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 PROLOGUE
THE RATIONALIST PHILOSOPHERS
All I Know Is That I Know Nothing 1 What Does All This Philosophy Stuff Have to
The Benefits of Having an Immortal
Soul 4
CHAPTER 1
The Metazoans' Dilemma
CELL DIFFERENTIATION AND NEURAL INDUCTION
1.1 Metazoans Evolved the Ability to Produce
Cells with Very Different Functions 8 as a Simple Tube
1.2 Preformationism Offered an Easy but
Wrong Solution, While Epigenesis
Seemed Incomprehensible 10
1.3 The Rediscovery of Genes Set the Stage
for Understanding Development 12
1.4 Gene Expression Directs Cell
Differentiation 13
RESEARCHERS AT WORK
Do Differentiating Cells Dispose of
Unused Genes? 14
1.5 Scientists Domesticated a Simple Worm
to Address the Questions of Cell
Differentiation 1 8
1.6 Mitotic Lineage Guides Cell
Differentiation in Worms 19
BOX 1. 1 KERFUFFLES IN LANGUAGE: ''CELL
FATE'' AND ''COMMITMENT'' 22
1.7 Embryonic Development Begins
by Forming Three Di sti net Germ
Layers 24
1
Do with This Book? 5
7
1.8 The Vertebrate Nervous System Begins
26
1.9 Many Embryos, Including All
Vertebrates, Display ''Self-
Regulation'' 30
1.10 Self-Regulation Seems Incompatible
with Mitotic Lineage-Directed
Differentiation 32
1.11 Experimental Embryology Revealed
Inductive Processes Underlying Self-
Regulation 34
1.12 A Reg ion of the Vertebrate
Embryo Seems to ''Organize''
Development 36
RESEARCHERS AT WORK The Dorsal Lip
of the Blastopore Can Organize a New
Individual 36
1.13 Long Abandoned, the Organizer
Was Uncovered through Molecular
Biological Techniques 38
RESEARCHERS AT WORK A Gene Is
Discovered That Acts as an Organizer 38
VIII CONTENTS
1.14 What Organizes the Organizer? 42
CHAPTER 2
Coordinating Fates
DEVELOPMENT OF A BODY PATTERN
2.1 Darwin Noted That Vertebrate Embryos
Start Off Looking Alike 52
BOX 2. 1 A STEP TOO FAR 54
2.2 Mother Knows Best: Maternal Factors
Establish a Basic Polarity of the
Body 55
RESEARCHERS AT WORK Two Heads
Are Not Better Than One 58
BOX 2.2 MEET DROSOPHILA
MELANOGASTER, THE WELL-SEGMENTED
ORGANISM 59
2.3 A Cascade of Gene Regulatory Proteins
Organizes a Body Plan 60
2.4 Some Mutations in Drosophila Transform
Body Parts Whole 65
2.5 Hox Genes Are Crucial for Vertebrate
Development, Too 68
CHAPTER 3
Upward Mobility
NEUROGENESIS AND MIGRATION
3.1 The Same Gene May Play a Role
in Many Different Developmental
Events 88
3.2 The Developing Brain Generates
Neurons at a Tremendous Rate
3.3 Shortly after Division, Neural Cells
Diverge to Become Neurons or
Glia 92
RESEARCHERS AT WORK Labeling of
Dividing Cells Disputes the Idea That
Lineage Determines Fate 93
1.15 In Insects, Epidermal Cells Compete to
Become Neuroblasts 43
SUMMARY 49
51
2.6 Hox Genes Direct ''Segmentation'' in
the Mammalian Brain 69
BOX 2.3 KERFUFFLES IN LANGUAGE:
''SEGMENTATION'' 73
2.7 Hindbrain Rhombomere Fates Are
Directed by Homeobox Genes 75
2.8 Several Signals Designate the Caudal
End of the Body and Nervous
System 77
2.9 Continued Gradients in BMP Signaling
Establish the Dorsal-Ventral Axis in the
Nervous System 80
RESEARCHERS AT WORK What
Notochord Factor Induces the Floor
Plate and Motor Neurons? 82
2.10 Find Out Where You Are to
Coordinate Your Fate with That of
Your Neighbors 84
SUMMARY 86
87
3.4 The Cerebellum and Cerebral Cortex
Form in Layers 95
3.5 We Can Label Newly Synthesized
DNA to Determine the Birthdates of
89 Cells 97
3.6 Newborn Cells Shinny Up Glial
Poles 100
RESEARCHERS AT WORK The Cortex
Develops in an Inside-Out Manner 102
3.7 A Few Brain Regions Display Continuing
Neurogenesis throughout Life 105

BOX 3. 1 THE CONTROVERSY OF
NEUROGENESIS IN ADULTHOOD 106
3.8 Neural Crest Cells migrate to Positions
throughout the Body 109
3.9 Cell Adhesion Molecules Attract and
Repel Migrating Cells 112
CHAPTER 4
Seeking Identity
NEURAL DIFFERENTIATION
4.1 The Fruit Fly Retina Develops through
an Orderly Progression of Gene
Expression and Signaling 128
BOX 4.1 TRANSGENICS, KNOCKOUTS,
AND KNOCKINS 131
4.2 Several Factors Influence Whether a Cell
Will Become a Neuron or a Glia 132
4.3 The Molecular Differentiation of Motor
Neurons Is Orderly 135
4.4 Neural Crest Cells Are Affected by Their
Migration and Destination 137
RESEARCHERS AT WORK Neural
Crest Cells Adopt New Fates after
Transplantation 138
CHAPTER 5
Feeling One's Way
AXONAL PATHFINDING 151
5.1 Ramon y Cajal Described Growth Cones
and Discerned Their Significance 152
5.2 In Vitro Approaches Reveal Principles of
Axonal Growth and Adhesion 155
RESEARCHERS AT WORK Getting a
Grip: The Role of Adhesion in Axonal
Growth 156
5.3 Guidance Cues May Be Attractive
to One Type of Growth Cone and
Repulsive to Others 158
CONTENTS IX
3.10 Cerebellar Granule Cells Parachute
Down from Above 1 16
RESEARCHERS AT WORK Weaver
Neurons Fail to Grasp Glial Fibers 119
3.11 Cells Crucial for Smell and
Reproduction Migrate into the
Embryonic Brain 121
SUMMARY 124
127
4.5 The Neurotransmitter Phenotypes of
Autonomic Neurons Are Guided by
Their Targets 140
RESEARCHERS AT WORK Targets Can
Regulate the Neurotransmitter Phenotype
of Afferents 141
4.6 The Fate of a Cortical Neuron Is
Influenced Both Before and After
Migration 142
RESEARCHERS AT WORK Cortical Neuron
Fate Is Specified after the S Phase 143
4.7 Later Events in Development Are More
Evolutionarily Labile 145
SUMMARY 150
5.4 Families of Receptors Offer a Multitude
of Guidance Cues 160
5.5 Pioneer Neurons and Guidepost
Cells Establish Pathways for Later
Axons 164
5.6 Many Axonal Growth Cones Have to
Deal with Crossing the Midline 167
RESEARCHERS AT WORK What Makes
the Floor Plate so Attractive? 169
X CONTENTS
5.7 Motor Neuronal Axons Must Find the
Correct Target Muscles 172
RESEARCHERS AT WORK Can You
Navigate Your Way Home? 172
5.8 The Axons of Retinal Ganglion Cells
Must Reach the Mid brain 174
CHAPTER 6
Making Connections
SYNAPSE FORMATION AND MATURATION
6.1 Calcium Regulators and Environmental
Sensors Evolved to Mediate Synaptic
Signaling 1 86
6.2 We Can Divide Synapse Structure and
Development into Three Parts 1 89
6.3 A Synapse Begins with Adhesion
RESEARCHERS AT WORK Dendritic
Spines Compete for Survival 191
6.4 Fragile X Syndrome Suggests There Can
Be Too Much of a Good Thing
6.5 Pre- and Postsynaptic Partners Tightly
Anchor One Another as a Synapse
Develops 1 9 5
RESEARCHERS AT WORK Presynaptic
and Postsynaptic Receptors Trigger
Synaptic Development 196
6.6 Neuromuscular Junctions Illustrate That
Synapse Formation Is a Da nee for Two
(or More) 200
6.7 Motor Neuronal Agrin Promotes
the Aggregation of Acetylcholine
Receptors 203
CHAPTER 7
Accepting Mortality
APOPTOSIS 221
7.1 The Death of Many Cells Is a Normal
Process in Development 222
RESEARCHERS AT WORK I'd Rather Walk
over Here 176
5.9 The Corpus Callosum Is Directed across
the Midline by a Glial Bridge 178
RESEARCHERS AT WORK Glia Can
Help Axons Cross a Border 180
SUMMARY 182
185
6.8 Neuregulins Boost Local AChR
Expression in Muscle and Maintain
Terminal Schwann Cells 205
6.9 Once Formed, the NMJ Leaves
an Imprint in the Extracellular
Matrix 207
190
RESEARCHERS AT WORK
Neuromuscular Junctions Leave a
Residue in the Basal Lamina 207
6.10 Ion Channels Change Subunits, and
193
Therefore Characteristics, during
Development 209
6.11 Embryonic Synapses Are Sluggish and
Slow, Then Become Progressively
Faster with Development 21 2
6.12 Myelination Extends into Adulthood to
Hasten Neuronal Communication 214
6.13 Myelinating Glia May Prevent
Regeneration in the Central Nervous
System 216
SUMMARY 219
7.2 The Extent of Death among Developing
Motor Neurons Is Regulated by the Size
of the Target 224

RESEARCHERS AT WORK Adding to the
Periphery Prevents Apoptosis of Motor
Neurons 224
7.3 Nerve Growth Factor (NGF) Is
Discovered to Regulate Apoptosis in
Sensory Neurons 229
RESEARCHERS AT WORK Screening for
Nerve Growth Factor 230
BOX 7.1 THE CONTROVERSY OVER THE
NOBEL PRIZE FOR NGF 231
7.4 NGF Has Both Tropic and Trophic
Effects on Selective Neuronal
Populations 233
7.5 The Search for Relatives of NGF Reveals
a Family of Neurotrophic Factors and
Their Receptors 235
7.6 Studies in C. e/egans Provide Crucial
Information a bout the Process of
Apoptosis 239
BOX 7.2 KERFUFFLES IN LANGUAGE:
PROGRAMMED CELL DEATH 240
RESEARCHERS AT WORK It Was
Suicide, Not Murder 240
7.7 Apoptosis Involves Active Self-
Destruction through a Cascade of
''Death Genes'' 24 1
INTERLUDE
THE EMPIRICISTS STRIKE BACK
The Tabula Rasa and the Importance of
Experience through the Senses 267
CHAPTER 8
Synaptic Plasticity
ACTIVITY-GUIDED NEURAL DEVELOPMENT
8. 1 Motor Neuronal Death Is Gated by
Neuronal Activity 274
8.2 Developing Muscle Fibers Start Off with
Polyneuronal Innervation 276
8.3 Autonomic Neurons Refine Their Inputs
and Outputs 281
CONTENTS XI
7.8 Do Motor Neurons Die in ALS for Lack
of Neurotrophic Factor(s)? 245
7.9 Hormones Direct Sexual Differentiation
of the Vertebrate Body and
Behavior 247
RESEARCHERS AT WORK Early
Exposure to Androgens Organizes the
Male Brain 250
7.10 The Brain Is Also Sexually
Dimorphic 253
7.11 Hormones Can Regulate Apoptosis
to Masculinize the Vertebrate
Brain 255
RESEARCHERS AT WORK Sometimes
the Tail Wags the Dog 256
7.12 Sexual Differentiation in Flies Is a Cell-
Autonomous Process 258
RESEARCHERS AT WORK Fruitless
Mutants Pursue Unrequited Love 260
7. 13 The Controversy over Sexua I
Orientation in Flies, Rats, and
People 263
SUMMARY 264
267
What Does All This Philosophy Stuff Have To
Do with This Book? 271
273
8.4 Donald Hebb Speculated about Neural
Plasticity 283
8.5 Long-Term Potentiation (LTP) Confirms the
Existence of Hebbian Synapses 284
RESEARCHERS AT WORK Cells That Fire
Together Wire Together 286
XII CONTENTS
8.6 A Class of Glutamate Receptors Enforces
Hebbian Rules 287
BOX 8. 1 DOES HIPPOCAMPAL LTP MEDIATE
LEARNING? 290
8.7 The Brain Must Integrate Input from the
Two Eyes 292
CHAPTER 9
Fine-Tuning Sensory Systems
EXPERIENCE-GUIDED NEURAL DEVELOPMENT
9.1 Humans Can Adapt to Seeing the World
in a New Way 306
9.2 Retinal Ganglion Cells in Adult
Amphibians and Fish Can Reestablish
Connections to the Tectum 308
9.3 Various Permutations of Retinotectal
Regeneration Refute a Strict Version of
Chemoaffinity 310
9.4 Visual Experience Fine-Tunes Frog
Reti notecta I Connections 31 3
RESEARCHERS AT WORK Three-Eyed
Frogs Show Us the Way 314
9.5 Mammals Require Visual Experience
during a Sensitive Period to Develop
Functional Vision 317
CHAPTER 10
Maximizing Fitness
SOCIALLY GUIDED NEURAL DEVELOPMENT
10.1 The Terms Instinct and Innate Are So
Vague That They Are Worthless 335
10.2 Species with Parental Behavior Develop
the Most Complex Brains and
Behavior 337
10.3 Maternal Behavior Can Regulate the
Stress Response of Offspring 339
BOX 1 O. 1 KERFUFFLES IN LANGUAGE:
EPIGENETIC 341
8.8 Even Spontaneous, Apparently Random
Activity Can Provide Order 296
RESEARCHERS AT WORK Spontaneous
Waves of Retinal Activity Form Ocular
Dominance Bands in the LGN 297
8.9 The Gray Matter of Human Cortex Thins
as We Mature 299
SUMMARY 304
305
9.6 Physiological Recordings Reveal How
Visual Deprivation Impairs Sight 319
RESEARCHERS AT WORK Strabismus in
Kittens Drastically Alters Visual System
Connections 321
9.7 Owls Can Use Visual Experience to Fine-
Tune Their Auditory Maps 324
9.8 Olfactory Receptor Maps Are Also
Sculpted by Experience 325
9. 9 Tactile Experience Gu ides the
Formation of Topographic Maps in
Somatosensory Cortex 328
SUMMARY 332
333
10.4 Many Species Look to Their Parents to
Recognize Mating Partners 344
10.5 Observational Learning Can Transmit
Behaviors across Generations 347
10.6 Birdsong Is a Learned Behavior Where
Young Males Model Their Father's
Song 348
RESEARCHERS AT WORK Sparrows Are
Predisposed to Learn Species-Specific
Song Elements 350
 CONTENTS XIII

10.7 Humans Are Predisposed to Learn 10.10 Intelligence Tests Demonstrate the
Language without Any Formal Pervasive Effects of Culture 364
Training 352
10.11 The Controversial Issue of Racial
RESEARCHERS AT WORK The Differences in Average IQ
Habituation Response Allows Us to Read
Performance 367
Babies' Minds 354
RESEARCHERS AT WORK Does Race
10.8 Primates Require Love to Develop Affect the IQ of German Offspring of
Properly 357 American G Is? 370
10.9 Postnatal Social Stimulation Continues SUMMARY 371
to Affect Brain Development 359
RESEARCHERS AT WORK Social
Stimulation Alters Neuregulin Signaling
to Promote Myelination 362

EPILOGUE
IMMANUEL KANT AND THE CRITIQUE OF
PURE REASON 373
The a Priori Embodiment of Space What Does All This Philosophy Stuff Have To
and Time 374 Do with This Book? 377

APPENDIX A-1
GLOSSARY G-1
REFERENCES R-1
AUTHOR INDEX Al-1
SUBJECT INDEX Sl-1
The growing number of undergraduate neuroscience
majors in colleges and universities has prompted Instruc-
tors to create a curriculum that covers the breadth of this
vibrant science. What neuroscience courses should be
offered after the introductory survey course? An argu-
ment could be made that developmental neuroscience is
the most active and dynamic subfield of the discipline
simply because at the annual meeting of the Society
for Neuroscience, there are more abstracts submitted
under ''Development'' than any other theme. Perhaps
an even stronger argument for the importance of de-
velopmental neuroscience is its scope: to understand
how a single microscopic cell, a human zygote, divides
and grows to form the most complicated machine in
the universe, the brain.
At Michigan State University we needed to create a
truly comprehensive undergraduate course in Devel-
opmental Neuroscience for our neuroscience majors.
Having taught the topic to graduate students, both
at MSU and at UC Berkeley, for over 20 years, I was
drawn to the challenge of creating a new undergraduate
course. When team-teaching the course at Berkeley, we
used Principles of Neural Development, an outstanding
textbook by Dale Purves and Jeff Lichtman, published
in 1985. Sadly, this wonderful book was never revised.
The other neural development textbooks published
in the subsequent 30 years seem more appropriate for
graduate students (or professors!), so I decided to write
a developmental neuroscience text deliberately aimed
at undergraduates.
Like virtually all books on developmental neurosci-
ence, the topics are presented in roughly the chronologi-
cal order in which they appear in brain development.
But beyond that I wanted to offer several perspectives
that are, as far as I know, unique to this book, reflecting
overviews that I've found to be helpful for students.
These additional perspectives offer a means of organiz-
ing the material into a narrative that makes sense, and
should help readers learn and remember the material
by showing them the really big picture.
An Evolutionary Perspective
The book emphasizes four watershed events, each re-
quired to enable those that came after, that led to the
evolution of the human brain:
1. The departure from a mosaic control of cell differen-
tiation to relying upon cell-cell interactions to direct cell
differentiation. This shift in developmental strategy
led to the evolution of extensive modes of cell-cell
communication, some relying on direct contact be-
tween cell membranes and others relying on diffus-
ible signals to guide development. These interactions
between cells not only establish an overall body plan
(Chapters 1-2), but also direct cell division and mi-
gration (Chapter 3), the differentiation of neurons
and glia (Chapter 4), the path of axonal growth cones
(Chapter 5), the initiation and maturation of synapses
(Chapter 6), and the decision about which cells will
be discarded by apoptosis (Chapter 7). These topics
make up the bulk of the literature in developmental
neuroscience and of the book.
2. The elaboration of cell-cell communication eventually
led to mechanisms by which the electrical activity of
neurons affects other cells, varying the strength or
number of synapses between them, or dismantling
synapses altogether (Chapter 8). By itself, this activity-
guided synaptic plasticity might have been simply
one more way for developing cells to affect one an-
other, each relying on information in the genome and
spontaneous activity to guide their differentiation.
But this mechanism also set the stage for another
rich influence on the growing brain.
3. The development of activity-dependent synaptic
plasticity enabled experience-dependent guidance of
development as sensory information began to control
synaptic fate. Among other things, this mechanism
permitted organisms to learn about their environ-
ment and to remember what they'd learned, but it
also served to fine-tune developing sensory systems,
optimizing them to detect important events in the
XVI PREFACE
physical world (Chapter 9). Thus information from
outside the brain, and outside the genome, began
shaping development.
4. Experience-dependent neural development in turn
enabled an enormous benefit for those species, pri-
marily birds and mammals, that evolved an extended
period of parental care and juvenile interactions, so
that social experience began shaping brain develop-
ment. Obviously, such socially guided experience is
crucial for human intelligence, language, and culture,
but social guidance of brain development is crucial
for maximizing fitness in many other species, too
(Chapter 10).
This progressive expansion of the sphere of influence
on the developing brain explains how it's possible to
get so much information into a brain using only about
10,000 different genes. The genes alone don't have nearly
enough information to specify the wiring of a well-
functioning brain, so instead they unfold a program that
pulls in information from the current environment and
even, through inter-generational social interactions, past
events. This progression of topics offers an organizing
narrative that I think anyone can understand and use
as they study neural development. It helps readers to
see how all the detailed mechanisms lead to the same
goal of a well-formed brain, which is essential for an
organism to survive and reproduce.
A Philosophical Perspective
In addition to the evolutionary perspective above, I've
included a brief introduction to philosophy as it relates to
the study of brain development. The quest of neuroscien-
tists to understand how the zygote divides and grows to
form the brain mirrors a much older quest of philosophers.
Over two thousand years ago, Plato wrestled with the
question of how a newborn can possibly come to learn
anything if it starts life knowing nothing, and other phi-
losophers fervently discussed this issue for the subsequent
millennia. Although they didn't know it, philosophers
like Plato, Descartes, Locke, Hume, and Kant, who were
wrestling with epistemology, the study of knowledge and
how we gain it, were in fact also asking how an effective
brain can possibly develop before and after birth. They
were accidental developmental neuroscientists who
knew nothing about neurons, axons, synapses, and the
like. Conversely, from the late nineteenth century to to-
day, scientists studying the developing nervous system
discovered, in broad strokes, answers to the questions
that the philosophers asked. And just as the philosophers
didn't know they were asking questions about the ner-
vous system, the developmental neuroscientists, for the
most part, didn't seem to realize they were answering
questions about epistemology.
To illustrate how these two intellectual histories par-
allel one another, I relate the history of the philosophical
debate in three brief asides: a Prologue, an Interlude
(after Chapter 7), and an Epilogue. The developmental
neuroscience chapters sandwiched in between illustrate
how the philosophers' conclusions were confirmed by
scientists' findings. The chapters sometimes refer to
the philosophical history, but students need not know
that history to understand the neuroscience. Instructors
who find the parallels uninteresting or distracting can
simply ignore the philosophical installments.
These two perspectives are also complementary the
philosophers used logic to foreshadow the mechanisms
that had to arise by natural selection to produce the hu-
man mind. As you might have gathered by now, these
different perspectives are also meant as a respite from
what can otherwise appear to be a textbook crammed
with facts. While I've tried to be very, very selective
about which studies to present, surveying only a few
of the most important findings and principles of neural
development, there are still nearly a thousand citations.
That's a lot of detail! My hope is that by showing how
these detailed mechanisms of cell signaling, axonal
guidance, and synaptic pruning are part of a larger,
coherent story, readers will retain the narrative thread,
seeing how the details fit into a larger whole.
Making the Material Accessible
I included several other pedagogical features to make
the material accessible to a wide range of readers. Each
chapter begins with a vignette about a human condi-
tion relevant to that topic, which the ensuing material
will shed light upon. To further pique readers' interest,
I consider several rather applied topics not typically
covered in neural development books, such as human
sexual orientation, kerfuffles over terminology ('' com-
mitment," ''innate," ''epigenetic''), and the controversy
over racial differences in average IQ. Each chapter has
several Researchers at Work, a feature in which I slow
down the pace, deliberately breaking down a classic
study to describe the overarching question, the specific
hypothesis, the test(s) devised, the results obtained, and
the conclusion(s) drawn. I hope this feature helps read-
ers not only understand the experimental process, but
also appreciate the underlying logic of science. Most
chapters also include one or more Boxes, special top-
ics of interest, including episodes in the history of this
field. The How's It Going? feature appears at the end
of each section and offers a few review questions for
readers to check their comprehension of the material. If
you really were engaged in the reading up to that point,
you should be able to answer the questions readily. If
you're not sure what the answers are, then you may
do well to go back and review the preceding material.
Another reader-friendly feature is the boldfacing of
Keywords and a Marginal Glossary (in addition to a
glossary and index in the back of the book). Each chap-

ter ends with a Summary to help readers self-review.
Finally, I've tried to establish a conversational tone
throughout, with an active voice, including specula-
tive consideration of various hypotheses (''thinking
out loud''), intended to engage the reader. I want to be
clear to accurately convey what I mean but I feel no
need to use long, impressive words when short, widely
understood words will do.
I hope these efforts will help you to enjoy reading
the pages that follow and to understand this fascinating
story, which is far from complete. Maybe reading this
book will encourage you to become a neuroscientist and
make your own contribution to this ultimate human
endeavor, begun thousands of years ago, to understand
the origins of our brain.
ACKNOWLEDGMENTS
A lot of people worked long hours to make this book
possible. Sinauer Associates Editor Syd Carroll was
immensely supportive and encouraging, especially
when I needed it most. Production Editor Kathaleen
Emerson still amazes me with her ability to keep track
of all the figures, boxes, citations, and revisions. Copy
Editor Lou Doucette's sharp eye caught many problems
that went right over my head (she even tried her best
to help me understand the conventions about gene
names). Photo researcher David Mcintyre worked his
PREFACE XVII
usual magic, finding photos and figures and keeping
track of all those permissions, with the assistance of
Michele Bekta. Joanne Delphia and Chris Small have
again assembled a beautiful visage for the book that
brings me such pleasure, and Elizabeth Morales did
a fabulous job drawing the figures. MSU students
Eloise Faust, Eliza Judge, and Alla Kedzierski read a
late draft of the book, offering many helpful sugges-
tions. The text also benefited from the selfless efforts
of many academic reviewers, including:
Ann Aguanno, Marymount Manhattan College
Ethan Bier, University of California, San Diego
Sara Clark, Tulane University
Gedeon Deak, University of California, San Diego
Mark Emerson, The City College of New York
Nancy Forger, Georgia State University
Alexander Jaworski, Brown University
James Jontes, The Ohio State University
Ronald Oppenheim, Wake Forest School of Medicine
Sarah Pallas, Georgia State University
Anita Quintana, The University of Texas at El Paso
Finally, my wife Cynthia L. Jordan, to whom this
work is dedicated, never stopped believing in the value
of this book. I could never have done it without her love
for the field and for me.
 to accompany
FOR THE STUDENT
Companion Website
(sites.sinauer. com/fond)
The Foundations ofNeural Development Companion Web-
site contains a range of media and review resources
to help students learn the material presented in each
chapter of the textbook and to visualize some of the
key processes discussed. The site includes the follow-
•
1ng resources:
• Chapter outlines
• Chapter summaries
• Animations: Detailed animations that cover some of
the key processes presented in the textbook.
• Videos: Links to fascinating videos that demonstrate
the processes and concepts of neural development.
• Flashcards: An easy way for students to learn and
review the key terms introduced in each chapter.
• Glossary
• News Feed: A continuously updated feed of links to
science news articles relevant to neural development.
FOR THE INSTRUCTOR
Instructor's Resource Library
The Foundations of Neural Development Instructor's Re-
source Library (available to qualified adopters) includes
a variety of resources to aid you in the development of
your course and the assessment of your students. The
IRL includes the following:
TEXTBOOK FIGURES & TABLES All of the figures
(including photos) and tables from the textbook are
provided as JPEGs, all optimized for use in presenta-
tions. Complex figures are provided in both whole and
split versions.
POWERPOINT PRESENTATIONS A PowerPoint pre-
sentation containing all figures and tables, with titles
and full captions, is provided for each chapter.
VIDEOS A collection of fascinating segments from
BBC programs that illustrate important concepts from
the textbook.
TEST BANK The Test Bank consists of a range of ques-
tions covering key facts and concepts in each chapter.
Multiple choice and short answer questions are includ-
ed, and all questions are ranked according to Bloom's
Taxonomy and referenced to specific textbook sections.
COMPUTERIZED TEST BANK The Test Bank is provided
in Blackboard's Diploma format (software included).
Diploma makes it easy to assemble quizzes and exams
from any combination of publisher-provided questions
and instructor-created questions.
COURSE MANAGEMENT SYSTEM SUPPORT The Test
Bank is also provided in Blackboard format, for easy
import into campus Blackboard systems. In addition,
using the Computerized Test Bank, instructors can eas-
XX MEDIA & SUPPLEMENTS

ily create and export quizzes and exams (or the entire
test bank) for import into other course management
systems, including Moodle, Canvas, and Desire2Learn/
Brightspace.
eBOOK
Foundations of Neural Development is available as an
eBook, in several different formats, including Vital-
Source, RedShelf, Yuzu, and BryteWave. The eBook can
be purchased as either a 180-day rental or a permanent
(non-expiring) subscription. All major mobile devices
are supported. For details on the eBook platforms of-
fered, please visit www.sinauer.com/ ebooks.
A ll of humanity's written work is subjected to a ruthless selection process: very
few things written today will still be of interest to anyone 5 years from now, includ-
ing, alas, college textbooks. Even best-sell ing novels, wh ich account for on ly a
tiny fraction of the novels published (wh ich are themselves a t iny fraction of the
novels submitted to publishers), are rare ly read 25 years later. Of the many works
written in Greece thousands of years ago, the very few avai lable to us are those
that were preserved, across hundreds of generations, because they continued to
be regarded as va luable.

ALL I KNOW IS THAT I KNOW NOTHING

These ancient Greek writings survived because they reflected an exciting t ime of
new ideas. There arose people who seemed eager to question everything about
themse lves and the world around them. Some practiced philosophy, the study
of the fundamental nature of knowledge, existence, and reality itself. Among the
ancient ph ilosophers, the most famous today are Aristotle (384-322 BCE) and Plato
(427-347 BCE), who rejected traditional and religious explanations for the world.
Both regarded the Greek gods as metaphors or fairy tales. They also had a healthy
skepticism about the way things seem to be versus the way things are. They knew
our senses are not always reliable. For example, Aristotle was interested in visua l
illusions, such as the so-called waterfall effect: if you stare at falling water for a
minute or so and then look away, stationary objects appear to stretch out like
drawings on an inflating balloon. You can see this "motion aftereffect" and many
other visual illusions at Michael Bach's wonderful website: www.michaelbach.de/ot.
Plato questioned our senses even more deeply than Aristotle. Knowing
that under certain circumstances people may hallucinate entire events that
never happened, Plato dared to think that everything we see may be illusion. I
should clarify here that almost al l of Plato's writings describe dialogues between
his wise teacher, Socrates (469-399 BCE), and other people. This means it is
impossible to separate Socrates' views from Plato's, and so, by convention, we
attribute them to Plato, since he was the one who wrote them down.
2 PRO LOG UE
Plato (427-347 BCE) and his great teacher, Socrates
(469-399 BCE) (Courtesy of M arie-Lan Nguyen.)
philosophy The study of the
fundamental natu re of knowledge,
existence, and reality itse lf.
parable of the cave Plato's
thought experiment about the
concept of real ity that peop le
would have if they grew up seeing
only the shadows of objects in the
wor ld.
epistemology The study of
know ledge and how we gain it.
In his famous parable of the cave, Plato proposes
a "thought experiment." What if people were raised
in a cave with a fire constantly blazing in the mouth
of the cave? Imagine these people were chained to a
rock such that the only thing they ever saw was a wall
in front of them on which were cast shadows of people
and animals passing in front of the fire behind them
(FIGURE P. 1). The prisoners would believe t he shadows
represented all there was in t h e world. If one of t h em
were unchained and allowed to see the fire at the
mouth of the cave and the three-dimensional people
and animals passing by the fire and casting shadows
on the wall, she would be astonished at this deeper
reality. Return ed to chains, that person would forever
have a d ifferent concept of the world and would have
a hard time convincing any of her neighbors that they
were viewing mere shadows, not reality itself (Plato's
Republic, book VII).
This deep skepticism about our perceptions influ-
ences Plato's ideas about epistemology, the study of
knowledge and how we gai n it. He reports on many of Socrates' dialogues with
other people that reveal that they knew someth ing w it h out be ing aware of it.
In these Socratic dialogues, Socrates almost never provides information, but
rather keeps asking t he other person questions and using that person's answers
to bring up t h e following questions. In one case Socrates asks a slave boy a
question about rectangles that someone w h o knew t h e Pythagorean theorem
would know, but of course t h e uneducated boy has never heard of Pythagoras
or the t h eorem. But by replyi n g to a series of questio ns t h at Socrates poses,
t h e boy eventually concludes that the square of the d iago n al is indeed equal
to t h e sum of the squares of the two sides, and t h at t h is must be true of all
Cave
.
openmg
Diffused
sunlight
Fire
cast
wall
Roadway w here
shad owmen
perform
Prisoners
FIGURE P.1 Plato's parable of the cave A revolut ionary thinker, Plato
t hought that anything and everything we lea rned through t he senses might
be false.
 THE RATIO NALI ST PHILOSO PHERS 3

...••.
•••
••

..... ...

FIGURE P.2 Is there a platonic Form of dog? Despite their t remendous vari-
ation in size, shape, and color, we easily recognize dogs. (Left© iSt ock.com/
Paul Shlykov; ot hers© iSt ock.com/Global P.).

rectangles, everywhere (Plato's Meno). Socrates concludes that this knowledge Form A lso called Platonic Form.
about geometry was hidden inside the slave boy's mind all along and the boy An eternal, perfect "blueprint"
was simply recollecting what he knew (but didn't know he knew). Furthermore, of an object or concept that we
recognize in its imperfect, highly
as the boy had never been instructed on any of the matters Socrates asked
variab le rea l-life examp les.
him about, he must have a/ways known them, and so had always known the
Pythagorean theorem. Thus Plato offers the radical idea that knowledge is not
something we acquire, but something everyone, even uneducated slaves, are
born with! Likewise, Plato concludes that our understanding of numbers, of
equality, of beauty, are not taught to us, but are somewhere inside us before
we are born. He quotes Socrates saying, "I cannot teach anybody anything, I
can only make them think."
Plato's notion that knowledge is inside us at birth, and not acquired by
experience of the world, is reinforced in his writing about Forms. We all know
what a "bed" is, even though beds come in many different sizes and shapes.
In fact, few of us have ever seen two or more beds that are exactly the same in
every way, yet we know they are all beds. Likewise, tonight we may see a bed
that is unlike any we've seen before, but we will still recognize it as a bed. How
did we learn what a bed is? It can't be because this bed is exactly like beds
we've seen before, because it's not. Likewise, there are bewildering varieties
of tables, horses, and dogs (FIGURE P.2), yet we have no trouble recognizing
each as a member of that class of things. Plato concluded that every object
and every abstract concept, like justice or beauty, is simply reflecting a Form ,
an eternal, perfect "blueprint" of that object or concept that we recognize
in its imperfect, highly variable real-life example. Just as the prisoners in the
cave must rely on the shadows of real objects to understand their world, we
must rely on our perception of imperfect Forms to understand ours. So how
do we come to recognize anything, anywhere? Plato's explanation is again that
our ideas about the perfect Forms are inside us at birth. We see an object,
detect its likeness to the eternal, perfect Form of that object in our mind, and
so recognize it as another particular, perhaps unique, example of that Form:
bed, horse, beauty.
4 PROLOGUE

•
In what, for Plato, is an atypical ly mystic reso lution, he con-
cludes that all this knowledge (the Pythagorean theorem, the
Forms of numbers, equality, beds, tables, justice, beauty) is stored
in a person's sou/, which existed eternal ly before the person was
born (P lato's Phaedo).
Plato's writings were cherished by Europeans through Medieval
and Renaissance eras, so the phi losophers of later t imes were
all aware of his ideas. For example, Rene Descartes (1596-1650)
explicitly vowed to ignore what previous philosophers had claimed,
but of course he had read al l of Plato's work, and it's clear that
he was influenced by it. Like Plato, Descartes distrusted his own
senses, not only because there were times when he knew they
m isled him, but also because the appearance of objects could
change, as when heating wax makes it change from opaque solid
to transparent liquid . One night Descartes was working at his desk,
writing phi losophy, when he sudden ly woke up in bed to find that
he had been dreaming it al l. Yet his experience at the desk had
seemed so rea l that Descartes wondered whether everything
that he regarded as real life might simp ly be a very vivid dream.
Descartes' extreme skepticism led him eventually to admit
that there was on ly one th ing he was abso lutely certain of his
famous phrase "I th ink, therefore I am" (in Latin, cogito ergo
sum). Even when he doubted whether th is was true, he realized
Rene Descartes (1596-1650) working at his
that doubting can only happen if there is a doubter, confirming
desk; or is he merely dreaming that he is at
his existence. From this beginning, Descartes used deduc-
his desk? (Image© Mansell/The LIFE Picture
Collection/Getty Images.) tion to reach other conclusions, some of which we m ight find
questionable today, such as that a benevo lent God exists. But his doubts sti ll
resonate, such as whether his body existed. I can't disprove the idea that our
entire world, including everyth ing we perceive, is just a computer simu lation.
So I may doubt that my body actua lly exists, but I know that I'm the doubter
(even if " I" am mere ly subroutine in a computer program, or a hallucinating
brain in a vat of f luid, kept alive by mach ines).
Descartes' skeptical ideas about obj ects in the outside world also ca ll to
m ind Plato's Forms. Descartes uses an analogy that if you heat up one stone
and put it next to others, those other stones can never be any hotter than the
orig inal. Just so, whatever we perceive of an obj ect can on ly be less rea l than
the obj ect itse lf, j ust as w ith Plato's cave dwellers living in a world consisting
of mere shadows cast by obj ects themselves. Descartes notes that, like Plato's
slave boy who discovered that he already "knew" the Pythagorean theorem,
he feels, " I do not so much appear to learn anything new, as to call to remem-
brance what I before knew" (Descartes' Meditations V[4]).

THE BENEFITS OF HAVING AN IMMORTAL SOUL

rationalist philosophers
Philosophers w ho be lieved that
the only way to understand t he
true nature of t he world is by use
o f the inte llect and reason, rat her
than t he senses.
Also like Plato, Descartes re lied on a sou/ that exists before we are born, provid-
ing us all t his information as a g ift from a benevolent God. A little later, Gottfried
Leibniz (1646-1716) in Germany wou ld p ropose t hat we each possess a monad, an
irreducible particle reflect ing the will of an all-knowing God, which sounds an awful
lot like a soul. Like Plato's and Descartes' soul, t he monad allows us to recognize
objects and t heoretical not ions like beauty, to know that God exists, and to know
right from wrong. Because Plato, Descartes, and Leibniz emphasized t hat reason,
the use of t he intellect rather t han the use of ou r senses, was the only pathway to
knowledge, they are known as rationalist philosophers.
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