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 PROACH

O XFO R D
U N I V E R S IT Y PRESS
Contents

Preface xix
About the Author xxix

Chapter 1 Nervous System Organization

How Do Neuroscientists Study the Brain?
• The Value of Why Questions 2
W hat Are the Basic Components of the Nervous System?
• Neuroanatomical Nomenclature 4
• Major Divisions of the Nervous System 9
• Neurons and Glial Cells 12

W hat Kinds of Circuits Do Neurons Form? 13

• Principles of Neural Circuit Organization 13
W hat Is the Brain's Functional Architecture?
• Early Ideas on Brain Organization 17
• Modern Views of Brain Organization 20
How Can Scientists "Reverse Engineer" the Brain?
• Functional Decomposition Strategies 22
• Neuropsychology 23
• Neuroethology 24
How Do Brains Evolve? 25
• Descent w ith Conservation and Modification 25
• Which Species to Study? 26
Summary 27
Key Terms 28
Additional Readings 28
■ Box 1.1 Neuroanatomical Techniques 6
■ Box 1.2 Physiological Techniques 16
■ Box 1.3 O pto-and Chemogenetic Techniques 19

VII
VIII Contents

Chapter 2 Computing with Neurons 31

W hat Are Neurons? 32
• History of the Neuron Doctrine 32
• Basic Features of a Stereotypical Neuron 34
W hat Mechanisms Generate Resting and Action Potentials?
• Ionic Basis of the Resting Potential 36
• Ionic Basis of the Action Potential 39
How Do Action Potentials Travel along Axons? 46
• A Traveling Wave of Membrane Depolarization 46
• The Effects of Myelination 48
How Do Neurons Transmit and Integrate Information?
• Synaptic Transmission 51
• Synaptic Integration 53
How Do Neurons Differ from One Another?
• Anatomical Variety 55
• Neurotransm itter Variety 57
• Receptor Variety 61
• Ion Channel Variety 62
Neuronal Information Processing 63
• How Neurons Encode Inform ation 63
• Brains versus Computers 66
Summary 67
Key Terms 68
Additional Readings 68
■ Box 2.1 Neuronal Membrane Math 38
■ Box 2.2 Patch Clamp Recording 40
■ Box 2.3 Molecular Biology of Voltage-gated Ion Channels 41
B Box 2.4 Nature's Neurotoxins 59
■ Box 2.5 Mood Molecules 60

Chapter 3 Neuronal Plasticity 71

How Are Synapses Strengthened in the Marine Snail Aplysial
• Sensitization in Aplysia 72
• Making Sensitization Last for Days 75
How Are Synapses Strengthened in Mammals?
• Hippocampal Long-term Potentiation 77
• Hebbian Long-term Potentiation 79
• Mechanisms of LTP Induction 80
• Mechanisms of LTP Stabilization 82
When Are Synapses Weakened? 84
• Cerebellar Long-term Depression 84
• Spike Tim ing-dependent Plasticity 86
Can Inactive Neurons Strengthen Their Inputs?
 Contents

Can Experiences Rewire the Brain? 87

• Turnover of Dendritic Spines 87
• Sprouting of Axonal Connections 87
• Sensory Cortex Plasticity 88
• Motor Cortex Plasticity 89
How Does Experience Affect Brain and Cortex Size? 92
Does Neural Plasticity Cause Learning and Memory? 92
Summary 94
Key Terms 94
Additional Readings 95
S Box 3.1 The Impact of Invertebrates on Neurobiology 74
■ Box 3.2 Hippocampal Structure and Functions 78
■ Box 3.3 B rain-M achine Interfaces 91

Chapter 4 Developing a Nervous System 97

Where in the Embryo Does the Nervous System Originate?
• Induction of the Nervous System 99
• Forming the Neural Tube 102 filaments

How Does the Neural Tube Get Subdivided?

• Rostrocaudal Patterning 102
• Dorsoventral Patterning 105
• Midbrain and Forebrain Patterning 106
e m a to d e
Where Do Neurons Come From? 108
• Neurogenesis 108 E v /H x

• Radial Neuronal Migration 109

P la ty h e lm in th
• Neurogenesis Timing and Cell Fate 110
3 /ftx ?

How Do Axons Find Their Targets?

• Axonal Growth Cones 112
• Growth Cone Guidance 113
• The Retinotectal System 115
How Do Synapses Form? 118
• Filopodial Interactions 118
• Synapse Formation 120
How Can a Neural Circuit Be Fine-Tuned? 121
• Developmental Neuron Death 121
• Pruning and Sprouting Neuronal Connections 124
W hat Are the Major Themes of Neural Development?
• Sensitive Periods 128
• Molecular Redeployment 128
• Some Regions Develop Faster Than Others 130
• Developmental Self-organization 130
Summary 130
Key Terms 131
Additional Readings 132
X Contents

■ Box 4.1 In Situ Hybridization 100

□ Box 4.2 Hox Genes in Evolution 104
Box 4.3 Drugs and a Baby's Brain 129

Chapter 5 Protecting and Maintaining the Adult Nervous System 133

Are New Neurons Added to Adult Brains?
• Neuronal Birth-dating Experiments 134
How Is the Brain Protected from Physical Trauma?
• Meninges and Cerebrospinal Fluid 139
• Pressure Kills Neurons 140
How Does the Brain Protect Itself against Toxins and Pathogens?
• The B lood-brain Barrier 142
• The Blood-CSF and Arachnoid Barriers 144
How Does the Nervous System Respond to an Attack?
• The Brain's Immune Response 146
• M inim izing Neuron Death 149
• Functional Recovery through Brain Rewiring 152
How Do Neurons Get Their Energy? 155
• Sources of Metabolic Energy 155
• Cerebral Blood Flow 156
• Linking Blood Flow to Neuronal Activity 158
W hat Links Body and Brain?
Summary 163
Key Terms 164
Additional Readings 164
■ Box 5.1 Delivering Drugs to the Brain 143
Box 5.2 Immune Responses in Alzheimer's Disease 150
■ Box 5.3 Functional M agnetic Resonance Imaging 160

Chapter 6 Sensors I: Remote Sensing 167

How Do We Sense Darkness and Light? 168
• Special Regions of the Retina 169
• Rod Photoreceptors 170
• Cone Photoreceptors 172
• Pathways through the Retina 175
• The Puzzle of the Inverted Vertebrate Retina 176
How Do We Sense Odors? 177
• Olfactory Epithelium 178
• Olfactory Receptor Molecules 179
• The Olfactory Bulb 182
How Do We Hear Sounds? 185
• Outer and Middle Ears 185
• The Cochlea 186
• Encoding Sound Parameters 191
 Contents XI

Are There Some Principles of Sensor Organization?

• Variability in Sensor Range 193
• Variability in Sensor Sensitivity 194
• Labeled Lines 196
• Sensory Maps 196
Summary 197
Key Terms 198
Additional Readings 199
■ Box 6.1 Anosmias: Does Your World Smell the Same as Mine? 180
■ Box 6.2 Cochlear Implants 192
■ Box 6.3 Electroreception and Other Alien Senses 195

Chapter 7 Sensors II: Sensing on Contact 201

How Do We Sense Touch and Vibration? 202
• Encapsulated Nerve Endings 202
• Central Projections of Mechanosensory Axons 205
How Do We Sense Pain? 208
• Axons That Transmit Pain 208
• Pain Modulation 211

How Do We Sense Temperature? 213

• Temperature-sensitive TRP Channels 214
• Food-activated TRP Channels 214
How Do We Taste Foods and Other Chemicals? 215
• Taste Cells 215
• Taste Receptor Molecules 216
• Central Taste Pathways 218
• Variations in Tasting Ability 219
How Can We Sense Our Body's Physiological Condition?
• Sensing Tissue Acidity 221
• Sensing Blood Chemistry 222
How Do We Sense Body Position and Movement?
• Proprioception 223
• Vestibular Sensors 225
W hat Are Some Common Themes of Contact Sensor Organization?
• Variability in Sensor Range and Sensitivity 229
• Labeled Lines and Sensory Maps 230
Summary 231
Key Terms 232
Additional Readings 233
Box 7.1 Shingles and Dermatomes 209
Box 7.2 Neurogenic Inflam m ation 212
■ Box 7.3 Cannabinoid Effects on Food Intake 220
□ Box 7.4 Feeling Less Pain in High C02 222
XII Contents

Chapter 8 Using Muscles and Glands 235

8.1 How Do Neurons Control Skeletal Muscles? 236
• The Contractile Machinery 237
• Excitation-contraction Coupling 238
• Controlling Muscle Force 240
• Muscle Spindles 244
8.2 W hat Makes the Heart Beat? 245
• Generation of the Cardiac Rhythm 246
• Modulation of the Cardiac Rhythm 247
8.3 W hat Is Special about Smooth Muscle? 248
• Smooth Muscle Anatomy 248
• Smooth Muscle Physiology 249
• Smooth Muscle Innervation 249
8.4 How Do Muscles Lengthen after Contractions? 249
• Muscles Must Be Antagonized 250
8.5 How Do Neurons Control Hormones, and Vice Versa? 253
• Exocrine Glands 253
• The Posterior Pituitary 253
• The Anterior Pituitary 255
• Hippocampal Regulation of Stress Hormones 259
Summary 261
Key Terms 262
Additional Readings 263
Box 8.1 Outer Hair Cell M otility 251
Box 8.2 Endocrine Disruptors 258

Chapter 9 Regulating Vital Bodily Functions 265

9.1 How Do We Maintain Physiological Stability? 266
9.2 W hat Parts of the Nervous System Control the Vital Bodily Functions? 267
• The Sympathetic Division of the Autonomic Nervous System 268
• The Parasympathetic Division of the Autonomic Nervous System 269
• Sensory Components of the Autonomic Nervous System 271
• The Enteric Nervous System 272
9.3 How Do Neural Circuits Regulate the Vital Bodily Functions? 273
• Adjusting Heart Rate 273
• Regulating Blood Pressure 276
• Controlling Breathing 278
• Regulating Body Temperature 280
9.4 How Do Neurons Control Fluid and Energy Balance? 283
• Balancing the Bodily Fluids 283
• Regulating Digestion 285
• Regulating Appetite 286
9.5 How Do We Coordinate Our Vegetative Processes? 288
• Circadian Regulation 290
 •••
Contents X III

• Dealing w ith Acute Stress 294

• Effects of Chronic Stress 296
Summary 298
Key Terms 299
Additional Readings 299
Box 9.1 Fainting Spells and Vagal Nerve Stimulation 274
■ Box 9.2 Tackling Obesity through Surgery 289
Box 9.3 Vegetative Control after Spinal Cord Injury 291
■ Box 9.4 Jet Lag and Night Shift Work 292

Chapter 10 Controlling Posture and Locomotion 301

W hat Is a Reflex? 302
• Pupillary Reflexes 302
10.2 How Do Reflexes Protect Us from Harm?
• The Eye Blink Reflex 304
• W ithdraw al Reflexes 304
10.3 How Do We Stabilize Our Body's Position?
• Muscle Stretch Reflexes 306
• Stabilizing the Eyes 308
• Stabilizing the Head 311
• Stabilizing the Body 312
• Modulation of Postural Reflexes 313
10.4 How Do Animals Move through the World?
• Central Pattern Generation 314
• Swimming in Fishes 316
• Walking in Quadrupeds 317
10.5 W hat Does the Motor Cortex Contribute to Motor Control?
• Pathways Descending from the Motor Cortex 320
• Cortical Motor Maps 321
• Encoding Movem ent Details 324
• Mirror Neurons in the Premotor Cortex 325
• Motor Cortex Plasticity 326
10.6 W hat Does the Cerebellum Contribute to Motor Control?
• Cerebellar Anatomy 327
• Cerebellar Function: Adaptive Feedforward Control 328
• Non-m otor Functions of the Cerebellum 331
10.7 How Do the Motor Systems Interact? 332
Summary 334
Key Terms 334
Additional Readings 335
■ Box 10.1 Using Animals in Research 319
Box 10.2 Locked-in Syndrome 323
■ Box 10.3 The Conditioned Eye Blink Response 329
XIV Contents

Chapter 11 Localizing Stimuli and Orienting in Space 337

How Do the Somatosensory and Visual Systems Encode Space?
• Spatial Mapping in the Somatosensory System 338
• Spatial Mapping in the Visual System 342
11.2 How Can Animals Determine Where a Sound Came From? 347
• Interaural Comparisons 347
• Encoding Space in the Auditory Midbrain and Forebrain 349
11.3 In Which Spatial Coordinate System Should Stimuli
Be Localized? 351
• Movable Sensor Arrays 351
• Spatial Coordinate Transformations 351
11.4 How Do Animals Orient toward an Interesting Stimulus? 353
• Targeted Eye Movements 354
• Targeted Head Movements 359
• Targeted Hand Movements 360
11.5 How Do Animals Navigate through Space? 362
• Testing for Allocentric Navigation in Animals 363
• Hippocampal Lesions Impair Allocentric Navigation 365
• Hippocampal Place Cells 366
Summary 370
Key Terms 371
Additional Readings 371
□ Box 11.1 Sound Localization in Barn Owls 350
■ Box 11.2 Recording Neural Activity in Awake Animals 361

Chapter 12 Identifying Stimuli and Stimulus Objects 373

W hat Coding Strategies Do Sensory Systems Employ?
• Sparse and Efficient Sensory Coding 375
• Grandmother Cells versus Combinatorial Coding 375
12.2 How Does the Visual System Identify Objects?
• Retinal Receptive Fields 377
• Thalamic Receptive Fields 379
• Edges and Line Detectors in V I 380
• Identifying Visual Motion 383
• Identifying Color 387
• Identifying Complex Visual Objects 390
12.3 How Do Neurons Encode Non-Visual Objects? 393
• Object Identification in the Olfactory System 394
• Identifying Sounds 395
• Identifying Things by Touch or Taste 397
12.4 Are We Born w ith All the Neural Circuitry We Use to Identify
Stimulus Objects? 398
• Sensory Deprivation Experiments 398
• Instructive Effects of Early Experience 399
 Contents xv

12.5 Why Do We Perceive Objects as Coherent Entities?

• Binding through Temporal Correlation 401
• Disorders of Perceptual Binding 404
Summary 404
Key Terms 405
Additional Readings 405
■ Box 12.1 Intrinsic Signal Optical Imaging 384
Box 12.2 Deficits in Object Identification: Agnosias 403

Chapter 13 Regulating Brain States 407

How Does the Brain Generate and Direct Attention?
• Psychological Aspects of Attention 408
• Neural Correlates of Involuntary Attention 411
• Neural Correlates of Voluntary Attention 414
13.2 W hat Mechanisms Generate Behavioral Arousal?
• The Electroencephalogram (EEG) 418
• Ascending Arousal Systems 419
• The Locus Coeruleus System 419
13.3 Why Do We Sleep, and W hat Helps Us Wake Up?
• Stages of Sleep 424
• The Origins of EEG Rhythms 425
• Brain Systems That Wake Us Up 427
• Brain Systems That Induce Sleep 429
13.4 What's Happening During REM Sleep?
• Muscle Atonia 431
• A REM Sleep Switch? 432
13.5 Why Does the Brain Have Discrete States? 432
• Do We All Have to Sleep? 432
• Energy Conservation, Mem ory Consolidation, and Toxin Removal 433
• Costs and Benefits of Arousal and Attention 434
Summary 435
Key Terms 435
Additional Readings 436
Box 13.1 Attention Deficits 416
■ Box 13.2 Anesthesia and the Death Penalty 430

Chapter 14 Remembering Relationships 437

How Many Forms of Learning and Memory Are There?
14.2 What's Wrong w ith H.M.? 439
• H.M.'s Amnesia 439
• The Sparing of Procedural Learning 442
14.3 Can H.M.'s Amnesia Be Reproduced in Non-humans? 443
• Subdivisions of the Medial Temporal Lobe 444
XVI Contents

• Object Recognition Tests in Rats 444

• W hat Does the Hippocampus Do? 446
14.4 How Are Hippocampus-dependent Memories Created,
and How Are They Recalled? 447
• Hippocampal Circuits and Synaptic Plasticity 447
• Pattern Learning w ithin the Hippocampus 448
• Mem ory Recall 451
14.5 W hat Happens to Memories as They Grow Old?
• Systems Consolidation 454
• The Formation of Neocortical Assemblies 456
14.6 W hat Makes Some Memories Stronger Than Others? 457
• Boosting the Initial Experience 457
• Post-training Mem ory Enhancement 457
• Mem ory Modulation by the Basolateral Amygdala 459
• Function of the Human Basolateral Amygdala 460
14.7 How Do Animals Learn What's Dangerous?
• Auditory Fear Conditioning 461
• Contextual Fear Conditioning 463
• Inhibitory Avoidance Training 464
14.8 How Do We Learn W hat to Eat or Not to Eat? 465
• Learning from Others 465
• Learning from Nausea 465
• Neural Substrates of Conditioned Taste Aversion 466
14.9 W hat Happens When Memories Conflict?
• Habit versus Place Learning 468
Summary 469
Key Terms 470
Additional Readings 470
■ Box 14.1 Mem ory Specialists 440
Box 14.2 Epilepsy 441
Box 14.3 Posttraumatic Stress 458

Chapter 15 Selecting Actions, Pursuing Goals 473

15.1 W hat Is the Frontostriatal System? 474
• Complexities of Basal Ganglia Nomenclature 474
• An Overarching Function for the Frontostriatal System 475
15.2 W hat Are the Direct and Indirect Pathways through
the Striatum? 475
• Direct Frontostriatal Loops 476
• The Indirect Pathway through the Striatum 478
15.3 W hat Is the Influence of Dopamine on the
Frontostriatal Loops? 479
• Dopaminergic Modulation of the Striatum 479
 Contents XVII

• Animal Models of Dopamine Depletion 481

• Dopamine and Drugs of Abuse 484
15.4 How Do We Learn W hat to Do When? 484
• Dopamine Bursts Can Follow or Precede Rewards 485
• Phasic Dopamine Bursts as Teaching Signals 487
15.5 How Do the Dorsal and the Ventral Striatum Relate to One Another?
• Drug-conditioned Place Preference 489
• Connections between the Dorsal and Ventral Striatal Loops 489
15.6 W hat to Do w ith the Prefrontal Cortex?
• Prefrontal Lobotomies 492
• Response Inhibition 495
• Working Mem ory 498
15.7 How Do the Components of the Frontostriatal System Work Together?
• Frontostriatal Interactions 501
Summary 502
Key Terms 503
Additional Readings 503
■ Box 15.1 Treating Parkinson's Disease 482
■ Box 15.2 Sex Drive and Sexual Conditioning 490

Chapter 16 Being Different from Others 505

16.1 Which Species Should Neuroscientists Study, and Why? 506
• The August Krogh Principle 506
• Problems w ith the Model Species Concept 508
• Studying Non-human Species for Their Own Sake 508
16.2 Who Evolved the Largest and Most Complex Brains? 509
• Evolutionary Increases in Brain Size and Complexity 510
• Allometric Brain Scaling 510
16.3 W hat Makes Human Brains Unique? 513
• Primate Brain Evolution 513
• The Neural Basis of Human Language 516
• The Evolution of Language-related Circuitry 519
16.4 Do Brains Differ between the Sexes? 520
• Mechanisms of Sexual Differentiation 520
• Sex Differences in the Spinal Cord, Hypothalamus, and Midbrain 522
• Sex Differences in the Telencephalon 524
16.5 Within a Sex, How Much Do Human Brains Vary? 527
• Implications of Brain Variability for Functional Brain Imaging 529
• Age-related Variability in Brains 531
16.6 W hat Can We Learn by Comparing Diverse Brains? 533
• Working w ith Animal Models 533
• Taking Advantage of "Natural Experiments" 536
x v iii Contents

Summary 537
Key Terms 538
Additional Readings 538
■ Box 16.1 The Challenges of Human Subjects Selection 528
Box 16.2 Complex Mental Disorders: Autism and Schizophrenia 534

Glossary 541
References 577
Credits 591
Index 599
Preface
To explicate the uses of the Brain seems as difficult a task as to paint the
Soul, of which it is commonly said that it understands all things but itself.
—Thomas Willis (1664)

lthough inquisitive individuals have long sought to understand the neural basis
A of our thoughts, our emotions, our “soul,” neurobiology is still a young and rap­
idly growing field. In 1971, the first meeting of the Society for Neuroscience had only
1,400 participants; by 2014, the list of attendees had swelled to 31,000. In parallel
with this explosive growth, the number of US educational institutions offering un­
dergraduate neurobiology majors increased from fewer than 10 in 1986 to more than
100 in 2008 (Ramos et al., 2011). Clearly, the quest to “explicate the uses of the Brain”
is attracting an ever-growing number of bright minds.
The most fascinating aspect of neurobiological knowledge is that it spans numer­
ous levels of analysis, ranging from DNA and other molecules to complex neural sys­
tems that interact with one another and the world. In contrast to other organs, the
brain contains a vast number of distinct cell types, all performing different functions.
Therefore, to understand the brain, it is not enough to know how a “generic neuron”
works; we also have to figure out how those diverse neurons interact with one an­
other and how they generate behavior. This task is enormous and, as you will see, still
far from completion.

The Functional Approach

Neurobiology: A Functional Approach is unusual among introductory neurobiology
textbooks in that it asks not only how the nervous system works but also why it works as it
doesj it isfocused on the problems that brains help organisms solve.
For example, the book explains why neurons use all-or-nothing action potentials
to communicate with other cells, and why the blood-brain barrier exists. Such “why”
questions can often be answered by describing a specific feature’s impact on survival
or reproduction. The blood-brain barrier, for example, can be understood as a set of
mechanisms that protect the brain, and thus the organism, from harmful compounds
in the blood. Alternatively, “why” questions can be answered in terms of engineering
principles. For example, the use of action potentials significantly improves the reli­
ability of signal transmission along axons. Because many neurobiological “why” ques­
tions currently lack definitive answers, this book focuses on the strongest and most
plausible hypotheses. Their primary purpose is to provoke thought and highlight
what remains unknown.
Another unique aspect of the book is its emphasis on neural circuits and systems.
It is relatively common for introductory neurobiology courses and texts to focus
either on the cellular and molecular end of the neuroscience spectrum or on the cogni­
tive end, neglecting the “middle ground.” By emphasizing circuits and systems, the
book allows readers to grasp the wide array of problems that nervous systems solve,

X IX
such as sensing stimuli, controlling movement, learning what to fear or desire, and
pursuing a goal. In keeping with this broad functional approach, the book covers
molecular and cellular information not just at the beginning, but wherever it is
relevant.

Organization
Neurobiology: A Functional Approach is organized around the major kinds of problems
that nervous systems solve or help to solve. After an introductory chapter that pro­
vides an overview of nervous system organization, Chapters 2-5 focus on problems
that are internal to the nervous system, such as the design of biological computing
elements and the embryological development of complex brains. Chapters 6-8 deal
with sensors that provide the brain with information about the outside world and with
effectors, specifically muscles and glands. Chapters 9-12 explore problems that in­
volve relatively simple interactions between the nervous system and its environment,
such as regulating bodily functions and orienting the eyes toward external objects.
Chapters 13-15 then focus on more complex interactions between organisms and
their environment, including attention, arousal, memory, and decision making. The
final chapter highlights how brains vary across species as well as within species.
If you are a student who is new to neurobiology, this books organization should
feel relatively natural because it progresses gradually from relatively simple functions,
such as neuronal signaling, to ever more complex functions, including memory, deci­
sion making, and language. However, if you have previously studied neurobiology
from other books, some aspects of this book will seem unusual to you.

Comparison to Other Textbooks

Neurobiology: A Functional Approach covers the cellular and molecular mechanisms
of neuronal signaling in just one chapter, instead of the more usual 4 -6 separate
chapters. This decision was driven by my desire to keep this textbook relatively short.
I also feel that it is important to familiarize students with the whole spectrum of
modern neurobiological research, and to do so from the outset, not just in more ad­
vanced courses.
A second unusual feature of the present book is that it separates the question
of how neurons sense stimuli from the question of how this sensory information is
analyzed and used by the rest of the brain. This division makes it easier to compare
and contrast the various senses. It also facilitates the discussion of multimodal sen­
sory integration and low-level sensorimotor control, two topics that get short shrift in
other books. Conventional treatments encourage you to think that the various sen­
sory pathways are separate from one another and from motor systems until they
reach the cerebral cortex, but this is not how real brains work.
The third big difference between this book and more traditional texts is that here
the basal ganglia and dopamine are not discussed in the context of movement con­
trol, which is how most books deal with them. Instead, I cover them in Chapter 15,
which explores the neural mechanisms of decision making, defined as the selection
of behavioral goals, actions, and movements. In this larger context, the dopamine
signals are viewed as helping organisms learn which behaviors are most appropriate
for a given situation. This function is much broader than movement control.
Chapter 15 also covers the prefrontal cortex, which most textbooks discuss in a
separate chapter on “executive functions.” My decision to combine the basal ganglia
with the prefrontal cortex was motivated by the dense anatomical connections be­
tween the prefrontal cortex and the striatum, the largest component of the basal gan­
glia. To understand the functions of these “frontostriatal loops,” it helps to realize
that both the striatum and the frontal lobe are hierarchically organized. This func­
tional similarity is easier to grasp when both brain regions are covered together.
The books last chapter discusses species, sex, and individual differences in brains.
Other textbooks tend to ignore individual differences and cover sex differences
only in the context of reproductive behaviors. However, both sorts of differences
are increasingly recognized as being both widespread and significant. Species differ­
ences are likewise important. Most textbooks cover brain evolution in an opening
chapter, but such discussions are more fruitful when you have already learned what
brains are all about. Combining species, sex, and individual differences into a single chap­
ter feels natural because, in all three cases, the differences exist on a background of
widespread similarities.
As you read Neurobiology: A Functional Approach, you will find numerous links to
neurological disorders and other clinical issues, but the books primary focus is on
the functioning of normal, intact brains. The rationale behind this emphasis is that
knowing how a system normally functions makes it much easier to understand how
the system can break. Of course, learning about neurological disorders is inherently
fascinating and motivates many of us to learn about the brain. Therefore, in­
structors may want to supplement their lectures with stories and videos about
disorders and treatments. Those in-class activities are especially useful if the stu­
dents have read the book ahead of class and come prepared to contribute their own
questions and ideas.

Special Features
Textbooks are most effective when they are fun to read and pull you into an unfold­
ing “story.” To achieve this goal, Neurobiology: A Functional Approach has been de­
signed with several features that make it more enjoyable and easier to use.

User-friendly Style
Written by a single author, the text contains a minimum of jargon and is written with
the beginning student in mind. A clear, consistent voice aims to engage you and make
you curious about the brain and what it does. The book is more an epic narrative than
an encyclopedic reference work. Yet it respects the brains complexity and avoids
oversimplification.

Experimental Emphasis
For any scientist, both young and old, it is important to know not only the key facts
and concepts in a field, but also how those facts and concepts were obtained. There­
fore, this book includes some historical information as well as descriptions of many
key experiments. Data from these experiments are presented in many of the books
illustrations, making it easier to “see” how neuroscience works.

Special Topics Boxes

The book includes 46 “special topics boxes” that complement the central narrative.
Some of the boxes focus on neurological disorders and therapies; others describe
techniques or fascinating facts; and some highlight the power of evolution. The boxes
can be skipped without breaking the text’s main storyline, but some are sure to pique
your interest.

Brain Exercise Questions

Sprinkled throughout the book are “brain exercise questions” that encourage you to
think about what you just read. These questions tend to be open-ended and lack
simple answers, but trying to answer them will help you integrate the information
and remember it. After all, none of us enjoy the feeling of having read large sections
of a book only to realize that we remember none of it. Our time is much too valuable.

Chapter Summaries
Each chapter ends with a bulleted “chapter summary” that reprises the major points.
These summaries can help you figure out which core concepts you remember—and
which ones you should revisit. The summaries will also help you think about what
you have learned and inscribe that knowledge in your long-term memory.
Annotated Bibliography
A list of additional readings at the end of each chapter provides interested readers
with an entry into the scientific literature. Some of the listed articles and books
review the field; others describe specific experiments. While some are broadly acces­
sible, others are aimed at specialists. To gauge the scope and content of each listed
publication, you can consult the annotated version of this bibliography, which is
available on the books website.

Key Terms and Glossary

Key terms are highlighted the first time they appear in the text and listed at the end
of each chapter. Concise explanations of those terms are provided in the glossary at
the end of the book.

Zoomable Human Brain Atlas

As you read about the brain, it helps to have a 3-dimensional image of what that brain
looks like. Therefore, I have created a web-based atlas of Nissl- and fiber-stained
tissue sections through real human brains. The user interface allows you to zoom in
on individual neurons and then zoom out again. Only about 50 structures are identi­
fied by name so that you will not be overwhelmed with information unrelated to this
book. This brain atlas is available through the course website.

Human Brain MRI Atlas

Contemporary neurobiologists rely heavily on the technique of magnetic resonance
imaging (MRI). Therefore, I have created for this book three sets of horizontal,
sagittal, and coronal MRI sections through a single human brain. The images are
designed to be viewed as a presentation in PDF viewing software. The labeling of
individual structures is kept to a minimum. This resource, too, is available through
the books website.
Visual Guide to the Book
Neurobiology: A Functional Approach is distinguished by the following approaches:
• Investigates not only how the nervous system works, but why it works as it does
• Focuses on the problems that brains help organisms solve
• Highlights evolutionary connections and real-world applications
• Emphasizes inquiry and the process of science

Chapter Introductions

Protecting and CHAPTER

• Each chapter opens with a summary of the Core
Questions being discussed and the Features used
Maintaining the 5
to bring the topics home. Adult Nervous System

5.1 Are New Neurons Added to Adult Brains?

5.2 How Is the Brain Protected from Physical Trauma?

CONTENTS FEATURES

5.3 How Does the Brain Protect Itself against Toxins Are New Neurons Added to Adult Brains? THERAPIES

Box 5.1 Delivering Drugs to the Brain

and Pathogens? How Is the Brain Protected from Physical Trauma?
N E U R O LO G IC A L DISO RDERS

How Does the Brain Protect Itself against Toxins Box 5.2 Immune Responses in Alzheimer's Disease
0 1 How Does the Nervous System Respond to an Attack? and Pathogens?
RESEARCH M E TH O D S

How Does the Nervous System Respond to an Attack?

5.5 How Do Neurons Get Their Energy? Box 5.3 Functional Magnetic Resonance Imaging

How Do Neurons Get Their Energy?

5.6 What Links Body and Brain? What Links Body and Brain?

Inside the Chapter

• The Core Questions posed at the beginning of the

chapter are reflected in the titles of each major section
in the chapter; they pique student interest and mirror
the spirit of scientific inquiry.
• Brain Exercise Questions integrated throughout the
chapter prompt students to think critically and help
them integrate and remember the chapter content.
• Bulleted End-of-Chapter Summaries, Key Terms,
and Suggested Further Readings remind students
of essential concepts and guide them to additional
resources.
BRAI N EXERCI SE
Imagine a piece o f shrapnel entered your skull and killed a large number of
neurons in your left auditory cortex, which is needed for speech production
and comprehension. How might you and your brain respond to this injury?
5 .3 How Does the Brain Protect Itself
against Toxins and Pathogens?
B ecause th e nervous system req u ires e n e rg y deriv ed m a in ly from glucose an d oxygen,
it m u s t b e su p p lie d w ith b lo o d . U n fo rtu n a te ly , b lo o d also c a rrie s w ith in it n u m e ro u s
su b sta n c e s th a t c a n d a m a g e n e u ro n s. L ead , m e rc u ry , p e stic id e s, v a rio u s o th e r p o llu t­
a n ts, p a th o g e n ic v iru se s, b a c te ria , a n d ev en th e b o d y ’s o w n im m u n e cells w o u ld all
w re a k h av o c in th e C N S if th e y h a d free access to it. F o rtu n a te ly , v e rte b ra te s evolved
tig h t b a rrie rs b e tw e e n th e b lo o d an d th e ir n e u ro n s.
The Blood-brain Barrier
T h e d isc o v e ry o f a b lo o d -b ra in b a rrie r d ates b a c k to th e 1880s, w h e n P au l E h rlic h
in je c te d v a rio u s a n ilin e d y e s in to t h e v e in s o f a n im a ls a n d n o te d t h a t t h e dyes
le a k ed o u t o f th e b lo o d vessels in to m o s t tissu es, b u t n o t in to th e b ra in a n d sp in a l
c o rd . T h is w as n o t w h a t E h rlic h h a d e x p e c te d . S tru g g lin g to in te r p r e t h is re s u lts ,
E h rlic h c o n c lu d e d t h a t t h e d y e s m u s t h a v e le a k e d in to th e b r a in a n d s p in a l c o rd ,
ju s t as th e y e n te re d all o th e r o rg an s, b u t w ere in cap ab le o f s ta in in g n e u ro n s o r glial
cells. T his h y p o th e s is w as w ro n g . In 1913, E d w in G o ld m a n , a s tu d e n t o f E h r lic h ’s,
in je c te d th e sam e dyes E h rlic h h a d u s e d d ire c tly in to th e C S F an d n o te d th a t th e
b ra in an d sp in a l co rd w ere s ta in e d ju s t fine. T h erefo re, G o ld m a n c o n c lu d e d , n e u ra l
tis s u e m u st b e se p a ra te d fro m th e b lo o d b y so m e s o rt o f b a rrie r th a t k eep s o u t a n ilin e

X X III
 Thematic Boxes
• A range of thematic boxes is used throughout the book to
explore intriguing tangents and real-world applications.
RESEARCH METHODS ^ J g
Box 5.3 FunctionalMagnetic Resonance Imaging
Functional m a g n e tic resonance im a g in g (fMRQ has b e co m e the
m o s t w id e s p re a d m e th o d o f im a g in g a c tiv ity in h u m a n brains.
CXjring a ty p ic a l fM RI scan, p a tie n ts are asked to place th e ir head
in s id e th e o p e n core o f a la rg e a n d n o is y m a c h in e (F igure bS.3),
to h o ld v e ry s till, a n d to p e rfo rm so m e re la tiv e ly s im p le tasks
w h ile th e m a ch in e scans th e ir b ra in . S cientists la te r process
th e se data in to im ages th a t s h o w w h ic h re g io n s o f th e brain
w e re m o re (o r less) a c tiv e d u rin g th e ta s k th a n d u rin g a c o m ­
p a ra b le re s t p e rio d (or s o m e a lte rn a tiv e task). These im ages
m a y seem easy t o u n d e rs ta n d , b u t th e fM RI te c h n iq u e is c o m ­
p le x, a n d its d a ta m u s t b e in te rp re te d w ith care.
To p ro d u c e an MRI b ra in scan, a person's h ead is pla ce d
in s id e a m a g n e tic fie ld th a t (a t 1 .5 -7 Tesla) is m o re th a n 100,000
tim e s as s tro n g as th e e a rth ’s m a g n e tic fie ld . In such a s tro n g
h e ld , th e p ro to n s o f h y d ro g e n a to m s in th e b o d y te n d to a lign
th e ir spin axes w ith th e im p o se d m a g n e tic held. Researchers then
a d d an o rth o g o n a l, o s c illa tin g e le c tro m a g n e tic p u lse th a t can.
Figure b5.3 Functional MRI. Shown in (A) is a clinical MRI scanner.
Panel (B) depicts BOLD-fMRI signals -colored} superimposed on struc­
tural MRI images (grayscale} fo r tw o horizontal sections through the
'averaged b ra in ' in the study. The color scale on the right shows the
percent change in BOLD signal strength w hen people perform ed a
sim ple task -detecting a letter hidden in visual noise} compared to
staring at a screen th a t merely says 're s t/ As you can see. some brain
regions became more active during the task; others became less active
!A courtesy o f Kasuga Huang; B fro m Stark and Squire. 2001]
Research Methods: Presents classic and modern
experiments and techniques that have profoundly
impacted current understanding.
NEUROLOGICAL DISORDERS ^§ g |
Box5.2 Immune Responses in Alzheimer's Disease
Alzheimer's disease is the most common form of dementia
affecting the elderly. Roughly 3 out of every 1,000 people aged
65-69 have Alzheimer's disease, and this rate rises to -56/1,000
in people over 90 years old. There are many aspects to
Alzheimer's disease (see Chapter 16), but an especially intrigu­
ing one is its relationship to the immune system.
A key step in the development of Alzheimer's disease is
the accumulation of amyloid (J-protein (AP). This molecule is
normally harmless, but Alzheimer's patients produce large
amounts of an Ap variant called AP42 that tends to form toxic
aggregates. The largest of these aggregates are visible as
amyloid plaques within the brain (Figure b5.2). In addition,
Alzheimer's patients accumulate within their neurons incor­
rectly folded forms of a protein called tau. These tau aggregates
are called neurofibrillary tangles (Figure b5.2). Although some
Alzheimer's patients exhibit no plaques or tangles in their
brain at autopsy, most neuroscientists believe that plaques
or tangles, or both, are closely linked to the causes of Alzheimer's
disease. Therefore, researchers have long been keen to prevent
or reverse plaque and tangle formation, hoping that this
might arrest or reverse the cognitive decline associated with
Alzheimer's disease.
A major step toward this goal was taken in 1999 when
researchers reported that an AP42 vaccine prevents plaque
0 T a n g es - c o n tr o l © T a n g le s - v a c c in e
**%
F ig u re b5.2 V a c c in e s t o c o m b a t A lz h e im e r's d is e a s e . S h a w n in (A) is th e n e o c o rte x o f a trans­
g e n ic m o u s e w ith n u m e ro u s a m y lo id p la q u e s (b ro w n ). W h e n such m ic e w e re s tim u la te d to p ro d u c e
a n tib o d ie s a g a in s t A 042, th e n u m b e r o f p la q u e s was re d u c e d (B). In a n o th e r s tu d y . A p 4 2 a n tib o d ie s
w e re in je c te d d ire c tly in to th e h ip p o c a m p u s o f tra n s g e n ic m ice th a t d e v e lo p n e u ro fib rilla ry ta n g le s
a s w e ll a s p la q u e s. Im a g e (C) sh o w s a se ctio n th r o u g h th e h ip p o c a m p u s o f an u n tre a te d c o n tro l
m ouse, s ta in e d f o r ta n g le s (b ro w n ). T he p h o to g ra p h in (D ) show s a c o m p a ra b le s e c tio n fr o m a
m ouse th a t re ce ive d th e A p 4 2 a n tib o d ie s . You can see th a t i t co n ta in s fe w e r ta n g le s a t th e in je c tio n
s ite (in th e c e n te r o f th e im age). (A a n d 8 fro m S chenk e t a lv 1999; C a n d D fro m O d d o e t al. 2004]
• Neurological Disorders: Motivates students through the
presentation of fascinating examples of what happens
when the nervous system doesn't function normally.
X X IV
a t th e a p p ro p ria te frequency, b u m p th e s p in n in g p ro to n s o u t
o f a lig n m e n t. W h e n th e pulse is tu rn e d o ff, th e p ro to n s m ove
back in to a lig n m e n t a n d th e re b y g e n e ra te a sig n a l th a t the
scanner can d e te c t. Im p o rta n tly, th e fre q u e n cy o f th e p u lse th a t
is m o s t e ffe c tiv e a t p e rtu rb in g th e s p in n in g p ro to n s (th e reso­
n a n t fre q u e n c y ) d e p e n d s o n th e p ro to n ’s c h e m ica l c o n te x t (its
a to m ic neighbors). This p h e n o m e n o n has lo n g fo rm e d th e basis
o f n u c le a r m a g n e tic re so n a n ce (NMR) s p e c tro s c o p y , w h ic h
c h e m ists use to d e te rm in e th e m o le c u la r c o m p o s itio n o f h o ­
m o g e n e o u s m a te ria ls . In th e 1970s, NMR s p e c tro s c o p y was
e x te n d e d to le t scie n tists visualize th e c h e m ica l c o m p o s itio n
o f n o n h o m o g e n e o u s m a te ria ls , in c lu d in g b ra in s . A s th e te c h ­
n iq u e evolved, th e sp a tia l re s o lu tio n o f these im ages increased
to th e p o in t w h e re i t is n o w sm aller th a n a grain o f rice. S cien­
tis ts a ls o le a rn e d t o fo c u s th e ir im a g e s o n d ive rse c h e m ica l
signatures. A lo n g th e w ay, th e y c h a n g e d th e n a m e o f th e te c h ­
n iq u e fro m N M R to MRI. T h is h e lp e d a lle via te p a tie n t concerns
a b o u t b e in g su b je cte d to som e so rt o f ’’n u c le a r' treatm ent
w h e n , in re a lity, n o io n iz in g ra d ia tio n is involved.
Early MRI scans w e re stru ctu ra l ra th e r than functional.
T he early images focused o n p ro to n s in gray m a tte r versus
w h ite m a tte r, ven tricle s, o r b o n e ; b u t Seiji O gaw a a n d his
co lla b o ra to rs in th e la te 19&0s tu rn e d th e ir a tte n tio n to
th e p ro to n s in o x y g e n a te d versus d e o x y g e n a te d h e m o ­
g lo b in . d e v e lo p in g w h a t is n o w c a lle d b lo o d oxygen
level dependent fM RI (B O D -fM R I). O gaw a reasoned th a t
a c tiv e n e u ro n s m u s t p u ll som e o xyg e n o u t o f th e local
b lo o d vessels a n d th a t th is decre a se in h e m o g lo b in
o x y g e n a tio n s h o u ld b e d e te c ta b le as a decrease in the
MRI signal. O gaw a tu rn e d o u t to b e co rre ct, b u t surpris­
ingly, th e in itia l d ip in th e MRI signal is fo llo w e d a fe w
seconds la te r b y a large increase sig n a l s tre n g th . Because
th e la te increase is larger a n d m o re re lia b le th a n th e in i­
tia l d ip , i t is th e fo c u s in m o s t fM RI a nalyses. W h y th e
delayed increase? M o s t lik e ly i t o ccu rs because neu ro n a l
a c tiv ity s tim u la te s a s tro c y te s , w h ic h th e n cause lo c a l
b lo o d vessels to d ila te . T h is increases lo c a l b lo o d flo w
a n d flushes th e d e o x y g e n a te d h e m o g lo b in o u t o f th e
local c a p illa ry beds.
A n im p o rta n t caveat to in te rp re tin g fM RI re su lts is
t h a t th e y u s u a lly d e p ic t d iffe re n c e s in a c t iv it y ra th e r
th a n a b s o lu te le v e ls .T h e y d o n 't s h o w y o u w h ic h regions
w e re a c tiv e d u rin g a ta s k b u t o n ly w h ic h regions w ere
m o re a ctive (or less a ctive ) d u rin g th is task th a n d u rin g
som e o th e r c o n tr o l task o r re s tin g p e rio d (F igure b5.3 B).
T h is fo cu s o n d iffe re n ce s g re a tly s im p lifie s th e analysis
(because ab so lute signal levels d e p e n d o n m a n y factors
th a t a re d iffic u lt to c o n tro l), b u t i t e a s ily m isleads th e
u n in itia te d , w h o assum e th a t th e " h o t s p o ts ' in a n fM RI
scan s h o w a ll th e b ra in areas th a t w e re a c tiv e d u rin g a
ta sk. T h is is n o t tru e ; th e y o n ly in d ic a te th o s e areas th a t
d iffe r e d in a c tiv ity b e tw e e n th e ta s k a n d its c o n tro l.
Keep th is in m in d w h e n y o u c o m e across fM RI re su lts in
u p c o m in g chapters.
formation in a transgenic mouse model of Alzheimer’s disease
(Figure b5.2 B). The mice in the original study were injected
with A(J42 and then created their own antibodies. In later
studies, the mice were injected with premanufactured AfJ42
antibodies. Either way, the antibodies consistently prevented
amyloid aggregation and, in some cases, removed the aggre­
gates that had already formed. In one study, A042 antibody
injections even cleared incipient tangles (Figure b5.2 D).These
studies have raised hopes that similar vaccines might prevent
or reverse Alzheimer's disease in humans as well. Indeed,
several Alzheimer's patients injected with a synthetic form of
AP42 as part of a clinical trial had few plaques in their brains
at autopsy. Unfortunately, the treatment did not arrest the
cognitive decline, as the patients still progressed to severe,
final-stage Alzheimer's disease. Furthermore, the trial was
aborted because some of the trial participants developed
severe meningitis.This is frustrating and a bit of a challenge to
the hypothesis that amyloid accumulations trigger Alzheimer's
disease. However, the vaccines may have been given too late
in the development of Alzheimer's disease, when the trigger
for cognitive decline had already been pulled.
Another potential therapy for Alzheimer's disease is to
manipulate the brain's innate immune response. The brains of
Alzheimer's patients tend to be chronically inflamed, showing
increased expression of cytokines
and chemokines, as well as
P la q u e s - v a c c in e
microglia around the edges of
amyloid plaques. These findings
suggest that the brain's own
immune response may be re­
sponsible for some of the neu
ron death and synapse loss in
Alzheimer's disease. Alternatively,
the brain's immune response may
2 0 0 pm
be a defensive measure, de­
signed to prevent the further
growth of amyloid plaques. To
distinguish between these pos­
sibilities, one would want to
know whether depressing the
brain's immune response with
drugs reduces the symptoms of
Alzheimer's disease or worsens
them. Unfortunately, the data on
this point are conflicting. Over­
2 5 0 pm
all, it seems likely that the brain's
immune response to Alzheimer's
disease is both good and bad.
It may, for example, reduce the
spread of plaques but kill some
neurons as collateral damage.
Future research will have to tease
the various effects apart.
EVOLUTION IN ACTION_______
Box 6.3 Electroreception and O ther Alien Senses
Because w e can perceive th e w orld only through our ow n lim­
ited set o f sensors, it is difficult to appreciate th a t other ani­
mals m ay w ell perceive th e w orld quite differently.The average
person is surprised to learn, for exam ple, th a t m any insects
and birds can see intricate (and to us q u ite invisible) patterns
o f U V lig h t reflec te d fro m flow ers. Similarly, fe w p e o p le are
aw are o f th e enorm ous racket m a d e by echolocating bats
during their nightly flights because o u r auditory sensors are
not tu n ed to ultrasonic frequencies. Still, w e can at least imag­
in e w h at it w o u ld b e like to see U V light o r to hear ultrasound.
These sensory abilities are just extensions o f senses th a t we
already have. However, som e animals possess senses that are
truly alien to us. It is now clear, for exam ple, th a t sea turtles can
sense th e earth's m agnetic field and use it to guide th em on
their m igrations. H om ing pigeons can likewise orient by the
terrestrial m agnetic field, although they prefer to use the sun as
their compass. A lthough th e behavioral evidence fo r magneto­
reception in these species is clear, th e mechanisms underlying
th e transduction o f m agnetic fields rem ain som ew hat mysteri­
ous. Crystals of m agnetite likely play som e role, but no one is
sure how th e physical or m agnetic orientation o f these crystals
is sensed by neurons.
An equally strange sense is electroreception. W e cannot
d e te c t w e a k electric fields, b u t m any anim als can, including
lam preys, m ost cartilaginous fishes, a n d a fe w b o n y fishes
(Figure b6.3). M any o f these species can d e te c t fields on the
order o f a few pV/cm, and som e are sensitive dow n to ~10 nV/cm.
In case you are not used to thinking in nanoVolts, this deg ree
o f sensitivity should, a t least in theory, allow a shark to sense
a difference o f 1 V o lt b etw een tw o electrodes th a t are sub­
m e rg e d in saltw ater a n d sep arated b y 10,000 km. A lthough
e le c tro recep tio n is an e v o lu t io n a r y an cien t tra it, it disap­
peared in th e verteb rate lineages th a t le ft th e w a te r and in­
vad ed land. Aquatic am phibians can sense electric fields, but
Figure b6.3 A fish that can both generate and sense weak electric
fields. The illustrated specimen of Campylomormyrus rhynchophorus
belongs to the mormyrid (elephant nose) family of bony fishes. Modified
muscle in its tail can generate weak electric fields, and electroreceptors
on its head and snout can sense those fields as well as signals coming
from moving prey. This specimen is approximately 14 cm long and was
captured in an African river. [From Leal and Losos, 2010]
Evolution in Action: Harnesses the explanatory power of
the theme of evolution, allowing students to move beyond
memorization and develop deep insight and intuition.
THERAPIES
Box25 M ood Molecules
Among the most successful therapeutic molecules are drugs
that improve or stabilize a person's mood. Most of these mood­
boosting molecules target a distinct population of neurons
that use serotonin (5-H T) as their neurotransmitter. The cell
bodies of these neurons are located in a few hindbrain nuclei
called the raphe nuclei, but the axons of these neurons termi­
nate widely throughout th e brain.
Many antidepressant drugs, notably Prozac, selectively in­
hibit the uptake of released serotonin back into presynaptic
terminals. The effect of this reuptake inhibition is that released
serotonin molecules remain in th e synaptic cleft for a longer
period o f tim e and therefore exert a greater effect on their
postsynaptic targets. The fact th a t antidepressants generally
boost serotonin signaling suggests th a t clinical depression
results from insufficient serotonin levels in the brain. It cannot
be this simple, however, because reuptake inhibitors typically
boost signaling within minutes or hours, whereas th e positive
effects on m ood take weeks to manifest. To explain this dis­
crepancy, it has been hypothesized th a t serotonin reuptake
inhibitors cause gradual, long-term changes in the sensitivity
and/or abundance of serotonin receptors. This hypothesis is
controversial, but it is consistent w ith the general principle
that chronic changes in transm itter abundance cause com­
pensatory changes in the corresponding receptors.
O ne problem w ith antidepressant medications is that they
tend to have side effects, including daytim e sleepiness, night­
tim e restlessness, nausea, diarrhea, and sexual dysfunction.
This is not particularly surprising because m any o f these drugs
also inhibit the reuptake of norepinephrine, which regulates
Figure b2.3 MDMA can destroy serotonergic axons. Serotonergic axons were stained with
an antibody so that they appear as white lines on a dark background. Panel (A) shows a section
through the frontal cortex of a control monkey. Panel (B) illustrates a similar section from a
monkey 2 weeks after it received subcutaneous injections of MDMA (5 mg/kg twice daily for
4 days). A depletion of the serotonergic axons is evident. Panel (Q depicts an equivalent section
from a monkey 7 years after receiving the MDMA injections. Despite some recovery, a deficit
persists. (From Hatzidimitriou et al, 1999]
Therapies: Highlights cutting-edge clinical applications
derived from basic scientific research of the nervous system.
reptiles, birds, and most m am m als cannot. This makes good
sense, as electric fields require a conductive m edium , such as
water, to propagate. Remarkably, m o n o trem e m am m als have
re-evo lved e le c tro re c e p tio n . T h e duck-billed platypus, for
o ne, has - 4 0 ,0 0 0 electrosensors o n its bill and can, w ith som e
tra in in g , use th e m to fin d a 1.5V m in iatu re b a tte ry hidden
under a rock. T h e spiny anteater (or echidna), a close relative of
th e platypus, also has num erous electrosensors on its snout. It
probably senses th e w eak electric fields produced by tin y prey
tunneling through m oist earth.
Indeed, th e most widespread function of electroreceptors
is th e detectio n o f electric fields generated by potential prey.
As Ad Kalmijn showed in 1971, hungry sharks atta ck a flatfish
buried u n d e r sand even if th a t flatfish is encased in agar,
w hich blocks the spread o f odors but is electrically transparent.
Kalmijn fu rth e r show ed th a t h u n g ry sharks have no interest
in buried flatfish covered w ith electrically opaque plastic, but
th a t th e y w ill atta ck w h en w e a k electrical current is passed
b etw een tw o buried stim ulating electrodes (stronger currents
te n d to repel sharks!). These studies suggest th a t sharks, rays,
and probably most electroreceptive animals use th e ir electro­
receptors to lo cate prey a t n ig h t, in m urky w ate r, or hidden
underground.
In addition, electroreceptors may be used for navigation.
Because som e inanim ate objects, especially m etallic ones, g en ­
erate w eak electric fields under water, electroreceptive animals
can find their w ay a t night or in m urky w ater by sensing the
"electric landscape* Some electroreceptive fishes have gone a
step further. They generate their ow n electric fields and then
d e te c t distortions in this field d u e to external objects. This sort
o f electrolocation is used by elephant nose fish (Figure b6.3)
and by m any o f th e knife fish th a t you can buy in pet stores.
Som e o f these anim als also com m unicate by means o f electric
signals.
H o w d o electrorecep tors work? T h e answ er dep ends
a b it on th e specific ty p e o f e lectro recep to r you are talk­
ing a b o u t. T h e m o st w idespread a n d sensitive ty p e of
e le c tro re c e p to r sits at th e b o tto m o f slender tubes inside
th e skin. Because th e tubes are o fte n flask shaped, these
receptors are called am pullary receptors (one ty p e of an­
cient Rom an flask was called an "am pulla*). A m pu llary
receptors are sim ilar to hair cells in th a t th e y have a few
m icrovillar "hairs" e x te n d in g fro m th e ir tops and form
ribbon synapses w ith n e rv e term inals. T h e v o lta g e across
th e rece p to r cell's basal m e m b ra n e (th e o n e facing inside
th e b o d y) changes in response to extern al electric fields,
w hich is th o u g h t to o p en o r close (depending on th e direc­
tio n o f th e vo ltag e change) v o ltag e-g ated calcium channels
in the receptor cell's m em brane. Changes in internal calcium
levels th e n a lte r th e ra te o f tra n s m itte r release, w hich
m odulates action potential firing in th e postsynaptic nerve
term inals.
arousal, and because serotonin itself has multiple functions.
O ne reason w hy there are so m any different antidepressants
on th e market is that each drug represents a different com­
promise b etw een benefits and side effects. Moreover, treat­
ing depression often involves a great deal of trial and error
because some compounds work well in one person but not in
another. A combination of several different drugs, at carefully
adjusted dosages, usually works best.
Given how difficult it is to treat a diseased brain, is it reason­
able to expect that we can alter the functions of a healthy brain
and cause no harm? Probably not, but many people try. In particu­
lar, some people boost their mood by taking illegal drugs. One of
these is MDMA (3,4-methylenedioxy-N-methamphetamine), also
known as ecstasy (or, more recently, Molly). This drug is popular
because it induces a strong sense of euphoria. Ecstasy does this
mainly by altering serotonin transporter molecules so that instead
of taking serotonin back up into the presynaptic terminal, they
release it into the synaptic deft. The result is a massive release of
serotonin followed by serotonin depletion. The serotonin release
feels good, but the depletion produces an ecstasy hangover
that can last for several days and is characterized by a lack of mo­
tivation, focus, and appetite. Thus, the temporary boost in mood
provided by ecstasy must be paid for later.
Research on rats and monkeys has shown th a t M DM A
can irreversibly dam age serotonergic axons in diverse brain
regions (Figure b2.3). In these experim ents, m ultiple doses
of M D M A w ere injected into the animals, w hich is not how
humans typically take M D M A . However, in squirrel monkeys
even a single oral dose o f M D M A reduces serotonin levels
for at least 1 w eek in m ultiple brain
areas. These data strongly suggest
th a t M D M A has serious and long-
lasting effects on brain function.
Indeed, studies w ith humans
have shown that heavy ecstasy users
have impaired verbal memory, dis­
play more impulsivity, and are more
likely to be depressed than control
subjects. These studies do not con­
trol for the fact that regular M DM A
users also tend to take other drugs,
such as amphetamines, that are al­
ready known to cause some brain
damage. However, it certainly seems
wise to find less risky, more creative
ways to boost your mood. Finally,
it is im portant to know that much
of th e so-called pure M DM A sold
"on th e street* (including Molly) is
hardly pure and sometimes not
M D M A at all. This lack of quality
control is thought to account for at
least some deaths associated with
the taking of MDMA-related drugs.
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