Primer on the Autonomic Nervous System

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

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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).

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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]