Principles of Neural Science, 6th Edition PDF by Eric R. Kandel, John D. Koester, Sarah H. Mack and Steven A. Siegelbaum

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Principles of Neural Science, Sixth Edition

By Eric R. Kandel, John D. Koester, Sarah H. Mack and Steven A. Siegelbaum

Principles of Neural Science, Sixth Edition

Contents

Preface xli

Acknowledgments xliii

Contributors xlv

Part I

Overall Perspective

1 The Brain and Behavior. . . . . . . . . . . . . . .7

Eric R. Kandel, Michael N. Shadlen

Two Opposing Views Have Been Advanced on the

Relationship Between Brain and Behavior 8

The Brain Has Distinct Functional Regions 10

The First Strong Evidence for Localization of Cognitive

Abilities Came From Studies of Language Disorders 16

Mental Processes Are the Product of Interactions Between

Elementary Processing Units in the Brain 21

Highlights 23

Selected Reading 23

References 24

2 Genes and Behavior. . . . . . . . . . . . . . . . .26

Matthew W. State, Cornelia I. Bargmann, Conrad Gilliam

An Understanding of Molecular Genetics and Heritability

Is Essential to the Study of Human Behavior 27

The Understanding of the Structure and Function of the

Genome Is Evolving 27

Genes Are Arranged on Chromosomes 30

The Relationship Between Genotype and Phenotype Is

Often Complex 31

Genes Are Conserved Through Evolution 32

Genetic Regulation of Behavior Can Be Studied

in Animal Models 34

A Transcriptional Oscillator Regulates Circadian

Rhythm in Flies, Mice, and Humans 34

Natural Variation in a Protein Kinase Regulates Activity

in Flies and Honeybees 42

Neuropeptide Receptors Regulate the Social Behaviors

of Several Species 44

Studies of Human Genetic Syndromes Have

Provided Initial Insights Into the Underpinnings

of Social Behavior 46

Brain Disorders in Humans Result From Interactions

Between Genes and the Environment 46

Rare Neurodevelopmental Syndromes Provide Insights

Into the Biology of Social Behavior, Perception, and

Cognition 46

Psychiatric Disorders Involve Multigenic Traits 48

Advances in Autism Spectrum Disorder Genetics

Highlight the Role of Rare and De Novo Mutations in

Neurodevelopmental Disorders 48

Identification of Genes for Schizophrenia Highlights the

Interplay of Rare and Common Risk Variants 49

Perspectives on the Genetic Bases of Neuropsychiatric

Disorders 51

Highlights 51

Glossary 52

Selected Reading 53

References 53

3 Nerve Cells, Neural Circuitry, and Behavior . . . . . . . . . . . . . . . . . . . . . . .56

Michael N. Shadlen, Eric R. Kandel

The Nervous System Has Two Classes of Cells 57

Nerve Cells Are the Signaling Units of the Nervous

System 57

Glial Cells Support Nerve Cells 61

Each Nerve Cell Is Part of a Circuit That Mediates

Specific Behaviors 62

Signaling Is Organized in the Same Way in All

Nerve Cells 64

The Input Component Produces Graded

Local Signals 65

The Trigger Zone Makes the Decision to Generate an

Action Potential 67

The Conductive Component Propagates an All-or-None

Action Potential 67

The Output Component Releases Neurotransmitter 68

The Transformation of the Neural Signal From

Sensory to Motor Is Illustrated by the Stretch-Reflex

Pathway 68

Nerve Cells Differ Most at the Molecular Level 69

The Reflex Circuit Is a Starting Point for Understanding

the Neural Architecture of Behavior 70

Neural Circuits Can Be Modified by Experience 71

Highlights 71

Selected Reading 72

References 72

4 The Neuroanatomical Bases by Which Neural Circuits Mediate Behavior. . . . .73

David G. Amaral

Local Circuits Carry Out Specific Neural Computations

That Are Coordinated to Mediate Complex Behaviors 74

Sensory Information Circuits Are Illustrated in the

Somatosensory System 74

Somatosensory Information From the Trunk and Limbs

Is Conveyed to the Spinal Cord 76

The Primary Sensory Neurons of the Trunk and Limbs

Are Clustered in the Dorsal Root Ganglia 79

The Terminals of Central Axons of Dorsal Root

Ganglion Neurons in the Spinal Cord Produce a

Map of the Body Surface 81

Each Somatic Submodality Is Processed in a Distinct

Subsystem From the Periphery to the Brain 81

The Thalamus Is an Essential Link Between Sensory

Receptors and the Cerebral Cortex 82

Sensory Information Processing Culminates in the

Cerebral Cortex 84

Voluntary Movement Is Mediated by Direct Connections

Between the Cortex and Spinal Cord 89

Modulatory Systems in the Brain Influence Motivation,

Emotion, and Memory 89

The Peripheral Nervous System Is Anatomically Distinct

From the Central Nervous System 92

Memory Is a Complex Behavior Mediated by Structures

Distinct From Those That Carry Out Sensation

or Movement 93

The Hippocampal System Is Interconnected With the

Highest-Level Polysensory Cortical Regions 94

The Hippocampal Formation Comprises Several

Different but Highly Integrated Circuits 94

The Hippocampal Formation Is Made Up Mainly of

Unidirectional Connections 95

Highlights 95

Selected Reading 96

References 96

5 The Computational Bases of Neural Circuits That Mediate Behavior. . . . . . .97

Larry F. Abbott, Attila Losonczy, Nathaniel B. Sawtell

Neural Firing Patterns Provide a Code

for Information 98

Sensory Information Is Encoded by Neural Activity 98

Information Can Be Decoded From Neural Activity 99

Hippocampal Spatial Cognitive Maps Can Be Decoded

to Infer Location 99

Neural Circuit Motifs Provide a Basic Logic for

Information Processing 102

Visual Processing and Object Recognition Depend on a

Hierarchy of Feed-Forward Representations 103

Diverse Neuronal Representations in the Cerebellum

Provide a Basis for Learning 104

Recurrent Circuitry Underlies Sustained Activity and

Integration 105

Learning and Memory Depend on

Synaptic Plasticity 107

Dominant Patterns of Synaptic Input Can be Identified

by Hebbian Plasticity 107

Synaptic Plasticity in the Cerebellum Plays a Key Role

in Motor Learning 108

Highlights 110

Selected Reading 110

References 110

6 Imaging and Behavior. . . . . . . . . . . . . .111

Daphna Shohamy, Nick Turk-Browne

Functional MRI Experiments Measure Neurovascular

Activity 112

fMRI Depends on the Physics of Magnetic

Resonance 112

fMRI Depends on the Biology of Neurovascular

Coupling 115

Functional MRI Data Can Be Analyzed in Several

Ways 115

fMRI Data First Need to Be Prepared for Analysis by

Following Preprocessing Steps 115

fMRI Can Be Used to Localize Cognitive Functions to

Specific Brain Regions 118

fMRI Can Be Used to Decode What Information Is

Represented in the Brain 118

fMRI Can Be Used to Measure Correlated Activity

Across Brain Networks 119

Functional MRI Studies Have Led to Fundamental

Insights 120

fMRI Studies in Humans Have Inspired

Neurophysiological Studies in Animals 120

fMRI Studies Have Challenged Theories From Cognitive

Psychology and Systems Neuroscience 121

fMRI Studies Have Tested Predictions From Animal

Studies and Computational Models 122

Functional MRI Studies Require

Careful Interpretation 122

Future Progress Depends on Technological

and Conceptual Advances 123

Highlights 125

Suggested Reading 126

References 126

Part II

Cell and Molecular Biology of Cells of the Nervous System

7 The Cells of the Nervous System. . . . .133

Beth Stevens, Franck Polleux, Ben A. Barres

Neurons and Glia Share Many Structural and Molecular

Characteristics 134

The Cytoskeleton Determines Cell Shape 139

Protein Particles and Organelles Are Actively Transported

Along the Axon and Dendrites 142

Fast Axonal Transport Carries Membranous

Organelles 143

Slow Axonal Transport Carries Cytosolic Proteins and

Elements of the Cytoskeleton 146

Proteins Are Made in Neurons as in Other

Secretory Cells 147

Secretory and Membrane Proteins Are Synthesized and

Modified in the Endoplasmic Reticulum 147

Secretory Proteins Are Modified in the Golgi

Complex 149

Surface Membrane and Extracellular Substances Are

Recycled in the Cell 150

Glial Cells Play Diverse Roles in Neural

Function 151

Glia Form the Insulating Sheaths for

Axons 151

Astrocytes Support Synaptic Signaling 154

Microglia Have Diverse Functions

in Health and Disease 159

Choroid Plexus and Ependymal Cells Produce

Cerebrospinal Fluid 160

Highlights 162

Selected Reading 163

References 163

8 Ion Channels. . . . . . . . . . . . . . . . . . . . . .165

John D. Koester, Bruce P. Bean

Ion Channels Are Proteins That Span the Cell

Membrane 166

Ion Channels in All Cells Share Several Functional

Characteristics 169

Currents Through Single Ion Channels Can Be

Recorded 169

The Flux of Ions Through a Channel Differs From

Diffusion in Free Solution 171

The Opening and Closing of a Channel Involve

Conformational Changes 172

The Structure of Ion Channels Is Inferred From

Biophysical, Biochemical, and Molecular Biological

Studies 174

Ion Channels Can Be Grouped Into Gene

Families 177

X-Ray Crystallographic Analysis of Potassium Channel

Structure Provides Insight Into Mechanisms of Channel

Permeability and Selectivity 180

X-Ray Crystallographic Analysis of Voltage-Gated

Potassium Channel Structures Provides Insight into

Mechanisms of Channel Gating 182

The Structural Basis of the Selective Permeability of

Chloride Channels Reveals a Close Relation Between

Channels and Transporters 185

Highlights 187

Selected Reading 188

References 188

9 Membrane Potential and the Passive Electrical Properties of the Neuron. . . . . . . . . . . . . . . . . . . . . . . .190

John D. Koester, Steven A. Siegelbaum

The Resting Membrane Potential Results From the

Separation of Charge Across the Cell Membrane 191

The Resting Membrane Potential Is Determined by

Nongated and Gated Ion Channels 191

Open Channels in Glial Cells Are Permeable to

Potassium Only 193

Open Channels in Resting Nerve Cells Are Permeable to

Three Ion Species 194

The Electrochemical Gradients of Sodium, Potassium,

and Calcium Are Established by Active Transport

of the Ions 195

Chloride Ions Are Also Actively Transported 198

The Balance of Ion Fluxes in the Resting Membrane Is

Abolished During the Action Potential 198

The Contributions of Different Ions to the Resting

Membrane Potential Can Be Quantified by the

Goldman Equation 199

The Functional Properties of the Neuron Can Be

Represented as an Electrical Equivalent Circuit 199

The Passive Electrical Properties of the Neuron Affect

Electrical Signaling 201

Membrane Capacitance Slows the Time Course of

Electrical Signals 203

Membrane and Cytoplasmic Resistance Affect the

Efficiency of Signal Conduction 204

Large Axons Are More Easily Excited

Than Small Axons 206

Passive Membrane Properties and Axon Diameter

Affect the Velocity of Action Potential

Propagation 207

Highlights 208

Selected Reading 209

References 210

10 Propagated Signaling: The Action Potential . . . . . . . . . . . . . . . . . . . . . . . . .211

Bruce P. Bean, John D. Koester

The Action Potential Is Generated by the Flow of Ions

Through Voltage-Gated Channels 212

Sodium and Potassium Currents Through

Voltage-Gated Channels Are Recorded With the

Voltage Clamp 212

Voltage-Gated Sodium and Potassium Conductances

Are Calculated From Their Currents 217

The Action Potential Can Be Reconstructed

From the Properties of Sodium and Potassium

Channels 219

The Mechanisms of Voltage Gating Have Been Inferred

From Electrophysiological Measurements 220

Voltage-Gated Sodium Channels Select for Sodium

on the Basis of Size, Charge, and Energy of Hydration of

the Ion 222

Individual Neurons Have a Rich Variety of

Voltage-Gated Channels That Expand Their Signaling

Capabilities 224

The Diversity of Voltage-Gated Channel Types Is

Generated by Several Genetic Mechanisms 225

Voltage-Gated Sodium Channels 225

Voltage-Gated Calcium Channels 227

Voltage-Gated Potassium Channels 227

Voltage-Gated Hyperpolarization-Activated Cyclic

Nucleotide-Gated Channels 228

Gating of Ion Channels Can Be Controlled by

Cytoplasmic Calcium 228

Excitability Properties Vary Between Types of

Neurons 229

Excitability Properties Vary Between Regions of the

Neuron 231

Neuronal Excitability Is Plastic 233

Highlights 233

Selected Reading 234

References 234

Part III

Synaptic Transmission

11 Overview of Synaptic Transmission . . . . . . . . . . . . . . . . . . . . .241

Steven A. Siegelbaum, Gerald D. Fischbach

Synapses Are Predominantly Electrical or

Chemical 241

Electrical Synapses Provide Rapid Signal

Transmission 242

Cells at an Electrical Synapse Are Connected by

Gap-Junction Channels 244

Electrical Transmission Allows Rapid and Synchronous

Firing of Interconnected Cells 247

Gap Junctions Have a Role in Glial Function and

Disease 248

Chemical Synapses Can Amplify Signals 248

The Action of a Neurotransmitter Depends on the

Properties of the Postsynaptic Receptor 249

Activation of Postsynaptic Receptors Gates Ion

Channels Either Directly or Indirectly 250

Electrical and Chemical Synapses Can Coexist and

Interact 251

Highlights 252

Selected Reading 252

References 253

12 Directly Gated Transmission: The Nerve-Muscle Synapse . . . . . . . .254

Gerald D. Fischbach, Steven A. Siegelbaum

The Neuromuscular Junction Has Specialized Presynaptic

and Postsynaptic Structures 255

The Postsynaptic Potential Results From a Local Change

in Membrane Permeability 255

The Neurotransmitter Acetylcholine

Is Released in Discrete Packets 260

Individual Acetylcholine Receptor-Channels

Conduct All-or-None Currents 260

The Ion Channel at the End-Plate Is Permeable to Both

Sodium and Potassium Ions 260

Four Factors Determine the End-Plate

Current 262

The Acetylcholine Receptor-Channels Have Distinct

Properties That Distinguish Them From the

Voltage-Gated Channels That Generate the Muscle

Action Potential 262

Transmitter Binding Produces a Series of

State Changes in the Acetylcholine

Receptor-Channel 263

The Low-Resolution Structure of the Acetylcholine

Receptor Is Revealed by Molecular and

Biophysical Studies 264

The High-Resolution Structure of the Acetylcholine

Receptor-Channel Is Revealed by X-Ray

Crystal Studies 267

Highlights 268

Postscript: The End-Plate Current Can Be Calculated From

an Equivalent Circuit 269

Selected Reading 272

References 272

13 Synaptic Integration in the Central Nervous System. . . . . . . . . . . . . . . . . . .273

Rafael Yuste, Steven A. Siegelbaum

Central Neurons Receive Excitatory and Inhibitory

Inputs 274

Excitatory and Inhibitory Synapses Have Distinctive

Ultrastructures and Target Different Neuronal

Regions 274

Excitatory Synaptic Transmission Is Mediated by

Ionotropic Glutamate Receptor-Channels Permeable to

Cations 277

The Ionotropic Glutamate Receptors Are Encoded by a

Large Gene Family 278

Glutamate Receptors Are Constructed From a Set of

Structural Modules 279

NMDA and AMPA Receptors Are Organized by a

Network of Proteins at the Postsynaptic

Density 281

NMDA Receptors Have Unique Biophysical and

Pharmacological Properties 283

The Properties of the NMDA Receptor Underlie

Long-Term Synaptic Plasticity 284

NMDA Receptors Contribute to

Neuropsychiatric Disease 284

Fast Inhibitory Synaptic Actions Are Mediated by

Ionotropic GABA and Glycine Receptor-Channels

Permeable to Chloride 287

Ionotropic Glutamate, GABA, and Glycine Receptors Are

Transmembrane Proteins Encoded by Two Distinct Gene

Families 287

Chloride Currents Through GABAA and Glycine

Receptor-Channels Normally Inhibit the

Postsynaptic Cell 288

Some Synaptic Actions in the Central Nervous System

Depend on Other Types of Ionotropic Receptors 291

Excitatory and Inhibitory Synaptic Actions Are Integrated

by Neurons Into a Single Output 291

Synaptic Inputs Are Integrated at the Axon

Initial Segment 292

Subclasses of GABAergic Neurons Target Distinct

Regions of Their Postsynaptic Target Neurons

to Produce Inhibitory Actions With Different

Functions 293

Dendrites Are Electrically Excitable Structures That Can

Amplify Synaptic Input 295

Highlights 298

Selected Reading 299

References 299

14 Modulation of Synaptic Transmission and Neuronal Excitability: Second Messengers. . . . . . . . . . . . . . . .301

Steven A. Siegelbaum, David E. Clapham, Eve Marder

The Cyclic AMP Pathway Is the Best Understood

Second-Messenger Signaling Cascade Initiated by

G Protein–Coupled Receptors 303

The Second-Messenger Pathways Initiated by G

Protein–Coupled Receptors Share a Common Molecular

Logic 305

A Family of G Proteins Activates Distinct

Second-Messenger Pathways 305

Hydrolysis of Phospholipids by Phospholipase C

Produces Two Important Second Messengers,

IP3 and Diacylglycerol 305

Receptor Tyrosine Kinases Compose the Second Major

Family of Metabotropic Receptors 308

Several Classes of Metabolites Can Serve as Transcellular

Messengers 309

Hydrolysis of Phospholipids by Phospholipase A2

Liberates Arachidonic Acid to Produce Other Second

Messengers 310

Endocannabinoids Are Transcellular Messengers That

Inhibit Presynaptic Transmitter Release 310

The Gaseous Second Messenger Nitric Oxide Is a

Transcellular Signal That Stimulates Cyclic GMP

Synthesis 310

The Physiological Actions of Metabotropic

Receptors Differ From Those of Ionotropic

Receptors 312

Second-Messenger Cascades Can Increase or

Decrease the Opening of Many Types of Ion

Channels 312

G Proteins Can Modulate Ion Channels

Directly 315

Cyclic AMP–Dependent Protein Phosphorylation Can

Close Potassium Channels 317

Second Messengers Can Endow Synaptic Transmission

with Long-Lasting Consequences 317

Modulators Can Influence Circuit Function by Altering

Intrinsic Excitability or Synaptic Strength 317

Multiple Neuromodulators Can Converge

Onto the Same Neuron and Ion Channels 320

Why So Many Modulators? 320

Highlights 321

Selected Reading 322

References 322

15 Transmitter Release . . . . . . . . . . . . . . .324

Steven A. Siegelbaum, Thomas C. Südhof,

Richard W. Tsien

Transmitter Release Is Regulated by Depolarization of the

Presynaptic Terminal 324

Release Is Triggered by Calcium Influx 327

The Relation Between Presynaptic Calcium

Concentration and Release 329

Several Classes of Calcium Channels Mediate

Transmitter Release 329

Transmitter Is Released in Quantal Units 332

Transmitter Is Stored and Released by

Synaptic Vesicles 333

Synaptic Vesicles Discharge Transmitter by Exocytosis

and Are Recycled by Endocytosis 337

Capacitance Measurements Provide Insight Into

the Kinetics of Exocytosis and Endocytosis 338

Exocytosis Involves the Formation of a

Temporary Fusion Pore 338

The Synaptic Vesicle Cycle Involves Several Steps 341

Exocytosis of Synaptic Vesicles Relies on a Highly

Conserved Protein Machinery 343

The Synapsins Are Important for Vesicle Restraint and

Mobilization 345

SNARE Proteins Catalyze Fusion of Vesicles With the

Plasma Membrane 345

Calcium Binding to Synaptotagmin Triggers Transmitter

Release 347

The Fusion Machinery Is Embedded in a Conserved

Protein Scaffold at the Active Zone 347

Modulation of Transmitter Release Underlies Synaptic

Plasticity 350

Activity-Dependent Changes in Intracellular Free

Calcium Can Produce Long-Lasting Changes in

Release 351

Axo-axonic Synapses on Presynaptic Terminals Regulate

Transmitter Release 351

Highlights 354

Selected Reading 356

References 356

16 Neurotransmitters. . . . . . . . . . . . . . . . .358

Jonathan A. Javitch, David Sulzer

A Chemical Messenger Must Meet Four Criteria to Be

Considered a Neurotransmitter 358

Only a Few Small-Molecule Substances Act as

Transmitters 360

Acetylcholine 360

Biogenic Amine Transmitters 361

Amino Acid Transmitters 364

ATP and Adenosine 364

Small-Molecule Transmitters Are Actively Taken Up Into

Vesicles 364

Many Neuroactive Peptides Serve as Transmitters 367

Peptides and Small-Molecule Transmitters Differ in

Several Ways 370

Peptides and Small-Molecule Transmitters Can Be

Co-released 370

Removal of Transmitter From the Synaptic Cleft

Terminates Synaptic Transmission 371

Highlights 376

Selected Reading 377

References 378

Part IV

Perception

17 Sensory Coding. . . . . . . . . . . . . . . . . . .385

Esther P. Gardner, Daniel Gardner

Psychophysics Relates Sensations to the Physical

Properties of Stimuli 387

Psychophysics Quantifies the Perception of Stimulus

Properties 387

Stimuli Are Represented in the Nervous System by the

Firing Patterns of Neurons 388

Sensory Receptors Respond to Specific Classes of

Stimulus Energy 390

Multiple Subclasses of Sensory Receptors Are Found in

Each Sense Organ 393

Receptor Population Codes Transmit Sensory

Information to the Brain 395

Sequences of Action Potentials Signal the Temporal

Dynamics of Stimuli 396

The Receptive Fields of Sensory Neurons Provide

Spatial Information About Stimulus Location 397

Central Nervous System Circuits Refine Sensory

Information 398

The Receptor Surface Is Represented Topographically in

the Early Stages of Each Sensory System 400

Sensory Information Is Processed in Parallel Pathways

in the Cerebral Cortex 402

Feedback Pathways From the Brain Regulate Sensory

Coding Mechanisms 403

Top-Down Learning Mechanisms Influence

Sensory Processing 404

Highlights 405

Selected Reading 406

References 406

18 Receptors of the Somatosensory System. . . . . . . . . . . . . . . . . . . . . . . . . . .408

Esther P. Gardner

Dorsal Root Ganglion Neurons Are the Primary Sensory

Receptor Cells of the Somatosensory System 409

Peripheral Somatosensory Nerve Fibers Conduct Action

Potentials at Different Rates 410

A Variety of Specialized Receptors Are Employed by the

Somatosensory System 414

Mechanoreceptors Mediate Touch and

Proprioception 414

Specialized End Organs Contribute to

Mechanosensation 416

Proprioceptors Measure Muscle Activity

and Joint Positions 421

Thermal Receptors Detect Changes in

Skin Temperature 422

Nociceptors Mediate Pain 424

Itch Is a Distinctive Cutaneous Sensation 425

Visceral Sensations Represent the Status of

Internal Organs 426

Action Potential Codes Transmit Somatosensory

Information to the Brain 426

Sensory Ganglia Provide a Snapshot of Population

Responses to Somatic Stimuli 427

Somatosensory Information Enters the Central Nervous

System Via Spinal or Cranial Nerves 427

Highlights 432

Selected Reading 433

References 433

19 Touch. . . . . . . . . . . . . . . . . . . . . . . . . . . .435

Esther P. Gardner

Active and Passive Touch Have Distinct Goals 436

The Hand Has Four Types of Mechanoreceptors 437

A Cell’s Receptive Field Defines Its Zone of

Tactile Sensitivity 438

Two-Point Discrimination Tests Measure

Tactile Acuity 439

Slowly Adapting Fibers Detect Object

Pressure and Form 444

Rapidly Adapting Fibers Detect Motion

and Vibration 446

Both Slowly and Rapidly Adapting Fibers Are

Important for Grip Control 446

Tactile Information Is Processed in the Central Touch

System 450

Spinal, Brain Stem, and Thalamic Circuits Segregate

Touch and Proprioception 450

The Somatosensory Cortex Is Organized Into

Functionally Specialized Columns 452

Cortical Columns Are Organized Somatotopically 454

The Receptive Fields of Cortical Neurons Integrate

Information From Neighboring Receptors 457

Touch Information Becomes Increasingly Abstract in

Successive Central Synapses 460

Cognitive Touch Is Mediated by Neurons in the

Secondary Somatosensory Cortex 460

Active Touch Engages Sensorimotor Circuits in the

Posterior Parietal Cortex 463

Lesions in Somatosensory Areas of the Brain Produce

Specific Tactile Deficits 464

Highlights 466

Selected Reading 467

References 467

20 Pain . . . . . . . . . . . . . . . . . . . . . . . . . . . . .470

Allan I. Basbaum

Noxious Insults Activate Thermal, Mechanical, and

Polymodal Nociceptors 471

Signals From Nociceptors Are Conveyed to Neurons in

the Dorsal Horn of the Spinal Cord 474

Hyperalgesia Has Both Peripheral and

Central Origins 476

Four Major Ascending Pathways Convey Nociceptive

Information From the Spinal Cord to the Brain 484

Several Thalamic Nuclei Relay Nociceptive Information

to the Cerebral Cortex 484

The Perception of Pain Arises From and Can Be

Controlled by Cortical Mechanisms 485

Anterior Cingulate and Insular Cortex Are Associated

With the Perception of Pain 485

Pain Perception Is Regulated by a Balance of Activity in

Nociceptive and Nonnociceptive Afferent Fibers 488

Electrical Stimulation of the Brain

Produces Analgesia 488

Opioid Peptides Contribute to Endogenous Pain

Control 489

Endogenous Opioid Peptides and Their Receptors Are

Distributed in Pain-Modulatory Systems 489

Morphine Controls Pain by Activating

Opioid Receptors 490

Tolerance to and Dependence on Opioids Are Distinct

Phenomena 493

Highlights 493

Selected Reading 494

References 494

21 The Constructive Nature of Visual Processing . . . . . . . . . . . . . . . . .496

Charles D. Gilbert, Aniruddha Das

Visual Perception Is a Constructive Process 496

Visual Processing Is Mediated by the Geniculostriate

Pathway 499

Form, Color, Motion, and Depth Are Processed in Discrete

Areas of the Cerebral Cortex 502

The Receptive Fields of Neurons at Successive Relays

in the Visual Pathway Provide Clues to How the Brain

Analyzes Visual Form 506

The Visual Cortex Is Organized Into Columns of

Specialized Neurons 508

Intrinsic Cortical Circuits Transform

Neural Information 512

Visual Information Is Represented by a Variety of Neural

Codes 517

Highlights 518

Selected Reading 519

References 519

22 Low-Level Visual Processing: The Retina . . . . . . . . . . . . . . . . . . . . . . .521

Markus Meister, Marc Tessier-Lavigne

The Photoreceptor Layer Samples the

Visual Image 522

Ocular Optics Limit the Quality of the Retinal

Image 522

There Are Two Types of Photoreceptors:

Rods and Cones 524

Phototransduction Links the Absorption of a Photon to a

Change in Membrane Conductance 526

Light Activates Pigment Molecules in the

Photoreceptors 528

Excited Rhodopsin Activates a Phosphodiesterase

Through the G Protein Transducin 529

Multiple Mechanisms Shut Off the Cascade 530

Defects in Phototransduction Cause Disease 530

Ganglion Cells Transmit Neural Images

to the Brain 530

The Two Major Types of Ganglion Cells Are ON Cells

and OFF Cells 530

Many Ganglion Cells Respond Strongly

to Edges in the Image 531

The Output of Ganglion Cells Emphasizes Temporal

Changes in Stimuli 531

Retinal Output Emphasizes Moving Objects 531

Several Ganglion Cell Types Project to the Brain

Through Parallel Pathways 531

A Network of Interneurons Shapes the

Retinal Output 536

Parallel Pathways Originate in Bipolar Cells 536

Spatial Filtering Is Accomplished by

Lateral Inhibition 536

Temporal Filtering Occurs in Synapses and Feedback

Circuits 537

Color Vision Begins in Cone-Selective Circuits 538

Congenital Color Blindness Takes Several Forms 538

Rod and Cone Circuits Merge in the Inner Retina 540

The Retina’s Sensitivity Adapts to Changes in

Illumination 540

Light Adaptation Is Apparent in Retinal Processing and

Visual Perception 540

Multiple Gain Controls Occur Within the Retina 541

Light Adaptation Alters Spatial Processing 543

Highlights 543

Selected Reading 543

References 544

23 Intermediate-Level Visual Processing and Visual Primitives. . . . . . . . . . . . . .545

Charles D. Gilbert

Internal Models of Object Geometry Help the Brain

Analyze Shapes 547

Depth Perception Helps Segregate Objects From

Background 550

Local Movement Cues Define Object Trajectory and

Shape 554

Context Determines the Perception of

Visual Stimuli 555

Brightness and Color Perception Depend on

Context 555

Receptive-Field Properties Depend on Context 558

Cortical Connections, Functional Architecture, and

Perception Are Intimately Related 558

Perceptual Learning Requires Plasticity in

Cortical Connections 559

Visual Search Relies on the Cortical Representation of

Visual Attributes and Shapes 559

Cognitive Processes Influence Visual Perception 560

Highlights 562

Selected Reading 563

References 563

24 High-Level Visual Processing: From Vision to Cognition. . . . . . . . . .564

Thomas D. Albright, Winrich A. Freiwald

High-Level Visual Processing Is Concerned With Object

Recognition 564

The Inferior Temporal Cortex Is the Primary Center for

Object Recognition 565

Clinical Evidence Identifies the Inferior Temporal

Cortex as Essential for Object Recognition 566

Neurons in the Inferior Temporal Cortex Encode

Complex Visual Stimuli and Are Organized in

Functionally Specialized Columns 568

The Primate Brain Contains Dedicated Systems for Face

Processing 569

The Inferior Temporal Cortex Is Part of a Network of

Cortical Areas Involved in Object Recognition 570

Object Recognition Relies on Perceptual

Constancy 571

Categorical Perception of Objects Simplifies

Behavior 572

Visual Memory Is a Component of High-Level Visual

Processing 573

Implicit Visual Learning Leads to Changes in the

Selectivity of Neuronal Responses 573

The Visual System Interacts With Working Memory and

Long-Term Memory Systems 573

Associative Recall of Visual Memories Depends on

Top-Down Activation of the Cortical Neurons That

Process Visual Stimuli 578The Cerebellum Adjusts the Vestibulo-Ocular

Reflex 643

The Thalamus and Cortex Use Vestibular Signals

for Spatial Memory and Cognitive and Perceptual

Functions 645

Vestibular Information Is Present in the Thalamus 645

Vestibular Information Is Widespread in the

Cortex 645

Vestibular Signals Are Essential for Spatial Orientation

and Spatial Navigation 646

Clinical Syndromes Elucidate Normal Vestibular

Function 647

Caloric Irrigation as a Vestibular Diagnostic

Tool 647

Bilateral Vestibular Hypofunction Interferes With

Normal Vision 647

Highlights 648

Selected Reading 649

References 649

28 Auditory Processing by the Central Nervous System. . . . . . . . . . . . . . . . . . .651

Donata Oertel, Xiaoqin Wang

Sounds Convey Multiple Types of Information to Hearing

Animals 652

The Neural Representation of Sound in Central Pathways

Begins in the Cochlear Nuclei 652

The Cochlear Nerve Delivers Acoustic Information

in Parallel Pathways to the Tonotopically Organized

Cochlear Nuclei 655

The Ventral Cochlear Nucleus Extracts Temporal and

Spectral Information About Sounds 655

The Dorsal Cochlear Nucleus Integrates Acoustic With

Somatosensory Information in Making Use of Spectral

Cues for Localizing Sounds 656

The Superior Olivary Complex in Mammals Contains

Separate Circuits for Detecting Interaural Time and

Intensity Differences 657

The Medial Superior Olive Generates a Map of

Interaural Time Differences 657

The Lateral Superior Olive Detects Interaural Intensity

Differences 659

The Superior Olivary Complex Provides Feedback to the

Cochlea 662

Ventral and Dorsal Nuclei of the Lateral Lemniscus

Shape Responses in the Inferior Colliculus With

Inhibition 663

Afferent Auditory Pathways Converge in the Inferior

Colliculus 664

Sound Location Information From the Inferior

Colliculus Creates a Spatial Map of Sound in the

Superior Colliculus 665

The Inferior Colliculus Transmits Auditory Information to

the Cerebral Cortex 665

Stimulus Selectivity Progressively Increases Along the

Ascending Pathway 665

The Auditory Cortex Maps Numerous Aspects of

Sound 668

A Second Sound-Localization Pathway From the

Inferior Colliculus Involves the Cerebral Cortex in Gaze

Control 669

Auditory Circuits in the Cerebral Cortex Are Segregated

Into Separate Processing Streams 670

The Cerebral Cortex Modulates Sensory Processing in

Subcortical Auditory Areas 670

The Cerebral Cortex Forms Complex

Sound Representations 671

The Auditory Cortex Uses Temporal and Rate Codes to

Represent Time-Varying Sounds 671

Primates Have Specialized Cortical Neurons That

Encode Pitch and Harmonics 673

Insectivorous Bats Have Cortical Areas Specialized for

Behaviorally Relevant Features of Sound 675

The Auditory Cortex Is Involved in Processing Vocal

Feedback During Speaking 677

Highlights 679

Selected Reading 680

References 680

29 Smell and Taste: The Chemical Senses. . . . . . . . . . . . . . . . . .682

Linda Buck, Kristin Scott, Charles Zuker

A Large Family of Olfactory Receptors Initiate the Sense

of Smell 683

Mammals Share a Large Family of Odorant

Receptors 684

Different Combinations of Receptors Encode Different

Odorants 685

Olfactory Information Is Transformed Along the Pathway

to the Brain 686

Odorants Are Encoded in the Nose by Dispersed

Neurons 686

Sensory Inputs in the Olfactory Bulb Are Arranged by

Receptor Type 687

The Olfactory Bulb Transmits Information to the

Olfactory Cortex 688

Output From the Olfactory Cortex Reaches Higher

Cortical and Limbic Areas 690

Olfactory Acuity Varies in Humans 691

Odors Elicit Characteristic Innate Behaviors 691

Pheromones Are Detected in Two Olfactory

Structures 691

Invertebrate Olfactory Systems Can Be Used to Study

Odor Coding and Behavior 691

Olfactory Cues Elicit Stereotyped Behaviors and

Physiological Responses in the Nematode 694

Strategies for Olfaction Have Evolved Rapidly 695

The Gustatory System Controls the Sense

of Taste 696

Taste Has Five Submodalities That Reflect Essential

Dietary Requirements 696

Tastant Detection Occurs in Taste Buds 696

Each Taste Modality Is Detected by Distinct Sensory

Receptors and Cells 698

Gustatory Information Is Relayed From the Periphery to

the Gustatory Cortex 702

Perception of Flavor Depends on Gustatory, Olfactory,

and Somatosensory Inputs 702

Insects Have Modality-Specific Taste Cells That Drive

Innate Behaviors 702

Highlights 703

Selected Reading 704

References 705

Part V

Movement

30 Principles of Sensorimotor Control. . . . . . . . . . . . . . . . . . . . . . . . . . .713

Daniel M. Wolpert, Amy J. Bastian

The Control of Movement Poses Challenges for the

Nervous System 714

Actions Can Be Controlled Voluntarily, Rhythmically, or

Reflexively 715

Motor Commands Arise Through a Hierarchy of

Sensorimotor Processes 715

Motor Signals Are Subject to Feedforward and Feedback

Control 716

Feedforward Control Is Required for Rapid

Movements 716

Feedback Control Uses Sensory Signals to

Correct Movements 719

Estimation of the Body’s Current State Relies on Sensory

and Motor Signals 719

Prediction Can Compensate for Sensorimotor

Delays 723

Sensory Processing Can Differ for Action and

Perception 724

Motor Plans Translate Tasks Into

Purposeful Movement 725

Stereotypical Patterns Are Employed in

Many Movements 725

Motor Planning Can Be Optimal at Reducing Costs 726

Optimal Feedback Control Corrects for Errors in a

Task-Dependent Manner 728

Multiple Processes Contribute to

Motor Learning 729

Error-Based Learning Involves Adapting Internal

Sensorimotor Models 730

Skill Learning Relies on Multiple Processes

for Success 732

Sensorimotor Representations Constrain Learning 734

Highlights 735

Selected Reading 735

References 735

31 The Motor Unit and Muscle Action. . . . . . . . . . . . . . . . . . . .737

Roger M. Enoka

The Motor Unit Is the Elementary Unit of Motor

Control 737

A Motor Unit Consists of a Motor Neuron and Multiple

Muscle Fibers 737

The Properties of Motor Units Vary 739

Physical Activity Can Alter Motor Unit Properties 742

Muscle Force Is Controlled by the Recruitment and

Discharge Rate of Motor Units 742

The Input–Output Properties of Motor Neurons Are

Modified by Input From the Brain Stem 745

Muscle Force Depends on the Structure

of Muscle 745

The Sarcomere Is the Basic Organizational Unit of

Contractile Proteins 745

Noncontractile Elements Provide Essential Structural

Support 747

Contractile Force Depends on Muscle Fiber Activation,

Length, and Velocity 747

Muscle Torque Depends on Musculoskeletal

Geometry 750

Different Movements Require Different Activation

Strategies 754

Contraction Velocity Can Vary in Magnitude and

Direction 754

Movements Involve the Coordination of Many

Muscles 755

Muscle Work Depends on the Pattern of Activation 758

Highlights 758

Selected Reading 759

References 759

32 Sensory-Motor Integration in the Spinal Cord . . . . . . . . . . . . . . . . . . . . . .761

Jens Bo Nielsen, Thomas M. Jessell

Reflex Pathways in the Spinal Cord Produce Coordinated

Patterns of Muscle Contraction 762

The Stretch Reflex Acts to Resist the

Lengthening of a Muscle 762

Neuronal Networks in the Spinal Cord Contribute to the

Coordination of Reflex Responses 762

The Stretch Reflex Involves a Monosynaptic Pathway 762

Gamma Motor Neurons Adjust the Sensitivity of Muscle

Spindles 766

The Stretch Reflex Also Involves Polysynaptic

Pathways 767

Golgi Tendon Organs Provide Force-Sensitive Feedback

to the Spinal Cord 769

Cutaneous Reflexes Produce Complex Movements That

Serve Protective and Postural Functions 770

Convergence of Sensory Inputs on Interneurons

Increases the Flexibility of Reflex Contributions

to Movement 772

Sensory Feedback and Descending Motor Commands

Interact at Common Spinal Neurons to Produce Voluntary

Movements 773

Muscle Spindle Sensory Afferent Activity Reinforces

Central Commands for Movements Through the Ia

Monosynaptic Reflex Pathway 773

Modulation of Ia inhibitory Interneurons and Renshaw

Cells by Descending Inputs Coordinate Muscle Activity

at Joints 775

Transmission in Reflex Pathways May Be Facilitated or

Inhibited by Descending Motor Commands 776

Descending Inputs Modulate Sensory Input to the

Spinal Cord by Changing the Synaptic Efficiency of

Primary Sensory Fibers 777

Part of the Descending Command for Voluntary

Movements Is Conveyed Through Spinal

Interneurons 778

Propriospinal Neurons in the C3–C4 Segments Mediate

Part of the Corticospinal Command for Movement of

the Upper Limb 778

Neurons in Spinal Reflex Pathways Are Activated Prior

to Movement 779

Proprioceptive Reflexes Play an Important

Role in Regulating Both Voluntary and Automatic

Movements 779

Spinal Reflex Pathways Undergo

Long-Term Changes 779

Damage to the Central Nervous System Produces

Characteristic Alterations in

Reflex Responses 780

Interruption of Descending Pathways to the Spinal Cord

Frequently Produces Spasticity 780

Lesion of the Spinal Cord in Humans Leads to a Period

of Spinal Shock Followed by Hyperreflexia 780

Highlights 781

Selected Reading 781

References 781

33 Locomotion. . . . . . . . . . . . . . . . . . . . . . .783

Trevor Drew, Ole Kiehn

Locomotion Requires the Production of a Precise and

Coordinated Pattern of Muscle Activation 786

The Motor Pattern of Stepping Is Organized

at the Spinal Level 790

The Spinal Circuits Responsible for Locomotion Can Be

Modified by Experience 792

Spinal Locomotor Networks Are Organized Into

Rhythm- and Pattern-Generation Circuits 792

Somatosensory Inputs From Moving Limbs Modulate

Locomotion 795

Proprioception Regulates the Timing and Amplitude of

Stepping 795

Mechanoreceptors in the Skin Allow Stepping to Adjust

to Unexpected Obstacles 798

Supraspinal Structures Are Responsible for Initiation and

Adaptive Control of Stepping 799

Midbrain Nuclei Initiate and Maintain Locomotion and

Control Speed 800

Midbrain Nuclei That Initiate Locomotion Project to

Brain Stem Neurons 800

The Brain Stem Nuclei Regulate Posture During

Locomotion 802

Visually Guided Locomotion Involves the Motor

Cortex 804

Planning of Locomotion Involves the Posterior Parietal

Cortex 806

The Cerebellum Regulates the Timing and Intensity of

Descending Signals 806

The Basal Ganglia Modify Cortical and Brain Stem

Circuits 807

Computational Neuroscience Provides Insights Into

Locomotor Circuits 809

Neuronal Control of Human Locomotion Is Similar to

That of Quadrupeds 809

Highlights 811

Suggested Reading 812

References 812

34 Voluntary Movement: Motor Cortices. . . . . . . . . . . . . . . . . . . .815

Stephen H. Scott, John F. Kalaska

Voluntary Movement Is the Physical Manifestation of an

Intention to Act 816

Theoretical Frameworks Help Interpret Behavior and

the Neural Basis of Voluntary Control 816

Many Frontal and Parietal Cortical Regions Are

Involved in Voluntary Control 818

Descending Motor Commands Are Principally

Transmitted by the Corticospinal Tract 819

Imposing a Delay Period Before the Onset of Movement

Isolates the Neural Activity Associated With Planning

From That Associated With Executing the Action 821

Parietal Cortex Provides Information About the World and

the Body for State Estimation to Plan and Execute Motor

Actions 823

The Parietal Cortex Links Sensory Information to Motor

Actions 824

Body Position and Motion Are Represented in Several

Areas of Posterior Parietal Cortex 824

Spatial Goals Are Represented in Several Areas of

Posterior Parietal Cortex 825

Internally Generated Feedback May Influence Parietal

Cortex Activity 827

Premotor Cortex Supports Motor Selection

and Planning 828

Medial Premotor Cortex Is Involved in the Contextual

Control of Voluntary Actions 829

Dorsal Premotor Cortex Is Involved in Planning

Sensory-Guided Movement of the Arm 831

Dorsal Premotor Cortex Is Involved in Applying Rules

(Associations) That Govern Behavior 833

Ventral Premotor Cortex Is Involved in Planning Motor

Actions of the Hand 835

Premotor Cortex May Contribute to Perceptual

Decisions That Guide Motor Actions 835

Several Cortical Motor Areas Are Active When the

Motor Actions of Others Are Being Observed 837

Many Aspects of Voluntary Control Are Distributed

Across Parietal and Premotor Cortex 840

The Primary Motor Cortex Plays an Important Role in

Motor Execution 841

The Primary Motor Cortex Includes a Detailed Map of

the Motor Periphery 841

Some Neurons in the Primary Motor Cortex Project

Directly to Spinal Motor Neurons 841

Activity in the Primary Motor Cortex Reflects

Many Spatial and Temporal Features of Motor

Output 844

Primary Motor Cortical Activity Also Reflects

Higher-Order Features of Movement 851

Sensory Feedback Is Transmitted Rapidly to the Primary

Motor Cortex and Other Cortical Regions 852

The Primary Motor Cortex Is Dynamic and

Adaptable 852

Highlights 856

Selected Reading 858

References 858

35 The Control of Gaze. . . . . . . . . . . . . . .860

Michael E. Goldberg, Mark F. Walker

The Eye Is Moved by the Six Extraocular Muscles 860

Eye Movements Rotate the Eye in the Orbit 860

The Six Extraocular Muscles Form Three

Agonist–Antagonist Pairs 862

Movements of the Two Eyes Are Coordinated 862

The Extraocular Muscles Are Controlled by

Three Cranial Nerves 862

Six Neuronal Control Systems Keep the Eyes on

Target 866

An Active Fixation System Holds the Fovea on a

Stationary Target 866

The Saccadic System Points the Fovea Toward Objects of

Interest 866

The Motor Circuits for Saccades Lie in the Brain

Stem 868

Horizontal Saccades Are Generated in the Pontine

Reticular Formation 868

Vertical Saccades Are Generated in the Mesencephalic

Reticular Formation 870

Brain Stem Lesions Result in Characteristic Deficits in

Eye Movements 870

Saccades Are Controlled by the Cerebral Cortex Through

the Superior Colliculus 871

The Superior Colliculus Integrates Visual and Motor

Information into Oculomotor Signals for the Brain

Stem 871

The Rostral Superior Colliculus Facilitates Visual

Fixation 873

The Basal Ganglia and Two Regions of Cerebral Cortex

Control the Superior Colliculus 873

The Control of Saccades Can Be Modified by

Experience 877

Some Rapid Gaze Shifts Require Coordinated Head and

Eye Movements 877

The Smooth-Pursuit System Keeps Moving Targets on the

Fovea 878

The Vergence System Aligns the Eyes to

Look at Targets at Different Depths 879

Highlights 880

Selected Reading 881

References 881

36 Posture. . . . . . . . . . . . . . . . . . . . . . . . . . .883

Fay B. Horak, Gammon M. Earhart

Equilibrium and Orientation Underlie

Posture Control 884

Postural Equilibrium Controls the Body’s

Center of Mass 884

Postural Orientation Anticipates Disturbances

to Balance 886

Postural Responses and Anticipatory

Postural Adjustments Use Stereotyped Strategies and

Synergies 886

Automatic Postural Responses Compensate for Sudden

Disturbances 887

Anticipatory Postural Adjustments Compensate for

Voluntary Movement 892

Posture Control Is Integrated With Locomotion 894

Somatosensory, Vestibular, and Visual Information Must

Be Integrated and Interpreted to Maintain Posture 894

Somatosensory Signals Are Important for Timing and

Direction of Automatic Postural Responses 894

Vestibular Information Is Important for Balance on

Unstable Surfaces and During Head Movements 895

Visual Inputs Provide the Postural System With

Orientation and Motion Information 897

Information From a Single Sensory Modality Can Be

Ambiguous 897

The Postural Control System Uses a Body Schema That

Incorporates Internal Models for Balance 898

Control of Posture Is Task Dependent 900

Task Requirements Determine the Role of

Each Sensory System in Postural Equilibrium

and Orientation 900

Control of Posture Is Distributed in the Nervous

System 900

Spinal Cord Circuits Are Sufficient for Maintaining

Antigravity Support but Not Balance 900

The Brain Stem and Cerebellum Integrate

Sensory Signals for Posture 901

The Spinocerebellum and Basal Ganglia Are Important

in Adaptation of Posture 902

Cerebral Cortex Centers Contribute to Postural

Control 905

Highlights 906

Suggested Reading 906

References 906

37 The Cerebellum. . . . . . . . . . . . . . . . . . .908

Amy J. Bastian, Stephen G. Lisberger

Damage of the Cerebellum Causes Distinctive Symptoms

and Signs 909

Damage Results in Characteristic Abnormalities of

Movement and Posture 909

Damage Affects Specific Sensory and Cognitive

Abilities 909

The Cerebellum Indirectly Controls Movement Through

Other Brain Structures 911

The Cerebellum Is a Large Subcortical

Brain Structure 911

The Cerebellum Connects With the Cerebral

Cortex Through Recurrent Loops 911

Different Movements Are Controlled by

Functional Longitudinal Zones 911

The Cerebellar Cortex Comprises Repeating Functional

Units Having the Same

Basic Microcircuit 918

The Cerebellar Cortex Is Organized Into Three

Functionally Specialized Layers 918

The Climbing-Fiber and Mossy-Fiber Afferent Systems

Encode and Process Information Differently 918

The Cerebellar Microcircuit Architecture

Suggests a Canonical Computation 920

The Cerebellum Is Hypothesized to Perform Several

General Computational Functions 922

The Cerebellum Contributes to Feedforward

Sensorimotor Control 922

The Cerebellum Incorporates an Internal Model of

the Motor Apparatus 922

The Cerebellum Integrates Sensory Inputs and Corollary

Discharge 923

The Cerebellum Contributes to Timing Control 923

The Cerebellum Participates in Motor

Skill Learning 923

Climbing-Fiber Activity Changes the Synaptic Efficacy

of Parallel Fibers 924

The Cerebellum Is Necessary for Motor Learning in

Several Different Movement Systems 925

Learning Occurs at Several Sites in the Cerebellum 928

Highlights 929

Selected Reading 929

References 930

38 The Basal Ganglia. . . . . . . . . . . . . . . . .932

Peter Redgrave, Rui M. Costa

The Basal Ganglia Network Consists of Three Principal

Input Nuclei, Two Main Output Nuclei, and One Intrinsic

Nucleus 934

The Striatum, Subthalamic Nucleus, and Substantia

Nigra Pars Compacta/Ventral Tegmental Area Are the

Three Principal Input Nuclei of the Basal Ganglia 934

The Substantia Nigra Pars Reticulata and the Internal

Globus Pallidus Are the Two Principal Output Nuclei of

the Basal Ganglia 935

The External Globus Pallidus Is Mostly an Intrinsic

Structure of the Basal Ganglia 935

The Internal Circuitry of the Basal Ganglia Regulates

How the Components Interact 935

The Traditional Model of the Basal Ganglia Emphasizes

Direct and Indirect Pathways 935

Detailed Anatomical Analyses Reveal a More Complex

Organization 936

Basal Ganglia Connections With External Structures Are

Characterized by Reentrant Loops 937

Inputs Define Functional Territories in the

Basal Ganglia 937

Output Neurons Project to the External

Structures That Provide Input 937

Reentrant Loops Are a Cardinal Principle

of Basal Ganglia Circuitry 937

Physiological Signals Provide Further Clues

to Function in the Basal Ganglia 939

The Striatum and Subthalamic Nucleus Receive Signals

Mainly from the Cerebral Cortex,

Thalamus, and Ventral Midbrain 939

Ventral Midbrain Dopamine Neurons Receive

Input From External Structures and Other

Basal Ganglia Nuclei 939

Disinhibition Is the Final Expression of Basal Ganglia

Output 940

Throughout Vertebrate Evolution, the Basal Ganglia Have

Been Highly Conserved 940

Action Selection Is a Recurring Theme in Basal Ganglia

Research 941

All Vertebrates Face the Challenge of Choosing

One Behavior From Several Competing

Options 941

Selection Is Required for Motivational, Affective,

Cognitive, and Sensorimotor Processing 941

The Neural Architecture of the Basal Ganglia Is

Configured to Make Selections 942

Intrinsic Mechanisms in the Basal Ganglia

Promote Selection 943

Selection Function of the Basal Ganglia

Questioned 943

Reinforcement Learning Is an Inherent Property of a

Selection Architecture 944

Intrinsic Reinforcement Is Mediated by Phasic

Dopamine Signaling Within the Basal

Ganglia Nuclei 944

Extrinsic Reinforcement Could Bias Selection by

Operating in Afferent Structures 946

Behavioral Selection in the Basal Ganglia Is Under

Goal-Directed and Habitual Control 946

Diseases of the Basal Ganglia May Involve Disorders of

Selection 947

A Selection Mechanism Is Likely to Be Vulnerable to

Several Potential Malfunctions 947

Parkinson Disease Can Be Viewed in Part as a Failure to

Select Sensorimotor Options 948

Huntington Disease May Reflect a Functional Imbalance

Between the Direct and Indirect Pathways 948

Schizophrenia May Be Associated With a General

Failure to Suppress Nonselected Options 948

Attention Deficit Hyperactivity Disorder and Tourette

Syndrome May Also Be Characterized by Intrusions of

Nonselected Options 949

Obsessive-Compulsive Disorder Reflects the Presence of

Pathologically Dominant Options 949

Addictions Are Associated With Disorders of

Reinforcement Mechanisms and Habitual Goals 949

Highlights 950

Suggested Reading 951

References 951

39 Brain–Machine Interfaces. . . . . . . . . .953

Krishna V. Shenoy, Byron M. Yu

BMIs Measure and Modulate Neural Activity to Help

Restore Lost Capabilities 954

Cochlear Implants and Retinal Prostheses Can Restore

Lost Sensory Capabilities 954

Motor and Communication BMIs Can Restore Lost

Motor Capabilities 954

Pathological Neural Activity Can Be Regulated by Deep

Brain Stimulation and Antiseizure BMIs 956

Replacement Part BMIs Can Restore Lost Brain

Processing Capabilities 956

Measuring and Modulating Neural Activity Rely on

Advanced Neurotechnology 956

BMIs Leverage the Activity of Many Neurons to Decode

Movements 958

Decoding Algorithms Estimate Intended Movements

From Neural Activity 960

Discrete Decoders Estimate Movement Goals 961

Continuous Decoders Estimate Moment-by-Moment

Details of Movements 961

Increases in Performance and Capabilities of Motor and

Communication BMIs Enable Clinical Translation 962

Subjects Can Type Messages Using

Communication BMIs 964

Subjects Can Reach and Grasp Objects Using

BMI-Directed Prosthetic Arms 965

Subjects Can Reach and Grasp Objects Using

BMI-Directed Stimulation of Paralyzed Arms 965

Subjects Can Use Sensory Feedback Delivered by Cortical

Stimulation During BMI Control 967

BMIs Can Be Used to Advance

Basic Neuroscience 968

BMIs Raise New Neuroethics Considerations 970

Highlights 971

Selected Reading 972

References 972

Part VI

The Biology of Emotion, Motivation, and Homeostasis

40 The Brain Stem . . . . . . . . . . . . . . . . . . .981

Clifford B. Saper, Joel K. Elmquist

The Cranial Nerves Are Homologous to the Spinal

Nerves 982

Cranial Nerves Mediate the Sensory and Motor

Functions of the Face and Head and the Autonomic

Functions of the Body 982

Cranial Nerves Leave the Skull in Groups and Often Are

Injured Together 985

The Organization of the Cranial Nerve Nuclei Follows the

Same Basic Plan as the Sensory and Motor Areas of the

Spinal Cord 986

Embryonic Cranial Nerve Nuclei Have a

Segmental Organization 987

Adult Cranial Nerve Nuclei Have a

Columnar Organization 987

The Organization of the Brain Stem Differs From the

Spinal Cord in Three Important Ways 992

Neuronal Ensembles in the Brain Stem Reticular

Formation Coordinate Reflexes and Simple Behaviors

Necessary for Homeostasis and Survival 992

Cranial Nerve Reflexes Involve Mono- and Polysynaptic

Brain Stem Relays 992

Pattern Generators Coordinate More Complex

Stereotypic Behaviors 994

Control of Breathing Provides an Example of How

Pattern Generators Are Integrated Into More Complex

Behaviors 994

Monoaminergic Neurons in the Brain Stem Modulate

Sensory, Motor, Autonomic, and Behavioral

Functions 998

Many Modulatory Systems Use Monoamines as

Neurotransmitters 998

Monoaminergic Neurons Share Many

Cellular Properties 1001

Autonomic Regulation and Breathing Are Modulated by

Monoaminergic Pathways 1002

Pain Perception Is Modulated by Monoamine

Antinociceptive Pathways 1002

Motor Activity Is Facilitated by

Monoaminergic Pathways 1004

Ascending Monoaminergic Projections Modulate

Forebrain Systems for Motivation and Reward 1004

Monoaminergic and Cholinergic Neurons Maintain

Arousal by Modulating Forebrain Neurons 1006

Highlights 1007

Selected Reading 1008

References 1008

41 The Hypothalamus: Autonomic, Hormonal, and Behavioral Control of Survival. . . . . . . . . . . . . . .1010

Bradford B. Lowell, Larry W. Swanson,

John P. Horn

Homeostasis Keeps Physiological Parameters Within a

Narrow Range and Is Essential

for Survival 1011

The Hypothalamus Coordinates

Homeostatic Regulation 1013

The Hypothalamus Is Commonly Divided Into Three

Rostrocaudal Regions 1013

Modality-Specific Hypothalamic Neurons Link

Interoceptive Sensory Feedback With Outputs That

Control Adaptive Behaviors and Physiological

Responses 1015

Modality-Specific Hypothalamic Neurons Also Receive

Descending Feedforward Input Regarding Anticipated

Homeostatic Challenges 1015

The Autonomic System Links the Brain to Physiological

Responses 1015

Visceral Motor Neurons in the Autonomic System Are

Organized Into Ganglia 1015

Preganglionic Neurons Are Localized in Three Regions

Along the Brain Stem and Spinal Cord 1016

Sympathetic Ganglia Project to Many Targets

Throughout the Body 1016

Parasympathetic Ganglia Innervate Single Organs 1018

The Enteric Ganglia Regulate the Gastrointestinal

Tract 1019

Acetylcholine and Norepinephrine Are the Principal

Transmitters of Autonomic Motor Neurons 1019

Autonomic Responses Involve Cooperation Between the

Autonomic Divisions 1021

Visceral Sensory Information Is Relayed to the Brain Stem

and Higher Brain Structures 1023

Central Control of Autonomic Function Can Involve

the Periaqueductal Gray, Medial Prefrontal Cortex, and

Amygdala 1025

The Neuroendocrine System Links the Brain to

Physiological Responses Through Hormones 1026

Hypothalamic Axon Terminals in the Posterior Pituitary

Release Oxytocin and Vasopressin Directly Into the

Blood 1027

Endocrine Cells in the Anterior Pituitary Secrete

Hormones in Response to Specific Factors Released by

Hypothalamic Neurons 1028

Dedicated Hypothalamic Systems Control Specific

Homeostatic Parameters 1029

Body Temperature Is Controlled by Neurons in the

Median Preoptic Nucleus 1029

Water Balance and the Related Thirst Drive Are

Controlled by Neurons in the Vascular Organ of the

Lamina Terminalis, Median Preoptic Nucleus, and

Subfornical Organ 1031

Energy Balance and the Related Hunger Drive Are

Controlled by Neurons in the Arcuate Nucleus 1033

Sexually Dimorphic Regions in the Hypothalamus

Control Sex, Aggression, and Parenting 1039

Sexual Behavior and Aggression Are Controlled by

the Preoptic Hypothalamic Area and a Subarea of the

Ventromedial Hypothalamic Nucleus 1040

Parental Behavior Is Controlled by the Preoptic

Hypothalamic Area 1041

Highlights 1041

Selected Reading 1042

References 1043

42 Emotion. . . . . . . . . . . . . . . . . . . . . . . . .1045

Daniel Salzman, Ralph Adolphs

The Modern Search for the Neural Circuitry of Emotion

Began in the Late 19th Century 1047

The Amygdala Has Been Implicated in Both Learned and

Innate Fear 1050

The Amygdala Has Been Implicated in Innate Fear in

Animals 1052

The Amygdala Is Important for Fear in Humans 1053

The Amygdala’s Role Extends to Positive

Emotions 1055

Emotional Responses Can Be Updated Through Extinction

and Regulation 1055

Emotion Can Influence Cognitive Processes 1056

Many Other Brain Areas Contribute to Emotional

Processing 1056

Functional Neuroimaging Is Contributing to Our

Understanding of Emotion in Humans 1059

Functional Imaging Has Identified Neural Correlates of

Feelings 1060

Emotion Is Related to Homeostasis 1060

Highlights 1062

Selected Reading 1063

References 1063

43 Motivation, Reward, and Addictive States. . . . . . . . . . . . . . . . . .1065

Eric J. Nestler, C. Daniel Salzman

Motivational States Influence Goal-Directed

Behavior 1065

Both Internal and External Stimuli Contribute to

Motivational States 1065

Rewards Can Meet Both Regulatory and Nonregulatory

Needs on Short and Long Timescales 1066

The Brain’s Reward Circuitry Provides a Biological

Substrate for Goal Selection 1066

Dopamine May Act as a Learning Signal 1068

Drug Addiction Is a Pathological Reward State 1069

All Drugs of Abuse Target Neurotransmitter Receptors,

Transporters, or Ion Channels 1070

Repeated Exposure to a Drug of Abuse Induces Lasting

Behavioral Adaptations 1071

Lasting Molecular Adaptations Are Induced in Brain

Reward Regions by Repeated Drug Exposure 1074

Lasting Cellular and Circuit Adaptations Mediate

Aspects of the Drug-Addicted State 1075

Natural Addictions Share Biological Mechanisms With

Drug Addictions 1077

Highlights 1078

Selected Reading 1079

References 1079

44 Sleep and Wakefulness. . . . . . . . . . .1080

Clifford B. Saper, Thomas E. Scammell

Sleep Consists of Alternating Periods of REM Sleep and

Non-REM Sleep 1081

The Ascending Arousal System Promotes Wakefulness 1082

The Ascending Arousal System in the Brain Stem and

Hypothalamus Innervates the Forebrain 1084

Damage to the Ascending Arousal System

Causes Coma 1085

Circuits Composed of Mutually Inhibitory Neurons

Control Transitions From Wake to Sleep and From Non-

REM to REM Sleep 1085

Sleep Is Regulated by Homeostatic and Circadian

Drives 1086

The Homeostatic Pressure for Sleep Depends on

Humoral Factors 1086

Circadian Rhythms Are Controlled by a Biological Clock

in the Suprachiasmatic Nucleus 1087

Circadian Control of Sleep Depends on Hypothalamic

Relays 1090

Sleep Loss Impairs Cognition and Memory 1091

Sleep Changes With Age 1092

Disruptions in Sleep Circuitry Contribute to Many Sleep

Disorders 1092

Insomnia May Be Caused by Incomplete Inhibition of

the Arousal System 1092

Sleep Apnea Fragments Sleep and Impairs

Cognition 1093

Narcolepsy Is Caused by a Loss of

Orexinergic Neurons 1093

REM Sleep Behavior Disorder Is Caused by Failure of

REM Sleep Paralysis Circuits 1095

Restless Legs Syndrome and Periodic Limb Movement

Disorder Disrupt Sleep 1095

Non-REM Parasomnias Include Sleepwalking, Sleep

Talking, and Night Terrors 1095

Sleep Has Many Functions 1096

Highlights 1097

Selected Reading 1098

References 1098

Part VII

Development and the Emergence of Behavior

45 Patterning the Nervous

System. . . . . . . . . . . . . . . . . . . . . . . . . .1107

Joshua R. Sanes, Thomas M. Jessell

The Neural Tube Arises From the Ectoderm 1108

Secreted Signals Promote Neural Cell Fate 1108

Development of the Neural Plate Is Induced by Signals

From the Organizer Region 1108

Neural Induction Is Mediated by Peptide Growth

Factors and Their Inhibitors 1110

Rostrocaudal Patterning of the Neural Tube Involves

Signaling Gradients and Secondary Organizing

Centers 1112

The Neural Tube Becomes Regionalized

Early in Development 1112

Signals From the Mesoderm and Endoderm Define the

Rostrocaudal Pattern of the Neural Plate 1112

Signals From Organizing Centers Within the

Neural Tube Pattern the Forebrain, Midbrain,

and Hindbrain 1113

Repressive Interactions Divide the Hindbrain

Into Segments 1115

Dorsoventral Patterning of the Neural Tube Involves

Similar Mechanisms at Different Rostrocaudal

Levels 1115

The Ventral Neural Tube Is Patterned by Sonic

Hedgehog Protein Secreted from the Notochord and

Floor Plate 1117

The Dorsal Neural Tube Is Patterned by Bone

Morphogenetic Proteins 1119

Dorsoventral Patterning Mechanisms Are Conserved

Along the Rostrocaudal Extent of the Neural Tube 1119

Local Signals Determine Functional Subclasses of

Neurons 1119

Rostrocaudal Position Is a Major Determinant

of Motor Neuron Subtype 1120

Local Signals and Transcriptional Circuits Further

Diversify Motor Neuron Subtypes 1121

The Developing Forebrain Is Patterned by Intrinsic and

Extrinsic Influences 1123

Inductive Signals and Transcription Factor Gradients

Establish Regional Differentiation 1123

Afferent Inputs Also Contribute to

Regionalization 1124

Highlights 1128

Selected Reading 1129

References 1129

46 Differentiation and Survival of Nerve Cells . . . . . . . . . . . . . . . . . . .1130

Joshua R. Sanes, Thomas M. Jessell

The Proliferation of Neural Progenitor Cells Involves

Symmetric and Asymmetric Cell Divisions 1131

Radial Glial Cells Serve as Neural Progenitors and

Structural Scaffolds 1131

The Generation of Neurons and Glial Cells Is Regulated

by Delta-Notch Signaling and Basic Helix-Loop-Helix

Transcription Factors 1131

The Layers of the Cerebral Cortex Are Established by

Sequential Addition of Newborn Neurons 1135

Neurons Migrate Long Distances From Their Site of

Origin to Their Final Position 1137

Excitatory Cortical Neurons Migrate Radially

Along Glial Guides 1137

Cortical Interneurons Arise Subcortically and Migrate

Tangentially to Cortex 1138

Neural Crest Cell Migration in the Peripheral Nervous

System Does Not Rely on Scaffolding 1141

Structural and Molecular Innovations Underlie the

Expansion of the Human Cerebral Cortex 1141

Intrinsic Programs and Extrinsic Factors Determine the

Neurotransmitter Phenotypes of Neurons 1143

Neurotransmitter Choice Is a Core Component

of Transcriptional Programs of Neuronal

Differentiation 1143

Signals From Synaptic Inputs and Targets Can Influence

the Transmitter Phenotypes of Neurons 1146

The Survival of a Neuron Is Regulated by Neurotrophic

Signals From the Neuron’s Target 1147

The Neurotrophic Factor Hypothesis Was Confirmed by

the Discovery of Nerve Growth Factor 1147

Neurotrophins Are the Best-Studied

Neurotrophic Factors 1147

Neurotrophic Factors Suppress a Latent Cell Death

Program 1151

Highlights 1153

Selected Reading 1154

References 1154

47 The Growth and Guidance of Axons . . . . . . . . . . . . . . . . . . . . . . . .1156

Joshua R. Sanes

Differences Between Axons and Dendrites Emerge Early

in Development 1156

Dendrites Are Patterned by Intrinsic and Extrinsic

Factors 1157

The Growth Cone Is a Sensory Transducer

and a Motor Structure 1161

Molecular Cues Guide Axons to Their Targets 1166

The Growth of Retinal Ganglion Axons Is Oriented in a

Series of Discrete Steps 1168

Growth Cones Diverge at the Optic Chiasm 1171

Gradients of Ephrins Provide Inhibitory

Signals in the Brain 1172

Axons From Some Spinal Neurons Are

Guided Across the Midline 1176

Netrins Direct Developing Commissural Axons Across

the Midline 1176

Chemoattractant and Chemorepellent Factors Pattern

the Midline 1176

Highlights 1179

Selected Reading 1179

References 1180

48 Formation and Elimination

of Synapses. . . . . . . . . . . . . . . . . . . . . .1181

Joshua R. Sanes

Neurons Recognize Specific Synaptic Targets 1182

Recognition Molecules Promote Selective Synapse

Formation in the Visual System 1182

Sensory Receptors Promote Targeting of

Olfactory Neurons 1184

Different Synaptic Inputs Are Directed to Discrete

Domains of the Postsynaptic Cell 1186

Neural Activity Sharpens Synaptic Specificity 1187

Principles of Synaptic Differentiation Are Revealed at the

Neuromuscular Junction 1189

Differentiation of Motor Nerve Terminals Is Organized

by Muscle Fibers 1190

Differentiation of the Postsynaptic Muscle Membrane Is

Organized by the Motor Nerve 1194

The Nerve Regulates Transcription of Acetylcholine

Receptor Genes 1196

The Neuromuscular Junction Matures in a Series of

Steps 1197

Central Synapses and Neuromuscular Junctions Develop

in Similar Ways 1198

Neurotransmitter Receptors Become Localized

at Central Synapses 1198

Synaptic Organizing Molecules Pattern Central Nerve

Terminals 1199

Some Synapses Are Eliminated After Birth 1204

Glial Cells Regulate Both Formation and Elimination of

Synapses 1205

Highlights 1207

Selected Reading 1208

References 1208

49 Experience and the Refinement of

Synaptic Connections. . . . . . . . . . . . .1210

Joshua R. Sanes

Development of Human Mental Function

Is Influenced by Early Experience 1211

Early Experience Has Lifelong Effects on Social

Behaviors 1211

Development of Visual Perception Requires Visual

Experience 1212

Development of Binocular Circuits in the Visual Cortex

Depends on Postnatal Activity 1213

Visual Experience Affects the Structure and Function of

the Visual Cortex 1213

Patterns of Electrical Activity Organize Binocular

Circuits 1215

Reorganization of Visual Circuits During a

Critical Period Involves Alterations in Synaptic

Connections 1219

Cortical Reorganization Depends on Changes in Both

Excitation and Inhibition 1219

Synaptic Structures Are Altered During the

Critical Period 1221

Thalamic Inputs Are Remodeled During

the Critical Period 1221

Synaptic Stabilization Contributes to Closing

the Critical Period 1223

Experience-Independent Spontaneous Neural Activity

Leads to Early Circuit Refinement 1224

Activity-Dependent Refinement of Connections Is a

General Feature of Brain Circuitry 1225

Many Aspects of Visual System Development

Are Activity-Dependent 1225

Sensory Modalities Are Coordinated During a Critical

Period 1227

Different Functions and Brain Regions Have Different

Critical Periods of Development 1228

Critical Periods Can Be Reopened in Adulthood 1229

Visual and Auditory Maps Can Be Aligned in

Adults 1230

Binocular Circuits Can Be Remodeled in Adults 1231

Highlights 1233

Selected Reading 1234

References 123450 Repairing the Damaged Brain. . . . .1236

Joshua R. Sanes

Damage to the Axon Affects Both the Neuron and

Neighboring Cells 1237

Axon Degeneration Is an Active Process 1237

Axotomy Leads to Reactive Responses

in Nearby Cells 1240

Central Axons Regenerate Poorly After Injury 1241

Therapeutic Interventions May Promote Regeneration of

Injured Central Neurons 1242

Environmental Factors Support the Regeneration

of Injured Axons 1243

Components of Myelin Inhibit Neurite

Outgrowth 1244

Injury-Induced Scarring Hinders Axonal

Regeneration 1246

An Intrinsic Growth Program Promotes

Regeneration 1246

Formation of New Connections by Intact Axons Can

Lead to Recovery of Function Following Injury 1247

Neurons in the Injured Brain Die but New Ones Can Be

Born 1248

Therapeutic Interventions May Retain or Replace Injured

Central Neurons 1250

Transplantation of Neurons or Their Progenitors Can

Replace Lost Neurons 1250

Stimulation of Neurogenesis in Regions of Injury May

Contribute to Restoring Function 1254

Transplantation of Nonneuronal Cells or Their

Progenitors Can Improve Neuronal Function 1255

Restoration of Function Is the Aim of

Regenerative Therapies 1255

Highlights 1256

Selected Reading 1257

References 1257

51 Sexual Differentiation of the Nervous System. . . . . . . . . . . . . . . . . . . . . . . . . .1260

Nirao M. Shah, Joshua R. Sanes

Genes and Hormones Determine Physical Differences

Between Males and Females 1261

Chromosomal Sex Directs the Gonadal Differentiation of

the Embryo 1261

Gonads Synthesize Hormones That Promote

Sexual Differentiation 1262

Disorders of Steroid Hormone Biosynthesis

Affect Sexual Differentiation 1263

Sexual Differentiation of the Nervous System Generates

Sexually Dimorphic Behaviors 1264

Erectile Function Is Controlled by a Sexually Dimorphic

Circuit in the Spinal Cord 1266

Song Production in Birds Is Controlled by Sexually

Dimorphic Circuits in the Forebrain 1267

Mating Behavior in Mammals Is Controlled

by a Sexually Dimorphic Neural Circuit in the

Hypothalamus 1272

Environmental Cues Regulate Sexually Dimorphic

Behaviors 1272

Pheromones Control Partner Choice in Mice 1272

Early Experience Modifies Later Maternal

Behavior 1274

A Set of Core Mechanisms Underlies Many Sexual

Dimorphisms in the Brain and Spinal Cord 1275

The Human Brain Is Sexually Dimorphic 1277

Sexual Dimorphisms in Humans May Arise From

Hormonal Action or Experience 1279

Dimorphic Structures in the Brain Correlate with

Gender Identity and Sexual Orientation 1279

Highlights 1281

Selected Reading 1282

References 1283

Part VIII

Learning, Memory, Language

and Cognition

52 Learning and Memory. . . . . . . . . . . .1291

Daphna Shohamy, Daniel L. Schacter,

Anthony D. Wagner

Short-Term and Long-Term Memory Involve Different

Neural Systems 1292

Short-Term Memory Maintains Transient

Representations of Information Relevant to Immediate

Goals 1292

Information Stored in Short-Term Memory Is Selectively

Transferred to Long-Term Memory 1293

The Medial Temporal Lobe Is Critical for Episodic

Long-Term Memory 1294

Episodic Memory Processing Involves Encoding,

Storage, Retrieval, and Consolidation 1297

Episodic Memory Involves Interactions Between the

Medial Temporal Lobe and Association Cortices 1298

Episodic Memory Contributes to Imagination and

Goal-Directed Behavior 1300

The Hippocampus Supports Episodic Memory by

Building Relational Associations 1300

Implicit Memory Supports a Range of Behaviors in

Humans and Animals 1303

Different Forms of Implicit Memory Involve Different

Neural Circuits 1303

Implicit Memory Can Be Associative or

Nonassociative 1304

Operant Conditioning Involves Associating a Specific

Behavior With a Reinforcing Event 1306

Associative Learning Is Constrained by the Biology of

the Organism 1307

Errors and Imperfections in Memory Shed Light on

Normal Memory Processes 1308

Highlights 1309

Suggested Reading 1310

References 1310

53 Cellular Mechanisms of Implicit Memory Storage and the Biological Basis of Individuality. . . . . . . . . . . . .1312

Eric R. Kandel, Joseph LeDoux

Storage of Implicit Memory Involves Changes in the

Effectiveness of Synaptic Transmission 1313

Habituation Results From Presynaptic Depression of

Synaptic Transmission 1314

Sensitization Involves Presynaptic Facilitation of

Synaptic Transmission 1316

Classical Threat Conditioning Involves Facilitation of

Synaptic Transmission 1317

Long-Term Storage of Implicit Memory Involves

Synaptic Changes Mediated by the cAMP-PKA-CREB

Pathway 1319

Cyclic AMP Signaling Has a Role in

Long-Term Sensitization 1319

The Role of Noncoding RNAs in the

Regulation of Transcription 1323

Long-Term Synaptic Facilitation Is Synapse

Specific 1324

Maintaining Long-Term Synaptic Facilitation Requires

a Prion-Like Protein Regulator of Local Protein

Synthesis 1327

Memory Stored in a Sensory-Motor Synapse Becomes

Destabilized Following Retrieval but

Can Be Restabilized 1330

Classical Threat Conditioning of Defensive Responses in

Flies Also Uses the cAMP-PKA-CREB Pathway 1330

Memory of Threat Learning in Mammals Involves the

Amygdala 1331

Learning-Induced Changes in the Structure

of the Brain Contribute to the Biological Basis of

Individuality 1336

Highlights 1336

Selected Reading 1337

References 1337

54 The Hippocampus and the Neural Basis of Explicit Memory Storage . . . . . . . . . . . . . . . . .1339

Edvard I. Moser, May-Britt Moser,

Steven A. Siegelbaum

Explicit Memory in Mammals Involves Synaptic Plasticity

in the Hippocampus 1340

Long-Term Potentiation at Distinct Hippocampal

Pathways Is Essential for Explicit Memory

Storage 1342

Different Molecular and Cellular Mechanisms

Contribute to the Forms of Expression of

Long-Term Potentiation 1345

Long-Term Potentiation Has Early and Late

Phases 1347

Spike-Timing-Dependent Plasticity Provides a

More Natural Mechanism for Altering Synaptic

Strength 1349

Long-Term Potentiation in the Hippocampus Has

Properties That Make It Useful as A Mechanism for

Memory Storage 1349

Spatial Memory Depends on Long-Term

Potentiation 1350

Explicit Memory Storage Also Depends on Long-Term

Depression of Synaptic Transmission 1353

Memory Is Stored in Cell Assemblies 1357

Different Aspects of Explicit Memory Are Processed in

Different Subregions of the Hippocampus 1358

The Dentate Gyrus Is Important for Pattern

Separation 1359

The CA3 Region Is Important for Pattern

Completion 1360

The CA2 Region Encodes Social Memory 1360

A Spatial Map of the External World Is Formed in the

Hippocampus 1360

Entorhinal Cortex Neurons Provide a Distinct

Representation of Space 1361

Place Cells Are Part of the Substrate for

Spatial Memory 1365

Disorders of Autobiographical Memory Result From

Functional Perturbations in the Hippocampus 1367

Highlights 1367

Selected Reading 1368

References 1368

55 Language. . . . . . . . . . . . . . . . . . . . . . . .1370

Patricia K. Kuhl

Language Has Many Structural Levels: Phonemes,

Morphemes, Words, and Sentences 1371

Language Acquisition in Children Follows a Universal

Pattern 1372

The “Universalist” Infant Becomes Linguistically

Specialized by Age 1 1373

The Visual System Is Engaged in Language Production

and Perception 1376

Prosodic Cues Are Learned as Early as In Utero 1376

Transitional Probabilities Help Distinguish Words in

Continuous Speech 1376

There Is a Critical Period for Language

Learning 1377

The “Parentese” Speaking Style Enhances

Language Learning 1377

Successful Bilingual Learning Depends on the Age at

Which the Second Language Is Learned 1378

A New Model for the Neural Basis of Language Has

Emerged 1378

Numerous Specialized Cortical Regions Contribute to

Language Processing 1378

The Neural Architecture for Language Develops

Rapidly During Infancy 1380

The Left Hemisphere Is Dominant for Language 1381

Prosody Engages Both Right and Left Hemispheres

Depending on the Information Conveyed 1382

Studies of the Aphasias Have Provided Insights into

Language Processing 1382

Broca’s Aphasia Results From a Large

Lesion in the Left Frontal Lobe 1382

Wernicke’s Aphasia Results From Damage to Left

Posterior Temporal Lobe Structures 1384

Conduction Aphasia Results From Damage to a Sector

of Posterior Language Areas 1384

Global Aphasia Results From Widespread Damage to

Several Language Centers 1386

Transcortical Aphasias Result From Damage to Areas

Near Broca’s and Wernicke’s Areas 1386

Less Common Aphasias Implicate Additional

Brain Areas Important for Language 1386

Highlights 1388

Selected Reading 1389

References 1390

56 Decision-Making and Consciousness. . . . . . . . . . . . . . . . . . .1392

Michael N. Shadlen, Eric R. Kandel

Perceptual Discriminations Require a Decision

Rule 1393

A Simple Decision Rule Is the Application of a

Threshold to a Representation of the

Evidence 1393

Perceptual Decisions Involving Deliberation Mimic

Aspects of Real-Life Decisions Involving Cognitive

Faculties 1395

Neurons in Sensory Areas of the Cortex Supply

the Noisy Samples of Evidence to

Decision-Making 1397

Accumulation of Evidence to a Threshold Explains the

Speed Versus Accuracy Trade-Off 1401

Neurons in the Parietal and Prefrontal Association Cortex

Represent a Decision Variable 1401

Perceptual Decision-Making Is a Model for Reasoning

From Samples of Evidence 1404

Decisions About Preference Use Evidence About

Value 1408

Decision-Making Offers a Framework for Understanding

Thought Processes, States of Knowing, and States of

Awareness 1409

Consciousness Can be Understood Through the Lens of

Decision Making 1412

Highlights 1415

Selected Reading 1415

References 1416

Part IX

Diseases of the Nervous System

57 Diseases of the Peripheral Nerve and Motor Unit . . . . . . . . . . . . . . . . . .1421

Robert H. Brown, Stephen C. Cannon,

Lewis P. Rowland

Disorders of the Peripheral Nerve, Neuromuscular Junction,

and Muscle Can Be Distinguished Clinically 1422

A Variety of Diseases Target Motor Neurons and

Peripheral Nerves 1426

Motor Neuron Diseases Do Not Affect Sensory Neurons

(Amyotrophic Lateral Sclerosis) 1426

Diseases of Peripheral Nerves Affect Conduction of the

Action Potential 1428

The Molecular Basis of Some Inherited Peripheral

Neuropathies Has Been Defined 1430

Disorders of Synaptic Transmission at the Neuromuscular

Junction Have Multiple Causes 1432

Myasthenia Gravis Is the Best-Studied Example of a

Neuromuscular Junction Disease 1433

Treatment of Myasthenia Is Based on the Physiological

Effects and Autoimmune Pathogenesis of the Disease 1435

There Are Two Distinct Congenital Forms of Myasthenia

Gravis 1435

Lambert-Eaton Syndrome and Botulism Also Alter

Neuromuscular Transmission 1436

Diseases of Skeletal Muscle Can Be Inherited or

Acquired 1437

Dermatomyositis Exemplifies Acquired

Myopathy 1437

Muscular Dystrophies Are the Most Common Inherited

Myopathies 1437

Some Inherited Diseases of Skeletal Muscle Arise From

Genetic Defects in Voltage-Gated Ion Channels 1441

Highlights 1445

Selected Reading 1445

References 1445

58 Seizures and Epilepsy . . . . . . . . . . . .1447

Gary Westbrook

Classification of Seizures and the Epilepsies Is Important

for Pathogenesis and Treatment 1448

Seizures Are Temporary Disruptions of

Brain Function 1448

Epilepsy Is a Chronic Condition of

Recurrent Seizures 1449

The Electroencephalogram Represents the Collective

Activity of Cortical Neurons 1450

Focal Onset Seizures Originate Within a Small Group of

Neurons 1454

Neurons in a Seizure Focus Have Abnormal Bursting

Activity 1454

The Breakdown of Surround Inhibition Leads to

Synchronization 1456

The Spread of Seizure Activity Involves Normal Cortical

Circuitry 1460

Generalized Onset Seizures Are Driven by

Thalamocortical Circuits 1461

Locating the Seizure Focus Is Critical to the Surgical

Treatment of Epilepsy 1463

Prolonged Seizures Can Cause Brain Damage 1465

Repeated Convulsive Seizures Are a

Medical Emergency 1465

Excitotoxicity Underlies Seizure-Related

Brain Damage 1466

The Factors Leading to Development of Epilepsy Are

Poorly Understood 1467

Mutations in Ion Channels Are Among the

Genetic Causes of Epilepsy 1467

The Genesis of Acquired Epilepsies Is a Maladaptive

Response to Injury 1469

Highlights 1470

Selected Reading 1471

References 1471

59 Disorders of Conscious and Unconscious Mental Processes. . . . .1473

Christopher D. Frith

Conscious and Unconscious Cognitive Processes Have

Distinct Neural Correlates 1474

Differences Between Conscious and Unconscious

Processes in Perception Can Be Seen in Exaggerated Form

After Brain Damage 1476

The Control of Action Is Largely Unconscious 1479

The Conscious Recall of Memories Is a

Creative Process 1482

Behavioral Observation Needs to Be Supplemented With

Subjective Reports 1483

Verification of Subjective Reports Is Challenging 1484

Malingering and Hysteria Can Lead to Unreliable

Subjective Reports 1485

Highlights 1485

Selected Reading 1486

References 1486

60 Disorders of Thought and Volition in Schizophrenia . . . . . . . . . . . . . . . . . . .1488

Steven E. Hyman, Joshua Gordon

Schizophrenia Is Characterized by Cognitive

Impairments, Deficit Symptoms, and

Psychotic Symptoms 1489

Schizophrenia Has a Characteristic Course of

Illness With Onset During the Second and Third

Decades of Life 1490

The Psychotic Symptoms of Schizophrenia

Tend to Be Episodic 1490

The Risk of Schizophrenia Is Highly Influenced by

Genes 1490

Schizophrenia Is Characterized by Abnormalities in Brain

Structure and Function 1492

Loss of Gray Matter in the Cerebral Cortex Appears to

Result From Loss of Synaptic Contacts Rather Than Loss

of Cells 1494

Abnormalities in Brain Development

During Adolescence May Be Responsible for

Schizophrenia 1494

Antipsychotic Drugs Act on Dopaminergic Systems in the

Brain 1497

Highlights 1499

Selected Reading 1499

References 1499

61 Disorders of Mood and Anxiety . . . . . . . . . . . . . . . . . . . . .1501

Steven E. Hyman, Carol Tamminga

Mood Disorders Can Be Divided Into Two General

Classes: Unipolar Depression and Bipolar Disorder 1501

Major Depressive Disorder Differs Significantly From

Normal Sadness 1502

Major Depressive Disorder Often Begins Early in Life 1503

A Diagnosis of Bipolar Disorder Requires an Episode of

Mania 1503

Anxiety Disorders Represent Significant Dysregulation of

Fear Circuitry 1504

Both Genetic and Environmental Risk Factors Contribute

to Mood and Anxiety Disorders 1506

Depression and Stress Share Overlapping Neural

Mechanisms 1508

Dysfunctions of Human Brain Structures and Circuits

Involved in Mood and Anxiety Disorders Can Be

Identified by Neuroimaging 1509

Identification of Abnormally Functioning Neural

Circuits Helps Explain Symptoms and May Suggest

Treatments 1509

A Decrease in Hippocampal Volume Is Associated With

Mood Disorders 1512

Major Depression and Anxiety Disorders

Can Be Treated Effectively 1512

Current Antidepressant Drugs Affect Monoaminergic

Neural Systems 1512

Ketamine Shows Promise as a Rapidly Acting Drug to

Treat Major Depressive Disorder 1515

Psychotherapy Is Effective in the Treatment of Major

Depressive Disorder and Anxiety Disorders 1515

Electroconvulsive Therapy Is Highly Effective Against

Depression 1518

Newer Forms of Neuromodulation Are Being

Developed to Treat Depression 1518

Bipolar Disorder Can Be Treated With Lithium and

Several Anticonvulsant Drugs 1519

Second-Generation Antipsychotic Drugs Are Useful

Treatments for Bipolar Disorder 1520

Highlights 1520

Selected Reading 1521

References 1521

62 Disorders Affecting Social Cognition: Autism Spectrum Disorder . . . . . . . . . . . . . . . . . . . . . . . .1523

Matthew W. State

Autism Spectrum Disorder Phenotypes Share

Characteristic Behavioral Features 1524

Autism Spectrum Disorder Phenotypes Also Share

Distinctive Cognitive Abnormalities 1525

Social Communication Is Impaired in Autism

Spectrum Disorder: The Mind Blindness

Hypothesis 1525

Other Social Mechanisms Contribute to Autism

Spectrum Disorder 1527

People With Autism Show a Lack of

Behavioral Flexibility 1528

Some Individuals With Autism Have Special

Talents 1528

Genetic Factors Increase Risk for Autism Spectrum

Disorder 1529

Rare Genetic Syndromes Have Provided Initial Insights

Into the Biology of Autism Spectrum Disorders 1531

Fragile X Syndrome 1531

Rett Syndrome 1531

Williams Syndrome 1532

Angelman Syndrome and Prader-Willi Syndrome 1533

Neurodevelopmental Syndromes Provide Insight Into

the Mechanisms of Social Cognition 1534

The Complex Genetics of Common Forms of Autism

Spectrum Disorder Are Being Clarified 1534

Genetics and Neuropathology Are Illuminating the

Neural Mechanisms of Autism Spectrum Disorder 1537

Genetic Findings Can Be Interpreted Using

Systems Biological Approaches 1537

Autism Spectrum Disorder Genes Have Been Studied in

a Variety of Model Systems 1538

Postmortem and Brain Tissue Studies Provide Insight

Into Autism Spectrum Disorder Pathology 1539

Advances in Basic and Translational Science Provide

a Path to Elucidate the Pathophysiology of Autism

Spectrum Disorder 1540

Highlights 1540

Selected Reading 1541

References 1541

63 Genetic Mechanisms in Neurodegenerative Diseases of the Nervous System. . . . . . . . . . . . . . . . . .1544

Huda Y. Zoghbi

Huntington Disease Involves Degeneration

of the Striatum 1545

Spinobulbar Muscular Atrophy Is Caused by Androgen

Receptor Dysfunction 1546

Hereditary Spinocerebellar Ataxias Share Similar

Symptoms but Have Distinct Etiologies 1546

Parkinson Disease Is a Common Degenerative Disorder of

the Elderly 1548

Selective Neuronal Loss Occurs After Damage to

Ubiquitously Expressed Genes 1550

Animal Models Are Productive Tools for Studying

Neurodegenerative Diseases 1552

Mouse Models Reproduce Many Features of

Neurodegenerative Diseases 1552

Invertebrate Models Manifest Progressive

Neurodegeneration 1553

The Pathogenesis of Neurodegenerative Diseases Follows

Several Pathways 1553

Protein Misfolding and Degradation Contribute to

Parkinson Disease 1553

Protein Misfolding Triggers Pathological

Alterations in Gene Expression 1555

Mitochondrial Dysfunction Exacerbates

Neurodegenerative Disease 1556

Apoptosis and Caspases Modify the Severity

of Neurodegeneration 1556

Understanding the Molecular Dynamics of

Neurodegenerative Diseases Suggests Approaches to

Therapeutic Intervention 1556

Highlights 1558

Selected Reading 1558

References 1558

64 The Aging Brain . . . . . . . . . . . . . . . . .1561

Joshua R. Sanes, David M. Holtzman

The Structure and Function of the Brain Change With

Age 1561

Cognitive Decline Is Significant and Debilitating in a

Substantial Fraction of the Elderly 1566

Alzheimer Disease Is the Most Common Cause of

Dementia 1567

The Brain in Alzheimer Disease Is Altered by Atrophy,

Amyloid Plaques, and Neurofibrillary Tangles 1568

Amyloid Plaques Contain Toxic Peptides That

Contribute to Alzheimer Pathology 1570

Neurofibrillary Tangles Contain Microtubule-Associated

Proteins 1573

Risk Factors for Alzheimer Disease Have Been

Identified 1574

Alzheimer Disease Can Now Be Diagnosed Well but

Available Treatments Are Unsatisfactory 1576

Highlights 1579

Selected Reading 1580

References 1580

Index 1583

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