From neuron to brain 5th edition pdf download

FIFTH EDITION
 From
Neuron
to Brain
FIFTH EDITION

John G. Nicholls
International School for Advanced Studies, Trieste, Italy

A. Robert Martin
Emeritus, University of Colorado School of Medicine

Paul A. Fuchs
The Johns Hopkins University School of Medicine

David A. Brown
University College London

Mathew E. Diamond
International School for Advanced Studies, Trieste, Italy

David A. Weisblat
University of California, Berkeley

Sinauer Associates, Inc. • Publishers

Sunderland, Massachusetts • USA
ABOUT THE COVER
Computer artwork of a human brain © Pasieka/Science Photo
Library/Fotosearch. Neurons (background) are from the
Third Edition cover, designed by Laszlo Meszoly.

From Neuron to Brain, Fifth Edition

Copyright © 2012 by Sinauer Associates, Inc.
All rights reserved. This book may not be reproduced in
whole or in part without permission.
Address inquiries and orders to
Sinauer Associates, Inc.
23 Plumtree Road
Sunderland, MA 01375 U.S.A.
FAX: 413-549-1118
E-mail: publish@sinauer.com
Internet: www.sinauer.com

Library of Congress Cataloging-in-Publication Data

From neuron to brain / John G. Nicholls ... [et al.]. -- 5th ed.
p. cm.
Includes bibliographical references and index.
ISBN 978-0-87893-609-0
1. Neurophysiology. 2. Brain. 3. Neurons. I. Nicholls, John G.
QP355.2.K83 2012
612.8--dc23
2011037528

8 7 6 5 4 3 2 1 Printed in U.S.A.
This book is dedicated to the memory of our friend
and colleague, Steve Kuffler.

In a career that spanned 40 years, Stephen Kuffler made experiments on funda-

mental problems and laid paths for future research to follow. A feature of his work
is the way in which the right problem was tackled using the right preparation.
Examples are his studies on denervation, stretch receptors, efferent control, in-
hibition, GABA and peptides as transmitters, integration in the retina, glial cells,
and the analysis of synaptic transmission. What gave papers by Stephen Kuffler a
special quality were the clarity, the beautiful figures, and the underlying excitement.
Moreover, he himself had done every experiment he described. Stephen Kuffler’s
work exemplified and introduced a multidisciplinary approach to the study of
the nervous system. At Harvard he created the first department of neurobiology,
in which he brought together people from different disciplines who developed
new ways of thinking. Those who knew him remember a unique combination of
tolerance, firmness, kindness, and good sense with enduring humor. He was the
J. F. Enders University Professor at Harvard, and was associated with the Marine
Biological Laboratory at Woods Hole. Among his many honors was his election
as a foreign member of the Royal Society.
Preface to the Fifth Edition
When the First Edition of our book appeared in 1976, its pref- date. In addition there are two obvious, major changes from the
ace stated that our aim was “…to describe how nerve cells go last edition. First, as in the original text by Kuffler and Nicholls,
about their business of transmitting signals, how the signals are a discussion of the visual system now comes in the first part of
put together, and how out of this integration higher functions the book, with the same intent. Placing this information at the
emerge. This book is directed to the reader who is curious about beginning of the book highlights its importance and immediately
the workings of the nervous system but does not necessarily have gives the reader a glimpse of the whole functioning “brain” that
a specialized background in biological sciences. We illustrate the comprises part of our title. Experience shows that a beginning
main points by selected examples…”. student who wants to know how the brain works is often drawn
This new, Fifth Edition has been written with the same aim in to the subject (as were the authors of this book) by fascination
mind but in a very different context. When the First Edition appeared with higher functions. Thanks to the elegance of work done on
there were hardly any books, and only a few journals devoted to the the retina and visual cortex, it is possible to show the clear link
nervous system. The extraordinary advances in molecular biology, between the properties of nerve cells and our visual perception.
genetics, and immunology had not yet been applied to the study of Moreover, this information can evoke curiosity about succeeding
nerve cells or the brain, and the internet was not available for searching chapters, which deal with the cellular, biophysical, and molecular
the literature. The explosion in knowledge since 1976 means that properties of nerve cells.
even though we still want to produce a readable narrative, the topics A second major change is in the number of authors. From
that have to be addressed and the number of pages have increased. two, then three and four, we have now grown to six authors. In
Inevitably, descriptions of certain older experiments have had to be the last years the amount of new information that is produced
jettisoned, even though they still seem beautiful. Nevertheless, our and the number of new techniques that must be described have
approach continues to be to follow ideas from their conception to grown faster than ever. As a result, the choices that have to be
the latest developments. To this end, in this edition we have retained made about what to include or leave out are so sophisticated that
descriptions of classical experiments as well as the newest findings. it would be a full-time task beyond the capabilities of two or three
In this way we hope to present key lines of research of interest for neuroscientists (especially if they still wished to continue their
practicing research workers and teachers of neurobiology, as well research and get grants). Nevertheless, as in the past, we have
as for readers who are not familiar with the field. aimed to maintain a consistent, continuous, narrative style. As in
For the Fifth Edition, new chapters have been added, others the past, we hope to make the whole book appear to the reader
have been completely rewritten and all have been brought up to as if it were the work of a single author.

John G. Nicholls A. Robert Martin Paul A. Fuchs

David A. Brown Mathew E. Diamond David A. Weisblat
October, 2011
Acknowledgments
We owe special thanks to our friend and colleague, Bruce Wal- and figures, including: K. Briggman, A. Brown, R. Constanzo, J.
lace, who was an author of the Third and Fourth Editions of Fernandez, D. Furness, M. S. Graziano, L. L. Iversen, A. Kaneko,
this book. Although it was not possible for him to collaborate J. Kinnamon, E. Knudsen, S. R. Levinson, A. Mallamaci, U. J.
for this Fifth Edition, material from his previous chapters has McMahan, R. Michaels, K. J. Muller, E. Newman, E. Puzuolo, R.
been used extensively in new chapters that have been rewrit- Reed, S. Roper, M. Ruegg, M. M. Salpeter, P. Shrager, P. Sterling,
ten and brought up to date. His work represents an essential M. Stryker, J. Taranda, R. Vassar, D. A. Wagenaar, and D. Zoccolan.
contribution and we are extremely grateful that we are able to It is a pleasure to thank Andy Sinauer, our publisher and
retain in the text much of his scholarly, clear, and authoritative friend. His remarkable sense of style, keen interest, and sound
expositions of key topics. judgment about the contents, illustrations, and appearance of the
We are grateful to the numerous colleagues who have encour- book have motivated and encouraged us at every stage. We were
aged us and influenced our thinking. We particularly thank Dr. fortunate to have the guidance of Sydney Carroll who was with
Denis Baylor, who read all of the chapters. For reading individual us from the inception of the book and provided valuable input to
chapters we thank Drs. W. Kolbinger, G. Legname, F. F. de Miguel, its design and layout. We are also grateful to Kathaleen Emerson,
K. J. Muller, U. J. McMahan, L. Szczupak, and C. Trueta. Helpful Chelsea Holabird, and Azelie Aquadro who edited our text with
discussions and advice were provided by E. Arabzadeh, S.Bensmaïa, great care and courtesy; Chris Small, Joan Gemme, and Marie
D. H. Jenkinson, W. B. Kristan, Jr., D.-H. Kuo, S. R. Levinson, A. Scavotto, who played major roles in producing this new edition,
Mallamaci, L. Mei, M. Ruegg, W. J. Thompson, and D. Zoccolan. and to artist Elizabeth Morales, who transformed our drawings
We are most grateful to colleagues who provided original plates and graphs into elegant and attractive figures.
From the Preface to the First Edition
Our aim is to describe how nerve cells go about their business and insoluble there lies a simplifying principle that will lead to an
of transmitting signals, how these signals are put together, and unraveling of the events. For example, the human brain consists
how out of this integration higher functions emerge. This book of over 10,000 million cells and many more connections that in
is directed to the reader who is curious about the workings of their detail appear to defy comprehension. Such complexity is
the nervous system but does not necessarily have a specialized at times mistaken for randomness; yet this is not so, and we can
background in biological sciences. We illustrate the main points show that the brain is constructed according to a highly ordered
by selected examples, preferably from work in which we have first- design, made up of relatively simple components. To perform all
hand experience. This approach introduces an obvious personal its functions it uses only a few signals and a stereotyped repeating
bias and certain omissions. pattern of activity. Therefore, a relatively small sampling of nerve
We do not attempt a comprehensive treatment of the ner- cells can sometimes reveal much of the plan of the organization
vous system, complete with references and background material. of connections, as in the visual system.
Rather, we prefer a personal and therefore restricted point of view, We also discuss “open-ended business,” areas that are devel-
presenting some of the advances of the past few decades by fol- oping and whose direction is therefore uncertain. As one might
lowing the thread of development as it has unraveled in the hands expect, the topics cannot at present be fitted into a neat scheme.
of a relatively small number of workers. A survey of the table of We hope, however, that they convey some of the flavor that makes
contents reveals that many essential and fascinating fields have research a series of adventures.
been left out: subjects like the cerebellum, the auditory system, From Neuron to Brain expresses our approach as well as our
eye movements, motor systems, and the corpus callosum, to name aims. We work mostly on the machinery that enables neurons to
a few. Our only excuse is that it seems preferable to provide a function. Students who become interested in the nervous system
coherent picture by selecting a few related topics to illustrate the almost always tell us that their curiosity stems from a desire to
usefulness of a cellular approach. understand perception, consciousness, behavior, or other higher
Throughout, we describe experiments on single cells or analyses functions of the brain. Knowing of our preoccupation with the
of simple assemblies of neurons in a wide range of species. In workings of isolated nerve cells or simple cell systems, they are
several instances the analysis has now reached the molecular level, frequently surprised that we ourselves started with similar motiva-
an advance that enables one to discuss some of the functional tions, and they are even more surprised that we have retained those
properties of nerve and muscle membranes in terms of specific interests. In fact, we believe we are working toward that goal (and
molecules. Fortunately, in the brains of all animals that have been in that respect probably do not differ from most of our colleagues
studied there is apparent a uniformity of principles for neuro- and predecessors). Our book aims to substantiate this claim and,
logical signaling. Therefore, with luck, examples from a lobster we hope, to show that we are pointed in the right direction.
or a leech will have relevance for our own nervous systems. As
physiologists we must pursue that luck, because we are convinced Stephen W. Kuffler John G. Nicholls
that behind each problem that appears extraordinarily complex August, 1975
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About the Authors

Mathew E. Diamond, David A. Weisblat, John G. Nicholls, Paul A. Fuchs,

A. Robert Martin, David A. Brown

John G. Nicholls is Professor of Neuro- A. Robert Martin is Professor Emeritus Paul A. Fuchs is Director of Research and
biology and Cognitive Neuroscience at in the Department of Physiology at the the John E. Bordley Professor of Otolar-
the International School for Advanced University of Colorado School of Medi- yngology-Head and Neck Surgery, Profes-
Studies in Trieste, Italy. He was born in cine. He was born in Saskatchewan in sor of Biomedical Engineering, Professor
London in 1929 and received a medical 1928 and majored in mathematics and of Neuroscience, and co-Director of the
degree from Charing Cross Hospital and physics at the University of Manitoba. Center for Sensory Biology at the Johns
a Ph.D in physiology from the Depart- He received a Ph.D. in Biophysics in 1955 Hopkins University School of Medicine.
ment of Biophysics at University College from University College, London, where Born in St. Louis, Missouri in 1951, Fuchs
London, where he did research under he worked on synaptic transmission in graduated in biology from Reed College
the direction of Sir Bernard Katz. He has mammalian muscle under the direction in 1974. He received a Ph.D. in Neuro-
worked at University College London, of Sir Bernard Katz. From 1955 to 1957 and Biobehavioral Sciences in 1979 from
at Oxford, Harvard, Yale, and Stanford he did postdoctoral research in the labo- Stanford University where he investigated
Universities and at the Biocenter in Basel. ratory of Herbert Jasper at the Montreal presynaptic inhibition at the crayfish neu-
With Stephen Kuffler, he made experi- Neurological Institute, studying the be- romuscular junction under the direction
ments on neuroglial cells and wrote the havior of single cells in the motor cor- of Donald Kennedy and Peter Getting.
First Edition of this book. He is a Fel- tex. He has taught at McGill University, From 1979 to 1981 he did postdoctoral
low of the Royal Society, a member of the University of Utah, Yale University, research with John Nicholls at Stanford
the Mexican Academy of Medicine, and and the University of Colorado Medical University, examining synapse formation
the recipient of the Venezuelan Order of School, and has been a visiting profes- by leech neurons. From 1981 to 1983 he
Andres Bello. He has given laboratory sor at Monash University, Edinburgh studied the efferent inhibition of audi-
and lecture courses in neurobiology at University, and the Australian National tory hair cells with Robert Fettiplace at
Woods Hole and Cold Spring Harbor, University. His research has contributed Cambridge University. He has taught at
and in universities in Asia, Africa, and to the understanding of synaptic trans- the University of Colorado and the Johns
Latin America. His work concerns re- mission, including the mechanisms of Hopkins University medical schools. His
generation of the nervous system after transmitter release, electrical coupling at research examines excitability and syn-
injury and mechanisms that give rise to synapses, and properties of postsynaptic aptic signaling of sensory hair cells and
the respiratory rhythm. ion channels. neurons in the vertebrate inner ear.
David A. Brown is Professor of Phar- Mathew E. Diamond is Professor of David A. Weisblat is Professor of Cell
macology in the Department of Neu- Cognitive Neuroscience at the Interna- and Developmental Biology in the De-
roscience, Physiology and Pharmacol- tional School for Advanced Studies in partment of Molecular and Cell Biology
ogy at University College London. He Trieste Italy (known by its Italian acro- at the University of California, Berkeley.
was born in London in 1936 and gained nym, SISSA). He earned a Bachelor of He was born in Kalamazoo, Michigan in
a B.Sc. in Physiology from University Science degree in Engineering from the 1949, studied biochemistry as an under-
College London and a Ph.D. from St. University of Virginia in 1984 and a Ph.D. graduate with Bernard Babior at Harvard
Bartholomew’s Hospital Medical Col- in Neurobiology from the University of College, where he was introduced to neu-
lege (“Barts”) in London studying trans- North Carolina in 1989. Diamond was robiology in a course led by John Nicholls.
mission in sympathetic ganglia in the a postdoctoral fellow with Ford Ebner at He received his Ph.D. from Caltech for
laboratory of Peter Quilliam (where he Brown University and then an assistant studies on the electrophysiology of Ascaris
first met John Nicholls). He then did a professor at Vanderbilt University before in 1976 with Richard Russell. He began
post-doc at the University of Chicago moving to SISSA to create the Tactile studying leech development with Gunther
where he helped design an integrated Perception and Learning Laboratory in Stent in the Department of Molecular
neurobiology course for graduate medi- 1996. His main interest is to specify the Biology at Berkeley and was appointed to
cal students. After returning to a junior relationship between neuronal activity the Zoology Department there in 1983.
faculty position at Barts, he subsequently and perception. The research is carried As a postdoc, he developed techniques for
chaired departments of Pharmacology at out mostly in the tactile whisker system cell lineage tracing by intracellular mi-
the School of Pharmacy in London and in rodents, but some experiments at- croinjection of tracer molecules. Current
finally at University College. In between tempt to generalize the principles found research interests include the evolution
times he has worked in several labs in the in the whisker system to the processing of segmentation mechanisms, D quad-
United States and elsewhere, including of information in the human tactile sen- rant specification, and axial patterning.
three semesters in A. M. Brown’s De- sory system. Work from his laboratory has helped to
partment of Physiology and Biophysics establish the leech Helobdella as a trac-
at the University of Texas in Galveston, table representative of the super-phylum
and a split year as Fogarty Scholar-in- Lophotrochozoa, for the study of evolu-
Residence at NIH in the labs of Michael tionary developmental biology. He has
Brownstein, Julie Axelrod, and Marshall assisted or organized courses in Africa,
Nirenberg. While at Galveston, he and India, Latin America, and at Woods Hole,
Paul Adams (another ex-Barts colleague) Massachusetts.
discovered the M-type potassium chan-
nel, which provided new insight into the
way neurotransmitters could alter nerve
cell excitability by indirectly regulating a
voltage-gated ion channel. He has since
worked on the regulation of other ion
channels by G protein–coupled recep-
tors and previously on the actions and
transport of GABA. He is a Fellow of the
Royal Society, a recipient of the Feldberg
Prize, and has an Honorary Doctorate
from the University of Kanazawa in Japan.
Brief Table of Contents

PART I Introduction to the Nervous PART IV Integrative Mechanisms 335

System 1 CHAPTER 17 Autonomic Nervous System 337
CHAPTER 1 Principles of Signaling and
CHAPTER 18 Cellular Mechanisms of Behavior
Organization 3
in Ants, Bees, and Leeches 355
CHAPTER 2 Signaling in the Visual System 23

CHAPTER 3 Functional Architecture of the Visual PART V Sensation and Movement 383
Cortex 43 CHAPTER 19 Sensory Transduction 385

CHAPTER 20 Transduction and Transmission

PART II Electrical Properties of in the Retina 407
Neurons and Glia 61
CHAPTER 21 Touch, Pain, and Texture
CHAPTER 4 Ion Channels and Signaling 63
Sensation 433
CHAPTER 5 Structure of Ion Channels 77
CHAPTER 22 Auditory and Vestibular Sensation 453
CHAPTER 6 Ionic Basis of the Resting Potential 99
CHAPTER 23 Constructing Perception 475
CHAPTER 7 Ionic Basis of the Action Potential 113
CHAPTER 24 Circuits Controlling Reflexes,
CHAPTER 8 Electrical Signaling in Neurons 129 Respiration, and Coordinated
Movements 497
CHAPTER 9 Ion Transport across Cell
Membranes 143
PART VI Development and
CHAPTER 10 Properties and Functions of Neuroglial Regeneration of the
Cells 159 Nervous System 529
CHAPTER 25 Development of the Nervous
PART III Intercellular System 531
Communication 183
CHAPTER 26 Critical Periods in Sensory
CHAPTER 11 Mechanisms of Direct Synaptic Systems 565
Transmission 185
CHAPTER 27 Regeneration of Synaptic Connections
CHAPTER 12 Indirect Mechanisms of Synaptic after Injury 589
Transmission 213

CHAPTER 13 Release of Neurotransmitters 243 PART VII Conclusion 613

CHAPTER 14 Neurotransmitters in the Central CHAPTER 28 Open Questions 615
Nervous System 273

CHAPTER 15 Transmitter Synthesis, Transport,

Storage, and Inactivation 299

CHAPTER 16 Synaptic Plasticity 317

Contents

PART I INTRODUCTION TO THE NERVOUS SYSTEM 1

■ CHAPTER 1 Principles of Signaling Integrative Mechanisms 18
and Organization 3 Complexity of the Information Conveyed by Action
Potentials 19
Signaling in Simple Neuronal Circuits 4
Reverse Traffic of Signals from Higher to Lower
Complex Neuronal Circuitry in Relation to Higher
Centers 19
Functions 4
Higher Functions of the Brain 20
Organization of the Retina 5
Cellular and Molecular Biology of Neurons 20
Shapes and Connections of Neurons 5
Cell Body, Axons, and Dendrites 7 Signals for Development of the Nervous System 20
Techniques for Identifying Neurons and Tracing Their Regeneration of the Nervous System after Injury 21
Connections 7
Non-Neuronal Cells 8 ■ CHAPTER 2 Signaling in the
Grouping of Cells According to Function 9 Visual System 23
Complexity of Connections 9 Pathways in the Visual System 24
Signaling in Nerve Cells 10 Convergence and Divergence of Connections 25
Universality of Electrical Signals 10 Receptive Fields of Ganglion and
Techniques for Recording Signals from Neurons with Geniculate Cells 26
Electrodes 11 Concept of Receptive Fields 26
Noninvasive Techniques for Recording The Output of the Retina 26
and Stimulating Neuronal Activity 11 Ganglion and Geniculate Cell Receptive Field
Spread of Local Graded Potentials and Passive Organization 27
Electrical Properties of Neurons 13 Sizes of Receptive Fields 28
Spread of Potential Changes in Photoreceptors and Classification of Ganglion and Geniculate Cells 29
Bipolar Cells 14
What Information Do Ganglion and Geniculate Cells
Properties of Action Potentials 14 Convey? 29
Propagation of Action Potentials along Nerve
■ Box 2.1 Strategies for Exploring the Cortex 30
Fibers 15
Action Potentials as the Neural Code 15 Cortical Receptive Fields 31
Synapses: The Sites for Cell-to-Cell Responses of Simple Cells 31
Communication 15 Synthesis of the Simple Receptive Field 33
Chemically Mediated Synaptic Transmission 15 Responses of Complex Cells 35
Excitation and Inhibition 16 Synthesis of the Complex Receptive Field 37
Electrical Transmission 17 Receptive Fields: Units for Form Perception 38
Modulation of Synaptic Efficacy 17
xiv Contents

■ CHAPTER 3 Functional Architecture of Cell Groupings for Color 52

the Visual Cortex 43 Connections of Magnocellular and Parvocellular
Pathways between V1 and Visual Area 2 (V2) 53
Retinotopic Maps 44
Relations between Ocular Dominance
From Lateral Geniculate Nucleus to Visual Cortex 45
and Orientation Columns 54
Segregation of Retinal Inputs to the Lateral Geniculate
Horizontal Intracortical Connections 55
Nucleus 45
Construction of a Single, Unified Visual Field from
Cytoarchitecture of the Visual Cortex 45
Inputs Arising in Two Eyes 56
Inputs, Outputs, and Layering of Cortex 47
■ Box 3.1 Corpus Callosum 57
Ocular Dominance Columns 48
Demonstration of Ocular Dominance Columns by Association Areas of Visual Cortex 57
Imaging 50 Where Do We Go from Here? 58
Orientation Columns 50

PART II ELECTRICAL PROPERTIES OF NEURONS AND GLIA 61

■ CHAPTER 4 Ion Channels and ■ Box 5.1 Classification of Amino Acids 81
Signaling 63 A Receptor Superfamily 81
Properties of Ion Channels 64 Receptor Structure and Function 82
The Nerve Cell Membrane 64 Structure of the Pore Lining 82
What Does an Ion Channel Look Like? 64 High-Resolution Imaging of the AChR 83
Channel Selectivity 65 Receptor Activation 84
Open and Closed States 65 Ion Selectivity and Conductance 84
Modes of Activation 66 Voltage-Activated Channels 86
Measurement of Single-Channel Currents 67 The Voltage-Activated Sodium Channel 86
Intracellular Recording with Microelectrodes 67 Amino Acid Sequence and Tertiary Structure of the
Channel Noise 67 Sodium Channel 86
Patch Clamp Recording 68 Voltage-Activated Calcium Channels 88
Single-Channel Currents 69 Voltage-Activated Potassium Channels 88
Channel Conductance 70 Pore Formation in Voltage-Activated Channels 89
Conductance and Permeability 72 High-Resolution Imaging of the Potassium
Channel 90
Equilibrium Potential 72
Selectivity and Conductance 90
The Nernst Equation 73
Gating of Voltage-Activated Channels 91
Nonlinear Current–Voltage Relations 73
Other Channels 92
Ion Permeation through Channels 74
Glutamate Receptors 92
■ Box 4.1 Measuring Channel Conductance 74
ATP-Activated Channels 94
Channels Activated by Cyclic Nucleotides 94
■ CHAPTER 5 Structure of Ion Calcium-Activated Potassium Channels 94
Channels 77 Voltage-Sensitive Chloride Channels 94
Ligand-Activated Channels 78 Inward-Rectifying Potassium Channels 95
The Nicotinic Acetylcholine Receptor 78 2P Channels 95
Amino Acid Sequence of AChR Subunits 79 Transient Receptor Potential (TRP) Channels 95
Higher Order Chemical Structure 79 Diversity of Subunits 95
Other Nicotinic ACh Receptors 79 Conclusion 96
 Contents xv

■ CHAPTER 6 Ionic Basis of the ■ CHAPTER 8 Electrical Signaling in

Resting Potential 99 Neurons 129
A Model Cell 100 Specific Electrical Properties of Cell Membranes 131
Ionic Equilibrium 100 Flow of Current in a Nerve Fiber 131
Electrical Neutrality 101 ■ Box 8.1 Relation between Cable Constants and
The Effect of Extracellular Potassium and Chloride on Specific Membrane Properties 133
Membrane Potential 102 Action Potential Propagation 134
Membrane Potentials in Squid Axons 103 Myelinated Nerves and
The Effect of Sodium Permeability 104 Saltatory Conduction 134
The Constant Field Equation 105 ■ Box 8.2 Classification of Vertebrate Nerve
The Resting Membrane Potential 106 Fibers 135

Chloride Distribution 107 Distribution of Channels in Myelinated Fibers 136

An Electrical Model of the Membrane 107 Geometry and Conduction Block 137
Predicted Values of Membrane Potential 108 Conduction in Dendrites 137
Contribution of the Sodium–Potassium Pump Pathways for Current Flow between Cells 139
to the Membrane Potential 109
What Ion Channels Are Associated with the Resting ■ CHAPTER 9 Ion Transport across Cell
Potential? 109 Membranes 143
Changes in Membrane Potential 110
The Sodium–Potassium Exchange Pump 144

■ CHAPTER 7 Ionic Basis of the Action Biochemical Properties of Sodium–Potassium

ATPase 144
Potential 113
Experimental Evidence that the Pump Is
Voltage Clamp Experiments 114 Electrogenic 144
Capacitative and Leak Currents 114 Mechanism of Ion Translocation 146
Ionic Currents Carried by Sodium and Calcium Pumps 147
Potassium 114
Endoplasmic and Sarcoplasmic Reticulum Calcium
Selective Poisons for Sodium ATPase 147
and Potassium Channels 115
Plasma Membrane Calcium ATPase 147
■ Box 7.1 The Voltage Clamp 116
Sodium–Calcium Exchange 147
Dependence of Ion Currents on Membrane The NCX Transport System 148
Potential 116
Reversal of Sodium–Calcium Exchange 148
Inactivation of the Sodium Current 117
Sodium–Calcium Exchange in Retinal Rods 149
Sodium and Potassium Conductances as Functions of
Potential 118 Chloride Transport 150
Inward Chloride Transport 150
Quantitative Description of Sodium
and Potassium Conductances 119 Outward Potassium–Chloride Cotransport 150
Reconstruction of the Action Potential 120 Chloride–Bicarbonate Exchange 150
Threshold and Refractory Period 120 Transport of Neurotransmitters 151
Gating Currents 122 Transport into Presynaptic Vesicles 151
Mechanisms of Activation and Transmitter Uptake 152
Inactivation 123 Molecular Structure of Transporters 153
Activation and Inactivation of Single Channels 124 ATPases 154
Afterpotentials 125 Sodium–Calcium Exchangers 155
The Role of Calcium in Excitation 127 Chloride Transporters 155
Calcium Action Potentials 127 Transport Molecules for Neurotransmitters 155
Calcium Ions and Excitability 128 Significance of Transport Mechanisms 156
xvi Contents

■ CHAPTER 10 Properties and Functions A Cautionary Note 171

of Neuroglial Cells 159 Effects of Neuronal Activity on Glial Cells 172
Historical Perspective 160 Potassium Accumulation in Extracellular Space 172
Appearance and Classification of Glial Cells 160 Potassium and Calcium Movement through Glial
Structural Relations between Neurons, Glia, and Cells 172
Capillaries 163 Calcium Waves in Glial Cells 173
Physiological Properties of Neuroglial Cell Spatial Buffering of Extracellular Potassium
Membranes 164 Concentration by Glia 174
Ion Channels, Pumps, and Receptors in Glial Cell Glial Cells and Neurotransmitters 174
Membranes 165 Release of Transmitters by Glial Cells 174
Electrical Coupling between Glial Cells 165 Immediate Effects of Glial Cells on Synaptic
Functions of Neuroglial Cells 165 Transmission 176
Myelin and the Role of Neuroglial Cells in Axonal Glial Cells and the Blood–Brain Barrier 176
Conduction 166 Astrocytes and Blood Flow through the Brain 177
Glial Cells and Development 168 ■ Box 10.1 The Blood–Brain Barrier 177
Role of Microglial Cells in CNS Repair and Transfer of Metabolites from Glial Cells to
Regeneration 169 Neurons 179
Schwann Cells as Pathways for Outgrowth in Peripheral
Glial Cells and Immune Responses of the CNS 179
Nerves 170

PART III INTERCELLULAR COMMUNICATION 183

■ CHAPTER 11 Mechanisms of Direct ■ Box 11.4 Electrical Model of the Motor End
Plate 198
Synaptic Transmission 185
Excitatory Synaptic Potentials in the CNS 199
Synaptic Transmission 186
Direct Synaptic Inhibition 201
Chemical Synaptic Transmission 186
Reversal of Inhibitory Potentials 201
■ Box 11.1 Electrical or Chemical
Transmission? 187
Presynaptic Inhibition 203
Transmitter Receptor Localization 205
Synaptic Structure 188
Synaptic Potentials at the Neuromuscular Electrical Synaptic Transmission 207
Junction 188 Identification and Characterization of Electrical
Synapses 207
■ Box 11.2 Drugs and Toxins Acting at the
Neuromuscular Junction 190 Comparison of Electrical and Chemical
Transmission 208
■ Box 11.3 Action of Tubocurarine at the Motor End
Plate 191
■ CHAPTER 12 Indirect Mechanisms of
Mapping the Region of the Muscle Fiber Receptive to Synaptic Transmission 213
ACh 192
Morphological Demonstration of the Distribution of Direct Versus Indirect Transmission 214
ACh Receptors 194 G Protein–Coupled Metabotropic Receptors and
Measurement of Ionic Currents Produced by ACh 195 G Proteins 215
Significance of the Reversal Potential 196 Structure of G Protein–Coupled Receptors 215
Relative Contributions of Sodium, Potassium, ■ Box 12.1 Receptors, G Proteins, and Effectors:
and Calcium to the End-Plate Potential 196 Convergence and Divergence in G Protein
Signaling 216
Resting Membrane Conductance and Synaptic Potential
Amplitude 196 G Proteins 216
Kinetics of Currents through Single ACh Receptor
Channels 197
 Contents xvii

Modulation of Ion Channel Function by Receptor- Statistical Analysis of the End-Plate Potential 252
Activated G Proteins: Direct Actions 217 ■ Box 13.1 Statistical Fluctuation in Quantal
G Protein Activation of Potassium Channels 217 Release 253
■ Box 12.2 Identifying Responses Mediated by G Quantum Content at Neuronal Synapses 255
Proteins 218 Number of Molecules in a Quantum 255
G Protein Inhibition of Calcium Channels Number of Channels Activated by a Quantum 256
Involved in Transmitter Release 221
Changes in Mean Quantal Size at the Neuromuscular
G Protein Activation of Cytoplasmic Second Junction 257
Messenger Systems 222 Nonquantal Release 257
β-Adrenergic Receptors Activate Calcium Channels via
Vesicles and Transmitter Release 258
a G Protein—the Adenylyl Cyclase Pathway 223
Ultrastructure of Nerve Terminals 258
■ Box 12.3 Cyclic AMP as a Second
Messenger 225
Morphological Evidence for Exocytosis 259
Release of Vesicle Contents by Exocytosis 261
■ Box 12.4 Phosphatidylinositol-4,5-bisphosphate
Monitoring Exocytosis and Endocytosis
(PIP2) and the phosphoinositide (PI) Cycle 227
in Living Cells 262
G Protein Activation of Phospholipase C 228 Mechanism of Exocytosis 264
Direct Actions of PIP2 229 High-Resolution Structure of Synaptic Vesicle
G Protein Activation of Phospholipase A2 230 Attachments 264
Convergence and Divergence of Signals Reuptake of Synaptic Vesicles 266
Generated by Indirectly Coupled Receptors 230 Vesicle Recycling Pathways 267
Retrograde Signaling via Endocannabinoids 231 Ribbon Synapses 269
■ Box 12.5 Formation and Metabolism of Vesicle Pools 270
Endocannabinoids 233
Signaling via Nitric Oxide and Carbon Monoxide 234 ■ CHAPTER 14 Neurotransmitters in the
Calcium as an Intracellular Second Messenger 235 Central Nervous System 273
Actions of Calcium 237 Chemical Transmission in the CNS 274
■ Box 12.6 Measuring Intracellular Calcium 238 Mapping Neurotransmitter Pathways 274
Prolonged Time Course of Indirect Transmitter ■ Box 14.1 The Discovery of Central Transmitters:
Action 239 I. The Amino Acids 275

■ Box 14.2 The Discovery of Central Transmitters:

■ CHAPTER 13 Release of II. Neuropeptides 277
Neurotransmitters 243 Visualizing Transmitter-Specific Neurons in Living
Characteristics of Transmitter Release 244 Brain Tissue 278
Axon Terminal Depolarization and Release 244 Key Transmitters 278
Synaptic Delay 245 Glutamate 279
Evidence that Calcium Is Required for Release 246 GABA (γ-Aminobutyric acid) and glycine 279
Measurement of Calcium Entry into Presynaptic Nerve Acetylcholine 281
Terminals 246 Biogenic Amines 287
Localization of Calcium Entry Sites 248 Adenosine Triphosphate (ATP) 290
Transmitter Release by Intracellular Concentration Peptides 292
Jumps 249 Substance P 293
Other Factors Regulating Transmitter Release 249 Opioid Peptides 293
Quantal Release 250 Orexins (Hypocretins) 294
Spontaneous Release of Multimolecular Quanta 251 Vasopressin and Oxytocin: The Social Brain 296
Fluctuations in the End-Plate Potential 252
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■ CHAPTER 15 Transmitter Synthesis, Removal of ATP by Hydrolysis 314

Transport, Storage, and Inactivation 299 Removal of Transmitters by Uptake 314
Neurotransmitter Synthesis 300
Synthesis of ACh 300 ■ CHAPTER 16 Synaptic Plasticity 317
Synthesis of Dopamine and Norepinephrine 302 Short-Term Changes in Signaling 318
Synthesis of 5-Hydroxytryptamine (5-HT) 304 Facilitation and Depression of Transmitter Release 318
Synthesis of GABA 305 Post-Tetanic Potentiation and Augmentation 319
Synthesis of Glutamate 305 Mechanisms Underlying Short-Term Synaptic
Short- and Long-Term Regulation of Transmitter Changes 320
Synthesis 305 Long-Term Changes in Signaling 323
Synthesis of Neuropeptides 306 Long-Term Potentiation 323
Storage of Transmitters in Synaptic Vesicles 307 Associative LTP in Hippocampal Pyramidal Cells 323
Co-Storage and Co-Release 308 Mechanisms Underlying the Induction of LTP 326
Axonal Transport 310 Silent Synapses 326
Rate and Direction of Axonal Transport 311 Presynaptic LTP 328
Microtubules and Fast Transport 311 Long-Term Depression 329
Mechanism of Slow Axonal Transport 311 LTD in the Cerebellum 331
Removal of Transmitters from the Synaptic Cleft 313 Mechanisms Underlying LTD 331
Removal of ACh by Acetylcholinesterase 313 Presynaptic LTD 332
Significance of Changes in Synaptic Efficacy 332

PART IV INTEGRATIVE MECHANISMS 335

■ CHAPTER 17 Autonomic Nervous From Behavior to Neurons and Vice Versa 356
System 337 Navigation by Ants and Bees 357
Functions under Involuntary Control 338 The Desert Ant’s Pathway Home 357
Sympathetic and Parasympathetic Nervous Polarized Light Detection by the Ant’s Eye 359
Systems 338 Strategies for Finding the Nest 361
Synaptic Transmission in Autonomic Ganglia 340 Polarized Light and Twisted Photoreceptors 361
M-Currents in Autonomic Ganglia 342 Additional Mechanisms for Navigation by Ants and
Transmitter Release by Postganglionic Axons 343 Bees 362
Purinergic Transmission 344 Neural Mechanisms for Navigation 364

■ Box 17.1 The Path to Understanding Sympathetic Behavioral Analysis at the Level of Individual
Mechanisms 344 Neurons in the CNS of the Leech 365
Leech Ganglia: Semiautonomous Units 365
Sensory Inputs to the Autonomic Nervous System 345
Sensory Cells in Leech Ganglia 367
The Enteric Nervous System 346
Motor Cells 370
Regulation of Autonomic Functions by the
Hypothalamus 347 Connections of Sensory and Motor Cells 371
Hypothalamic Neurons That Release Hormones 347 Higher Order Behaviors in the Leech 373
Distribution and Numbers of GnRH Cells 349 Habituation, Sensitization, and Conduction Block 374
Circadian Rhythms 349 Circuits Responsible for the Production of Rhythmical
Swimming 377
■ CHAPTER 18 Cellular Mechanisms To Swim or to Crawl? Neurons that Determine
Behavioral Choices in the Leech 378
of Behavior in Ants, Bees, and
Leeches 355 Why Should One Work on Invertebrate Nervous
Systems? 381
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PART V SENSATION AND MOVEMENT 383

■ CHAPTER 19 Sensory Structure of Rhodopsin 413
Transduction 385 Cones and Color Vision 413
Stimulus Coding by Mechanoreceptors 386 Color Blindness 415
Short and Long Receptors 386 Transduction 415
Encoding Stimulus Parameters by Stretch Properties of the Photoreceptor Channels 415
Receptors 387 Molecular Structure of Cyclic GMP–Gated
The Crayfish Stretch Receptor 388 Channels 416
Muscle Spindles 389 The cGMP Cascade 416
Responses to Static and Dynamic Muscle Stretch 390 Amplification through the cGMP Cascade 417
Mechanisms of Adaptation in Mechanoreceptors 391 Responses to Single Quanta of Light 417
Adaptation in the Pacinian Corpuscle 391 ■ Box 20.1 Adaptation of Photoreceptors 418
Direct Transduction by Mechanosensory Hair Circadian Photoreceptors in the Mammalian
Cells 392 Retina 420
Mechanosensory Hair Cells of the Vertebrate Ear 392 Synaptic Organization of the Retina 420
Structure of Hair Cell Receptors 393 Bipolar, Horizontal, and Amacrine cells 420
Transduction by Hair Bundle Deflection 394 Molecular Mechanisms of Synaptic Transmission in the
Tip Links and Gating Springs 395 Retina 421
Transduction Channels in Hair Cells 395 Receptive Fields of Retinal Neurons 422
Adaptation of Hair Cells 396 Responses of Bipolar Cells 423
Olfaction 397 Receptive Field Organization of Bipolar Cells 424
Olfactory Receptors 397 Rod Bipolar Cells 424
The Olfactory Response 398 Horizontal Cells and Surround Inhibition 424
Cyclic Nucleotide-Gated Channels in Olfactory Significance of Receptive Field Organization of Bipolar
Receptors 399 Cells 426
Coupling the Receptor to Ion Channels 399 Receptive Fields of Ganglion Cells 426
Odorant Specificity 400 The Output of the Retina 426
Mechanisms of Taste (Gustation) 401 Ganglion Cell Receptive Field Organization 427
Taste Receptor Cells 401 Sizes of Receptive Fields 427
Taste Modalities 402 Classification of Ganglion Cells 427
Pain and Temperature Sensation in Skin 403
Synaptic Inputs to Ganglion Cells Responsible
for Receptive Field Organization 428
Activation and Sensitization of Nociceptors 404
Amacrine Cell Control of Ganglion Cell
Responses 429
■ CHAPTER 20 Transduction and What Information Do Ganglion Cells Convey? 429
Transmission in the Retina 407
The Eye 408 ■ CHAPTER 21 Touch, Pain, and Texture
Anatomical Pathways in the Visual System 408 Sensation 433
Layering of Cells in the Retina 408 From Receptors to Cortex 434
Phototransduction in Retinal Rods and Cones 409 Receptors in the Skin 434
Arrangement and Morphology of Photoreceptors 410 Anatomy of Receptor Neurons 436
Electrical Responses of Vertebrate Photoreceptors to Sensations Evoked by Afferent Signals 436
Light 411
Ascending Pathways 437
Visual Pigments 412 Somatosensory Cortex 438
Absorption of Light by Visual Pigments 412
Pain Perception and its Modulation 439
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Somatosensory System Organization and Texture The Vestibulo-Ocular Reflex 471

Sensation in Rats and Mice 440 Higher Order Vestibular Function 471
The Whiskers of Mice and Rats 440
Magnification Factor 440 ■ CHAPTER 23 Constructing
Topographic Map of the Whiskers and Columnar Perception 475
Organization 441