic Vomiting
Chapter 125. Fecal Incontinence
Chapter 126. Panic Disorder
Chapter 127. Physical Measures
Chapter 128. Water and the Osmopressor Response
Chapter 129. Droxidopa (L-DOPS)
Chapter 130. Midodrine, Adrenergic Agonists and Antagonists
Chapter 131. Agents Potentiating Sympathetic Tone
Chapter 132. Acetylcholinesterase and its Inhibitors
Chapter 133. Fludrocortisone
Chapter 134. Acarbose
Chapter 135. Erythropoietin in Autonomic Failure
Chapter 136. Somatostatin Agonists
Chapter 137. Harnessing the Autonomic Nervous System for Therapeutic Intervention
Chapter 138. Acupuncture Regulation of Cardiovascular Function
Chapter 139. Bionic Baroreflex
Chapter 140. Anesthetic Management in Autonomic Disorders
Chapter 141. Evolution of the Cardiovascular Autonomic Nervous System in Vertebrates
Chapter 142. Human Physiome
Chapter 143. Modeling the Autonomic Nervous System
Chapter 144. Optogenetics
Index
Front-matter
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
Academic Press is an imprint of Elsevier
Copyright
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: permissions@elsevier.com. 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 13 14 15 10 9 8 7 6 5 4 3 2 1
Preface
David Robertson
Italo Biaggioni
Geoffrey Burnstock
Phillip A. Low
Julian F.R. Paton
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 david.robertson@vanderbilt.edu.
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
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
ⅈ 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
ⅈ 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
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 Erlangen-Nuremberg, 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
ⅈ Wilfrid Jänig
Physiologisches Institut, Christian-Albrechts-Universität 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
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
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
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
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
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
Chapter 1. Development and Differentiation of Autonomic Neurons
Chun-Hyung Kim and Kwang-Soo Kim
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 fate-determining 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.
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 fate-determining 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.
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 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.
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] and [3].
Signaling Molecules Regulate the Developmental Processes of the ANS
Recent studies have demonstrated that various signaling molecules, e.g., members of the bone morphogenic 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], [2], [3], [4] and [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] and [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] and [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 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] and [11].
Transcriptional Regulatory Code Underlying the Development and Phenotypic Specification of the ANS
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] and [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, 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], [16] and [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] and [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, 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.
GATA3
The zinc finger transcription factor GATA-3 is a master regulator of type 2T 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] and [27]. Loss-of-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 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′ 1.1kb 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 site-directed mutational analyses indicate that as little as 486bp 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 −263bp appears to have a cell-specific silencer function, the proximal part spanning −262 to +1bp is essential for high-level and cell-specific DBH promoter activity. In this 262bp 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 cis-regulatory 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 Phox2-binding 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] and [30]. DBH deficiency is a severe autonomic disorder exhibiting sympathetic noradrenergic 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], [34] and [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 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).
References
[1] Liem Jr, KF; Tremml, G; Roelink, H; Jessell, TM, Dorsal differentiation of neural plate cells induced by BMP-mediated signals from epidermal ectoderm, Cell 82 (1995) 969–979.
[2] Sauka-Spengler, T; Bronner-Fraser, M, A gene regulatory network orchestrates neural crest formation, Nat Rev Mol Cell Biol 9 (2008) 557–568.
[3] Christiansen, JH; Coles, EG; Wilkinson, DG, Molecular control of neural crest formation, migration and differentiation, Curr Opin Cell Biol 12 (2000) 719–724.
[4] Edlund, T; Jessell, TM, Progression from extrinsic to intrinsic signaling in cell fate specification: a view from the nervous system, Cell 96 (1999) 211–224.
[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 411 (2001) 325–330.
[6] Stern, CD; Artinger, KB; Bronner-Fraser, M, Tissue interactions affecting the migration and differentiation of neural crest cells in the chick embryo, Development 113 (1991) 207–216.
[7] Ernsberger, U; Rohrer, H, The development of the noradrenergic transmitter phenotype in postganglionic sympathetic neurons, Neurochem Res 21 (1996) 823–829.
[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 24 (1999) 861–870.
[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 20 (2000) 3004–3014.
[10] Francis, NJ; Landis, SC, Cellular and molecular determinants of sympathetic neuron development, Annu Rev Neurosci 22 (1999) 541–566.
[11] Taraviras, S; Pachnis, V, Development of the mammalian enteric nervous system, Curr Opin Genet Dev 9 (1999) 321–327.
[12] Goridis, C; Brunet, JF, Transcriptional control of neurotransmitter phenotype, Curr Opin Neurobiol 9 (1999) 47–53.
[13] Goridis, C; Rohrer, H, Specification of catecholaminergic and serotonergic neurons, Nat Rev Neurosci 3 (2002) 531–541.
[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 75 (1993) 463–476.
[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 80 (2002) 905–916.
[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 Phox2a-binding sites, J Neurosci 18 (1998) 8247–8260.
[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 beta-hydroxylase gene, J Neurochem 71 (1998) 1813–1826.
[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 125 (1998) 599–608.
[19] Brunet, JF; Pattyn, A, Phox2 genes - from patterning to connectivity, Curr Opin Genet Dev 12 (2002) 435–440.
[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 18 (1997) 411–423.
[21] Pattyn, A; Goridis, C; Brunet, JF, Specification of the central noradrenergic phenotype by the homeobox gene Phox2b, Mol Cell Neurosci 15 (2000) 235–243.
[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 126 (1999) 4087–4094.
[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 25 (2000) 209–212.
[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 98 (2006) 773–781.
[25] Hong, SJ; Choi, HJ; Hong, S; Huh, Y; Chae, H; et al., Transcription factor GATA-3 regulates the transcriptional activity of dopamine beta-hydroxylase by interacting with Sp1 and AP4, Neurochem Res 33 (2008) 1821–1831.
[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 283 (2008) 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 46 (2011) 245–251.
[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 314 (1986) 1494–1497.
[29] Seo, H; Yang, C; Kim, HS; Kim, KS, Multiple protein factors interact with the cis-regulatory elements of the proximal promoter in a cell-specific manner and regulate transcription of the dopamine beta-hydroxylase gene, J Neurosci 16 (1996) 4102–4112.
[30] Man in’t Veld, AJ; Boomsma, F; Moleman, P; Schalekamp, MA, Congenital dopamine-beta-hydroxylase deficiency. A novel orthostatic syndrome, Lancet 1 (1987) 183–188.
[31] Biaggioni, I; Goldstein, DS; Atkinson, T; Robertson, D, Dopamine-beta-hydroxylase deficiency in humans, Neurology 40 (1990) 370–373.
[32] Thomas, SA; Matsumoto, AM; Palmiter, RD, Noradrenaline is essential for mouse fetal development, Nature 374 (1995) 643–646.
[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 108 (2002) 140–147.
[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 41 (2004) 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 286 (2011) 9196–9204.
[36] Habecker, BA; Klein, MG; Sundgren, NC; Li, W; Woodward, WR, Developmental regulation of neurotransmitter phenotype through tetrahydrobiopterin, J Neurosci 22 (2002) 9445–9452.
Chapter 2. Central Autonomic Control
Eduardo E. Benarroch
Central control of the sympathetic and parasympathetic outputs involves several interconnected areas distributed throughout the neuraxis. The functions of the central autonomic network are organized in four hierarchical levels, spinal, bulbopontine, pontomesencephalic and forebrain levels. 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 responses to stress. The brainstem autonomic areas include the periaqueductal gray, the parabrachial nucleus, nucleus of the solitary tract, ventrolateral medulla, and medullary raphe. The forebrain regions involved in control of autonomic functions include the insular cortex, anterior cingulate cortex, amygdala, and the hypothalamus. These regions participate in integrated control of autonomic responses for homeostasis, adaptation, and emotional and goal-oriented behaviors.
Keywords
anterior cingulate; insula; paraventricular nucleus; periaqueductal gray; parabrachial nucleus; nucleus of the solitary tract; ventrolateral medulla.
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.
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.
Insular Cortex
The insular cortex is the primary interoceptive cortex and integrates visceral, pain and temperature sensations [1]