HANDBOOK OF
DEVELOPMENTAL
COGNITIVE NEUROSCIENCE
Second Edition

Developmental Cognitive Neuroscience

Neurodevelopmental Disorders, Helen Tager-Flusberg, ed. (1999)
Handbook of Developmental Cognitive Neuroscience, Charles A. Nelson
and Monica Luciana, eds. (2001)
Modeling Neural Development, Arjen van Ooyen, ed. (2003)
Handbook of Developmental Cognitive Neuroscience, second edition,
Charles A. Nelson and Monica Luciana, eds. (2008)

HANDBOOK OF
DEVELOPMENTAL
COGNITIVE NEUROSCIENCE
Second Edition

Edited by
Charles A. Nelson and Monica Luciana

A BRADFORD BOOK
THE MIT PRESS
CAMBRIDGE, MASSACHUSETTS
LONDON, ENGLAND

© 2008 Massachusetts Institute of Technology

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Library of Congress Cataloging-in-Publication Data

Handbook of developmental cognitive neuroscience / edited by
Charles A. Nelson and Monica Luciana.—2nd ed.
p. ; cm.—(Developmental cognitive neuroscience)
Includes bibliographical references and index.
ISBN 978-0-262-14104-8 (hardcover : alk. paper)
1. Developmental neurobiology—Handbooks, manuals, etc.
2. Cognitive neuroscience—Handbooks, manuals, etc.
I. Nelson, Charles A. (Charles Alexander) II. Luciana,
Monica. III. Series.
[DNLM: 1. Nervous System—growth & development.
2. Central Nervous System Diseases—physiopathology.
3. Cognition—physiology. 4. Human Development. 5. Per-
ception—physiology. WL 102 H23535 2008]
QP363.5.H365 2008
612.8'2—dc22

2008007886
10 9 8 7 6 5 4 3 2 1

CONTENTS

Preface to the Second Edition xi

I. FUNDAMENTALS OF DEVELOPMENTAL
NEUROBIOLOGY 1

A. GENERAL PRINCIPLES 3

1. The Formation of Axons and Dendrites by Developing Neurons 5
Paul Letourneau

2. Imaging Developmental Changes in Gray and White Matter
in the Human Brain 23
Elizabeth D. O’Hare and Elizabeth R. Sowell

3. Gyrification and Development of the Human Brain 39
Tonya White and Claus C. Hilgetag

4. Adult Neurogenesis in the Hippocampus 51
Yevgenia Kozorovitskiy and Elizabeth Gould

5. The LHPA System and Neurobehavioral Development 63
Amanda R. Tarullo, Karina Quevedo, and Megan R. Gunnar

6. The Effects of Monoamines on the Developing Nervous System 83
Gregg D. Stanwood and Pat Levitt

v

B. STRUCTURAL FOUNDATIONS OF SENSATION,
PERCEPTION, AND COGNITION 95

7. Mechanisms of Auditory Reorganization during Development:
From Sounds to Words 97
Richard N. Aslin, Meghan A. Clayards, and Neil P. Bardhan

8. Brain Correlates of Language Processing during the
First Years of Life 117
Angela D. Friederici

9. Brain-Behavior Relationships in Early Visual Development 127
Bogdan F. Iliescu and James L. Dannemiller

10. Motor Systems Development 147
Rosa M. Angulo-Barroso and Chad W. Tiernan

11. Neurodevelopment of Social Cognition 161
Melissa D. Bauman and David G. Amaral

12. Pre- and Postnatal Morphological Development of the Human
Hippocampal Formation 187
László Seress and Hajnalka Ábrahám

13. Structural Development of the Human Prefrontal Cortex 213
Ivica Kostović, Miloš Judaš, and Zdravko Petanjek

14. White Matter Maturation and Cognitive
Development during Childhood 237
Torkel Klingberg

II. METHODOLOGICAL PARADIGMS 245

15. Electrophysiological Methods in Studying Infant
Cognitive Development 247
Gergely Csibra, Elena Kushnerenko, and
Tobias Grossmann

16. Eye Tracking Studies of Normative and Atypical Development 263
Canan Karatekin

17. Diffusion Tensor Imaging 301
Jeffrey R. Wozniak, Bryon A. Mueller, and Kelvin O. Lim

18. Functional MRI Methods in Developmental Cognitive Neuroscience 311
Kathleen M. Thomas and Angela Tseng

19. Mechanisms of Language Acquisition: Imaging and
Behavioral Evidence 325
Jacques Mehler, Marina Nespor, Judit Gervain, Ansgar Endress, and
Mohinish Shukla

vi contents

20. Magnetic Resonance Spectroscopy of Developing Brain 337
Balasrinivasa Rao Sajja and Ponnada A. Narayana

21. The Integration of Neuroimaging and Molecular Genetics in the
Study of Developmental Cognitive Neuroscience 351
Essi Viding, Douglas E. Williamson, Erika E. Forbes,
and Ahmad R. Hariri

22. Neural Network Models of Cognitive Development 367
Yuko Munakata, Jennifer Merva Stedron,
Christopher H. Chatham, and Maria Kharitonova

III. NEURAL PLASTICITY IN DEVELOPMENT 383

23. Early Brain Injury, Plasticity, and Behavior 385
Bryan Kolb, Wendy Comeau, and Robbin Gibb

24. Developmental Plasticity and Reorganization of Function
Following Early Diffuse Brain Injury 399
Linda Ewing-Cobbs, Mary R. Prasad, and Khader M. Hasan

25. Plasticity of the Visual System 415
Daphne Maurer, Terri L. Lewis, and Catherine J. Mondloch

26. Cross-Modal Plasticity in Development: The Case of Deafness 439
Teresa V. Mitchell

27. Plasticity of Speech (Animal Model) 453
Teresa A. Nick

IV. COGNITION 465

28. The Development and Integration of the Dorsal and Ventral
Visual Pathways in Object Processing 467
Mark H. Johnson, Denis Mareschal, and Gergely Csibra

29. Attention in Young Infants: A Developmental Psychophysiological
Perspective 479
John E. Richards

30. Nonhuman Primate Models of Memory Development 499
Jocelyne Bachevalier

31. Neurocognitive Mechanisms for the Development of
Face Processing 509
Michelle de Haan

32. The Development of Visuospatial Processing 521
Joan Stiles, Brianna Paul, and Wendy Ark

contents vii

33. Mechanisms of Change: A Cognitive Neuroscience Approach to
Declarative Memory Development 541
Jenny Richmond and Charles A. Nelson

34. The Development of Executive Function in Childhood 553
Philip David Zelazo, Stephanie M. Carlson,
and Amanda Kesek

35. The Development of Prefrontal Cortex Functions in Adolescence:
Theoretical Models and a Possible Dissociation of Dorsal versus
Ventral Subregions 575
Elizabeth A. Olson and Monica Luciana

36. Cognition and Aging: Typical Development 591
Jonas Persson and Patricia A. Reuter-Lorenz

37. Cognition and Aging-Dementia 607
Mischa de Rover, Sharon Morein-Zamir, Andrew D. Blackwell,
and Barbara J. Sahakian

V. NEURODEVELOPMENTAL ASPECTS OF
CLINICAL DISORDERS 621

38. The Role of Nutrition in Cognitive Development 623
Anita J. Fuglestad, Raghavendra Rao, and Michael K. Georgieff

39. Fetal Alcohol Syndrome 643
Sarah N. Mattson, Susanna L. Fryer, Christie L. McGee,
and Edward P. Riley

40. Impact of Prenatal Cocaine Exposure on the Developing
Nervous System 653
Eric M. Langlois and Linda C. Mayes

41. Neurocognitive Models of Early-Treated Phenylketonuria: Insights
from Meta-analysis and New Molecular Genetic Findings 677
Marilyn Welsh, Kathryn DeRoche, and David Gilliam

42. Research into Williams Syndrome: The State of the Art 691
Annette Karmiloff-Smith

43. Neurocognitive Development in Autism 701
Mikle South, Sally Ozonoff, and Robert T. Schultz

44. Tics and Compulsions: Disturbances of Self-Regulatory Control
in the Development of Habitual Behaviors 717
Rachel Marsh, James F. Leckman, Michael H. Bloch,
Yanki Yazgan, and Bradley S. Peterson

45. Developmental Dyslexia 739
Guinevere F. Eden and D. Lynn Flowers

viii contents

46. The Development and Cognitive Neuroscience of Anxiety 755
Daniel S. Pine and Christopher S. Monk

47. Developmental Neuropsychology of Unipolar Depressions 771
Ian M. Goodyer and Zoë Kyte

VI. EMOTION/COGNITION INTERACTIONS 785

48. Toward a Neurobiology of Attachment 787
Myron A. Hofer and Regina M. Sullivan

49. Sleep, Cognition, and Emotion: A Developmental View 807
Oskar G. Jenni and Ronald E. Dahl

50. Neural Systems, Gaze Following, and the Development of
Joint Attention 819
Peter Mundy and Amy Van Hecke

51. The Biology of Temperament: An Integrative Approach 839
Nathan A. Fox, Heather A. Henderson, Koraly Pérez-Edgar,
and Lauren K. White

52. The Developing Adolescent Brain: Molecular Mechanisms Underlying
Nicotine Vulnerability 855
Charles F. Landry, Terri L. Schochet, and Ann E. Kelley

53. Environmental Influences on Brain-Behavioral Development: Evidence
from Child Abuse and Neglect 869
Jessica E. Shackman, Alison B. Wismer Fries, and Seth D. Pollak

54. Neurocognitive Development of Performance Monitoring
and Decision Making 883
Eveline A. Crone and Maurits W. van der Molen

Contributors 897

Index 901

contents ix

Preface to the Second Edition
The first edition of this Handbook appeared in 2001, at a time when the field of develop-
mental cognitive neuroscience had only recently taken root. The volume contained forty-
one chapters distributed over eight topical areas, including overviews of the fundamentals
of developmental neurobiology, a surveying of methodological paradigms, neural plasticity
and its expression during development and in the context of disease, sensory and motor
system development, language development, cognition (broadly construed), neurodevelop-
mental aspects of clinical disorders, and emotion-cognition interactions.
Seven years have now passed since the first edition was published and the field of devel-
opmental cognitive neuroscience has expanded enormously. To illustrate how the field has
grown, we recently conducted Medline searches spanning the interval from 1902 to 2007
using the following three search parameters combined: brain, development, and cognition.
From 1902 to 2001, there were 972 articles that represented this intersection of topics.
From 2002 to 2007 alone, there were 988 articles. Thus, developmental cognitive neurosci-
ence, following the pattern of its parent discipline, cognitive neuroscience, is growing at
an exponential rate, with evidence of massive proliferation over the past five years. Many
accomplishments within the field have resulted from the application of new methods to
developmental samples. This proliferation of activity is also evident through other, more
concrete, indices of change, including (a) an exponential increase in the number of devel-
opmental papers published in the Journal of Cognitive Neuroscience, (b) the appearance of
special issues on this topic in a number of other journals, including Developmental Review,
Child Development, Human Development, Neuropsychologia, and Developmental Psychology, (c) authored
and edited volumes by a number of senior investigators (e.g., Mark Johnson, Michelle de
Haan), and finally (d) the ease with which we were able to expand this volume. We have
expanded to fifty-four chapters from the original forty-one. More importantly, we now
present a number of areas that in our view represent new inroads made possible by
advances in both developmental and cognitive neuroscience. First, there is a greater
emphasis on affective and social neuroscience. This offshoot of cognitive neuroscience has
firmly taken root in the adult literature and is gradually trickling down to the developmen-
tal literature. Second, we have placed a greater emphasis on clinical disorders. We have
done so primarily because such work is inherently translational in nature, and translational
research is currently receiving a great deal of attention by many working at the interface
of brain and behavior. Finally, one chapter exclusively, and several to a lesser degree,
discuss the breakthroughs being made in imaging genomics. In our mind the intersec-
tion of brain, behavior, and genetics represents an exciting new area of inquiry that will
gain considerable traction in coming years, due in large part to advances being made in
genetics/genomics and in neuroimaging.
We are pleased to bring you this second edition and trust that it will serve as a resource
for all those interested in the development of brain-behavior relations in the context of
both typical and atypical development.
Charles A. Nelson
Monica Luciana

xi

I FUNDAMENTALS
OF
DEVELOPMENTAL
NEUROBIOLOGY

A. GENERAL
PRINCIPLES

1 The Formation of Axons and
Dendrites by Developing Neurons
PAUL LETOURNEAU

Introduction Microtubules Provide Support and a Means of
Transport Microtubules are hollow cylinders 25 nm in
The neuronal circuitry that underlies human behavior and diameter that extend through the cytoplasm of neuronal
other neural functions develops over a prolonged period perikarya, axons, and dendrites (figures 1.1, 1.2). The wall
lasting from the second fetal month through adolescent of a microtubule consists of subunits of highly conserved
years. These circuits arise from the extensive development proteins, alpha tubulin and beta tubulin. Microtubules have
of elaborate neuronal processes, as neurons express intrinsic no defined length, and single neuronal microtubules can
morphogenetic behaviors, while interacting with other cells exceed 100 μm (Letourneau, 1982). Microtubules are rigid
and molecules of the developing nervous system. First, and resist compression to support the elaborate extensions
immature neurons migrate from their birthplaces to the sites of axons and dendrites. Microtubules are also the “rails”
where they are organized into layers, nuclei, and ganglia of along which organelles are transported via linkage to the
neuronal perikarya. Next, immature neurons sprout axons motor proteins, kinesins, and dynein (Hirokawa and
and dendrites that elongate, sometimes for many centime- Takemura, 2004). These two functions, providing structural
ters, to make synaptic connections with target neurons or support and being rails for intracellular transport, are the
other cells. This chapter describes intrinsic mechanisms of functions of neuronal microtubules.
morphogenesis of axons and dendrites and the extrinsic
environmental features that regulate where and when axons Formation of Microtubules in Cells Tubulin sub-
and dendrites grow to create neural circuits. units polymerize by endwise addition to form microtubules.
The ability to extend neuronal processes, or neurites, is Because of inherent asymmetry of the tubulin protein,
intrinsic to neurons. This is demonstrated when immature microtubules are polarized with a distinct molecular face at
neurons, such as from prenatal hippocampus, are placed each end. Tubulin subunits are added more rapidly at one
into tissue culture. Within a few hours the neurons sprout end, called the plus (+) end, while the less likely end for
processes that elongate onto the substrate, each tipped by an growth is called the minus (−) end (figure 1.1 and plate 1).
adherent motile structure called a growth cone. These neu- Microtubules in neurons are formed in the centrosomal
rites mature to become axons and dendrites and form syn- region near the nucleus and extend throughout the
apses in vitro. These events in a neutral in vitro environment perikaryon with their minus ends anchored at the centrosome.
show that the neuronal phenotype defines the intrinsic The plus ends of cytoplasmic microtubules undergo bouts of
behaviors that produce neuronal shape. The most significant growing and shrinking called dynamic instability, in which
cellular components in neuronal morphogenesis are the a microtubule end may undergo rapid disassembly, either
protein polymers of the neuronal cytoskeleton. In the next completely or partially, which is followed by “rescue” and
section the neuronal cytoskeleton and the intrinsic mecha- renewed growth (Tanaka, Ho, and Kirschner, 1995).
nisms of neurite formation and elongation will be discussed.
In the following three sections the regulation of axonal and Regulation of Microtubule Organization by MAPs
dendritic growth by extrinsic molecules will be discussed. In neurons, microtubule organization is regulated by a group
of proteins called MAPs (microtubule-associated proteins).
The dynamic neuronal cytoskeleton MAPs bind to microtubules and regulate all aspects of
their organization, including assembly and disassembly,
Neuronal morphogenesis depends on the organization and stability, and binding to neurofilaments, actin filaments,
dynamic properties of two cytoskeletal polymers, microtu- and other microtubules (Dehmelt and Halpain, 2004;
bules and actin filaments (Dent and Gertler, 2003; Luo, Gordon-Weeks, 2000). Motor proteins, such as kinesin, bind
2002). These cytoskeletal polymers are present in all cell to microtubules and move cargo toward microtubule plus
types, although specific mechanisms determine cytoskeletal ends, while dynein motors move cargo toward microtubule
functions in neurons. minus ends. The protein katanin binds microtubules and

5

Figure 1.1 Actin filaments and microtubules are polarized poly- GTP-tubulin dimers adding to the plus or growing end and GDP-
mers. Actin filaments are polarized polymers for which the addition tubulin dimers dissociating from the minus end. Microtubules also
of ATP-actin is more likely at the barbed end than the pointed end. exhibit posttranslational modifications (detyrosination shown here)
After hydrolysis of ATP-actin to ADP-actin, subunits dissociate at that correlate with the age and stability of the polymer. (From Dent
the pointed end. Microtubules are also polarized structures with and Gertler, 2003.) (See plate 1.)

severs them, promoting reorganization of microtubules and depending on microtubule length and connections with
remodeling of neuronal shape (Baas and Buster, 2004). Some other structures. Long microtubules in axons are stationary,
maps, such as MAP2, are localized in dendrites, while other although their plus ends undergo considerable dynamic
MAPs, such as tau and MAP1B, are localized in axons. instability of growth and shrinkage. Possibly, tubulin sub-
Several features distinguish microtubules in axons and units or short microtubules are transported distally via
dendrites. Unlike most cell types, the minus ends of micro- dynein motors and then disassembled to release tubulin for
tubules in axons and dendrites are not anchored to the addition to longer, stable microtubules. This dynamic assem-
centrosome; rather, microtubules lie entirely within these bly of tubulin onto existing microtubules is a critical event
processes. Microtubules are formed at the centrosome and in the morphogenesis of axons and dendrites (Tanaka and
then transported into axons or dendrites. Nearly all axonal Kirschner, 1995).
microtubules have their plus ends oriented toward the ter-
minal, while microtubules in dendrites have mixed polarity, Actin Filaments in Neurons Actin filaments are
some with plus ends and some with minus ends oriented the other important cytoskeletal components in neuronal
toward dendritic termini. Many axonal and dendritic micro- morphogenesis (Dent and Gertler, 2003; Luo, 2002). In
tubules are highly stable as a result of enzymatic modifica- mature neurons, actin filaments form a cortical meshwork
tions of the tubulin protein and from binding of certain beneath the plasma membrane that organizes ion channels,
MAPs. vesicles, membrane proteins, and neurotransmitter receptors
Although microtubules must always be present to support at nodes of Ranvier and at synapses. However, at the ends
neurites, it is uncertain how microtubules and tubulin sub- of growing axons and dendrites, elaborate networks of actin
units are advanced as neurites grow (Baas and Buster, 2004). filaments are the organizing component that drives the
Dynein motor molecules can slide short microtubules along, searching behaviors that are necessary for navigation of

6 fundamentals of developmental neurobiology

Again. actin filaments. like micro- 1971).2 The distribution of microtubules and actin filaments growth cones and along the shafts of the axons.2.2 and plate Like microtubule polymerization. neurons contain many proteins. especially at the motile leading margin. the microtubules from the central bundle of the bundled in the axons and branches. (See plate 2. and Wessells. 1979. 2003). Microtubules of actin filament dynamics may give rise to collateral branches (B). regulating letourneau: formation of axons and dendrites by developing neurons 7 . like microtu- Actin filaments with a diameter of about 6–7 nm are bules. Letourneau. stability. actin subunits are lost from filaments. where a dynamic actin filament Regulation of Actin Filament Organization by network fills flattened projections. where small areas in developing neurons and in axonal growth cones. Spooner. fingerlike functions (Dent and Gertler. whose function is to individually not stiff. and individual microtubules extend filament networks and bundles in the peripheral domains (P) of the into the P domain and into filopodia (arrows). Unlike the cortical networks in mature neurons. but bundles of actin filaments have regulate the polymerization. Also. actin filament arrays in growth cones are extensive. actin filaments poly- 2. Actin filaments are arrayed in central domain (C) splay apart. called lamellipodia. 1983). tubules. the inherent asymmetry of the actin subunit leads to polarity of actin filaments. Yamada. called filopodia (figure 1. projections. Letourneau.Figure 1. merize by endwise addition of subunits.1).) growth cones to their synaptic targets (figure 1. 2003. Pollard and Borisy. 1983. (green) are densely packed with the neuronal cell bodies (S) and are In a growth cone. in which the “barbed” end is Organization of Actin in Cells Actin filaments are favored for polymerization and the “pointed” end is where polymers of the conserved globular protein actin (figure 1. and interactions of stiffness. One class of ABPs binds actin subunits. and ABPs Actin-binding proteins (ABPs) have numerous bundles of actin filaments fill the cores of transient.

changes in cytoskeletal organization that drive neuronal which share common features of their motor activity. resented by symbols of similar color and shape.their availability for polymerization. other ABPs cross-link generating forces to move components and reshape actin filaments into meshworks and bundles. ABPs are the barbed and pointed ends of actin filaments regulate the critical to regulating the behaviors of growth cones of addition and loss of actin subunits to filaments. Lines depict activa- ance cues may function either alone or in a complex to activate tion pathways that have been demonstrated experimentally in cytoplasmic adaptors and mediators. In summary. and phosphoinositides that bind MAPs and Figure 1. or other cargoes and to exert tensions on cytoskeletal Cytoskeletal organization can be rapidly changed by components and associated structures (Rochlin et al. promoting the remodeling of actin filament arrays. 2001.. where the Dynamics by Cytoplasmic Signaling Pathways As noted addition of actin subunits is promoted by several ABPs. ABPs bind actin filaments and sever them. MAPs and ABPs are regulated by intracellular actin filaments and generate forces to move actin filaments. Several developing axons and dendrites. previously. 2004). but in an immediate Bridgman. actin Regulation of Microtubule and Actin Organization and filament barbed ends face the leading cell margin. ABPs that bind developing axons and dendrites. cGMP. the organization of microtubules and actin Myosins are motor molecules that bind and move cargoes filaments is regulated by MAPs and ABPs. Membrane receptors for extracellular guid. Myosin II in growth cones is particularly important in cAMP. There are more than 10 myosins. vesicles. signaling and cytoplasmic second-messenger pathways. but morphogenesis reflect the activities of MAPs and ABPs. Similar types of molecules are rep- growth cone motility. which are responsible for regulating the assembly and link guidance receptors with cytoskeletal dynamics underlying disassembly of actin filaments. The dynamic along actin filaments. 1995). Myosins in growth cones interact with fashion. In growth cones. levels of these proteins are regulated by gene filaments and in cargoes that are moved (Brown and transcription and protein synthesis.) may be pivotal links between guidance signals and actin-associated 8 fundamentals of developmental neurobiology . which differ in the direction that they move cargoes along Certainly. fluctuations in levels of small molecules such as Ca++ ions. (From Song and Poo.3 The interwoven network of signaling molecules that proteins. The Rho family of GTPases different systems.

Rac1.2). microtubules preferentially grow along actin bundles in filopodia.4). Actin-microtubule interactions are present in lamellipodia at all stages.3 Stage 2 are important regulatory proteins that relay signaling from the cell surface intracellularly to the cytoskeleton (Jaffe and Hall. Thus by regulating GTPases MAPs might promote these membrane events regulate cytoskeletal proteins. figure 1. although the mechanisms tightly packed into parallel arrays inside the nascent neurite (stage are less well understood than for actin filaments. are particularly important in neurite elonga. As mentioned earlier. Panel B depicts a more detailed view of the proposed Microtubule-Actin Interactions Are Important cytoskeletal organization in stage 1. which we a physical link between the structures exists. Preceding the initial neurite outgrowth. Letourneau. 2005).4 A model for cytoskeletal reorganization during neurite activates the motor protein myosin II. significant. where adhesive initiation of neurites from a spherical perikaryon or in proteins. Microtubule organization and polymerization are newly formed protrusion then elongates. 2). microtubule/actin Activation of RhoA. depending on whether they are bound to the nucleotides GTP (on) or guanosine diphosphate (GDP) (off). A rich B variety of guanine nucleotide exchange factor proteins (GEFs) selectively activate GTPases by exchanging GDP for GTP. Proteins that mediate interactions between protein kinases and phosphates also rapidly regulate their microtubule plus ends and actin filaments are particularly activities. Interestingly.1). such as protein kinases and phosphatases. 2001. and Cdc42. GTPase-activating proteins (GAPs) stimulate MAPs stabilize microtubules hydrolysis of GTP to inactive GTPases.2 Stage 1. The motility. the lamellipodium growth cone can cause collapse of microtubule arrays and becomes segmented at one or more sites (stage 1. Multifunctional MAPs will describe. The Rho family of small guanosine triphosphatase A (GTPase) proteins. 2004. and other ligands bind membrane directing the advance of a growth cone (Rodriquez et al. microtubules maintain the shapes of axons and dendrites 2003. (A) Shortly after plating. increasing mechanical initiation. Rac1. Stage 1. (From Dehmelt and Halpain. Then the significant neurite retraction. GAPs.. If RhoA extend a uniform lamellipodium that surrounds the cell soma (stage levels are highly elevated. in particular RhoA. concurrent with microtubule advance into the initiation site present in the growth cone and contribute to growth cone and formation of an ordered microtubule array (stage 1. tion and growth cone migration.3). These molecules and pathways are.3.1 Stage 1. Rac1- GTP activates several ABPs to stimulate actin polymeriza- tion and formation of lamellipodia. cultured hippocampal neurons tensions and rearrangements of actin filaments. or plakins are candidates to act as such links. 2004).) letourneau: formation of axons and dendrites by developing neurons 9 . 2003. and GDIs are regulated by cell surface microtubule bundling ligand-receptor interactions. suggesting that Two particular interactions of actin filaments. regu. and GDP dissocia- tion inhibitors (GDIs) inhibit activation of GTPases by GEFs. or Cdc42 has distinct effects interactions on actin filament organization (Jaffe and Hall. in turn. These microtubule-actin interactions link the rally modulate the levels and activities of these regulatory microtubule functions of structural support and organelle molecules. All three Rho GTPases are lamellipodium migrates away from the cell soma to form a growth cone. Gallo and developing neuron (figure 1. 2003). strong contractile forces in the 1. Song and Poo. MAP2. and microtubules become also regulated by Rho GTPases. like MAP1B. growth factors. while Cdc42-GTP also MAPs stimulates actin polymerization and formation of filopodia. figure 1.ABPs and regulate them allosterically (Dent and Gertler. Rho GTPases bind to and regulate MAPs and ABPs or their upstream regulators. The addition to and and resist compressive forces that would collapse or withdraw removal of phosphate groups from MAPs and ABPs by these processes. 2005. receptor proteins to trigger events that locally and tempo. Actin Microtubules RhoA-GTP activates the kinase ROCK. Thus cytoplasmic signaling activities that cascade transport to the dynamic cortical actin filaments and from ligand-receptor interactions at the plasma membrane associated membrane receptors that detect extrinsic signals rapidly and locally regulate cytoskeletal organization during and regulate the cytoskeletal activities that shape the neuronal morphogenesis (Dent and Gertler. because these proteins may be important in the lated by events at the plasma membrane. A critical feature of GTPases is that their activity is rapidly switched on or off. which phosphory- lates several substrates to suppress actin polymerization and Figure 1.3).3). MAPs might promote These GEFs.

vigorous actin polymerization A mechanism for neurite initiation and growth pushes the cell margin forward. figure 1. The rearward transported fila. This motility microtubules extend into the P-domain. 1979). and retrograde flow are equal. the C-domain (central). while simultaneously myosin II. kinases. which mediate cell-cell and Forscher.5): (1) the advance. comprising withdraw cylindrical filopodia and flattened lamellipodia. enhancing their resistance to the bules via polymerization. 2000). actin filaments and and moves away from the cell body. As cell-cell contacts are initiated by that neurites can be pulled out from a neuron by attaching intercellular binding. (Schaefer. and Only when the leading edge forms transient adhesive growth cone migration by neurons will be described.2. In this section. At the growth cone’s leading margin. balanced by the myosin- powered rearward sliding of untethered actin filaments. If these microtubules persist and around the nucleus. figure 1. 2003). 2001). tethered by a cylindrical membrane components that are not stabilized by adhesions nascent neurite. From the C-domain individual like waves lapping on a beach (see figure 1. Kabir. adhesive contacts. microtubule- microtubules. expansion. which mediate cell directed forces in neurite initiation is illustrated by findings adhesion to ECM. called the P-domain (peripheral). the growth cone (Gordon-Weeks. and adhesion of the leading margin of the growth cone. actin filaments linked to adhe- noncovalent bonds between cells or between cells and sive sites can interact with myosin II motors and pull micro- extracellular matrices (ECM). these activities produce no stabilized at adhesive sites (figure 1. figures 1. microtubules remain in a loose network Suter and Forscher. of plasma membrane. 2000. At sites where organelles via microtubule-based transport. 2002). and extend and from the neurite into the central growth cone. GEFs. When developing neurons are placed in based motor proteins move microtubules and organelles culture. 1979. and the integrin proteins. cytoplasmic signals gener- actin filaments involves the adhesive interactions of cells that ated at the adhesive sites may promote microtubule transport are mediated by membrane receptor proteins that form and polymerization.4). The significance of these outwardly adhesions. another key function of tubules can advance. formation of actin filaments become anchored to the adhesive apparatus. trusive motility moves forward ahead of the microtubules Thus neurite elongation proceeds by three activities (Dent and organelles (Da Silva and Dotti. neurite elongation. and (3) the advance of leading margin (Dehmelt and Halpain. tau. activities may prompt neurite initiation. sion of MAPs. 2000). empha.5). By way of bead and attached elongating neurite away from the nerve transmembrane linkage these clustered adhesion receptors cell body (Fass and Odde. domain advances and the neurite extends. and myosin II–powered exertion of 10 fundamentals of developmental neurobiology . located subunits to microtubule plus ends. and a number of ABPs that link actin filaments to Organization of Growth Cones and Growth Cone the adhesive sites and induce actin polymerization. (2) the advance of microtu- stabilize microtubules. The coordina- protrusions make firm adhesive contacts with the substrate. An increased expres. and any microtubules that enter the are followed by other microtubules and organelles. The critical step that distinguishes neurite or associations with microtubules are recycled at the back formation from the initial protrusive activity occurs when of the growth cone by the myosin II–powered retrograde microtubules and associated organelles enter and remain flow and by disassembly of actin filaments and endocytosis within a filopodial or lamellipodial protrusion and the pro. Finally. creating space into which micro- to interactions with microtubules.4). receptors cluster within the plasma an adhesive bead to a neuronal surface and then pulling the membrane to form discrete adhesive contacts. At the base of a growth cone.Actin Filaments and Adhesive Contacts In addition and retrograde flow stops. regulated (Zamir and Geiger. The major adhesion receptors tubules and organelles toward the adhesive sites in opposition are the cadherins and the adhesion proteins of the to the retrograde flow of untethered actin filaments (Suter immunoglobulin-like superfamily. neuritogenesis. 2002. which pushes the powered by molecular motors and elongating by adding cell margin outward. and if the protrusion microtubules advance into filopodia or lamellipodia. 2004). Letourneau. Initially. may driven by actin polymerization. To complete However. and Forscher. and MAP1B. transport. most of these microtubules back into the C-domain ward in a retrograde flow. 1. Retrograde flow pulls behind the cell margin. net change. Thus Migration A typical neurite has a central bundle adhesive sites are loci from which regulatory signals emanate of microtubules with associated organelles and a motile and where actin filament organization and anchorage are terminal expansion. and linkage to actin and myosin-based retrograde forces pulling actin back from the adhesive sites (Letourneau. some ments are severed and depolymerized. Several and Gertler. Importantly. In addition. GAPs. sliding forward is driven by actin filament polymerization. pulls newly formed filaments back. contacts that link to actin filaments does the retrograde sizing the dynamic cytoskeleton of actin filaments and flow attenuate. eventually a filopodium or lamellipodium thickens the cycle of growth cone movement. tion of actin-driven membrane expansion. the neurons settle on the substrate. create docking sites for signaling enzymes. such as MAP2. 2003.2. the C- protrusions are swept back with the retrograde flow of actin.

while the myosin II–powered tension generated at adhesive sites at “pull” of actin-based motility in growth cones is neither the growth cone margin (Lamoureux.5 Stages of axon and branch growth. Experimental studies show that the “push” of micro- “push” from the advance of microtubules and “pull” from tubule advance is necessary for neurite elongation. Letourneau. Letourneau et al. the growth cone forward. This process also occurs during the formation of collateral of bundled and meshlike F-actin networks. forming a cylindrical axon often between filopodia. and Consolidation occurs when the majority of F-actin depolymerizes consolidation (Goldberg and Burmeister. Three stages of vesicles and organelles (mitochondria. 1986). However. Engorgement occurs branches off the growth cone or axon shaft. 1981. 2003. letourneau: formation of axons and dendrites by developing neurons 11 . (From Dent and when microtubules invade protrusions bringing membranous Gertler. Buxbaum. around the bundle of microtubules. These extensions are primarily composed shaft. endoplasmic reticulum). Protrusion occurs in the neck of the growth cone.. allowing the membrane to shrink with the rapid extension of filopodia and thin lamellar protrusions.Figure 1. and necessary nor sufficient for neurite elongation. engorgement. axon outgrowth have been termed protrusion.) tension on these adhesive sites generates a force that pulls Heidemann. 1989. Thus neurite elongation involves 1987).

On the other complex in vivo environment. are sufficiently strong or persistent. stabilization.growth cone “pull” accelerates neurite elongation and. because the P-domain expands faster on one side as a or retreat of a growth cone in response to guidance cues result of locally enhanced actin polymerization. while a repel- microtubules in the peripheral domain of growth cones that is lent inhibits actin polymerization and advance of microtubules. microtubule advance on that such as Ca++ or cyclic nucleotides (Gomez and Zheng. In a neutral in vitro environment.6 Summary of reorganization of actin filaments and polymerization. might directly promote microtubule polymerization or domain into the P-domain. 1995). so that microtubules preferentially advance to this elongation may occur first to one side and then to the one side of the P-domain (Challacombe et al. adhesion. 1997. Tanaka and Kirschner. or other signals triggered by extrinsic cues reduce actin-mediated ligands that interact with growth cone receptors to generate protrusion on one side of a growth cone or if myosin II– local differences in the activities of Rho GTPases. advance. Figure 1. is necessary for growth cone navigation.) a repellent guidance molecule. Localized signals of microtubules and organelles from the growth cone C. retrograde actin flow. An attractant promotes actin 12 fundamentals of developmental neurobiology . On the other side. Song and Poo. 2002. protein phosphatases. or second messengers. Guan and Rao. or linkage of actin filaments to As described previously. however. if these local variations in regulatory cues described later. side will be reduced.6.. protein powered retrograde flow of actin filaments increases on kinases. 2003. there are local hand (see figure 1. upper panels). lower panels). This outcome might occur synaptic targets occurs by the selective turning. if local differences in differences in adhesive surfaces.6. 2001). reduced that a growth cone encounters within developing tissues. keeping the growth cone on a straight path. other. and microtubule advance. In a Dickson. and the growth cone will turn toward 2006. a neurite elongates by the advance adhesive sites (figure 1. involved in turning toward an attractant and turning away from (Adapted from Dickson. they produce local differences in actin-based motility and microtubule advance Growth Cone Turning Growth cone navigation to that cause growth cone turning. extrinsic factors. 2002. as the one hand. one side of a growth cone.

and it accumulates of the ventricular zone of the telencephalon to establish the proteins typical of axons. The microtubule-severing protein katanin may mechanisms to generate neural circuits (Tessier-Lavigne and promote branch formation by severing microtubules in the Goodman. such as In a neutral tissue culture environment. which then sprout letourneau: formation of axons and dendrites by developing neurons 13 . In vitro manipulations. These molecules concentrate at Retzius cells of the marginal zone. perhaps by locally activating PI3 model organism. In either case. the advance of microtubules proliferation of neural precursors in the ventricular zone of and organelles into the branch sustains its growth. and the specification of lamellipodia (figure 1. so microtubule polymerization or stability. produced by Cajal- 2005. After one netrin produced by ventrally located cells causes localized neurite becomes the axon. and small Rho GTPases (Arimura and Kaibuchi. It is unclear oldest neurons inhabit the lowest layer VI. Migrating neurons and Banker. Gallo and Letourneau. as well as growth neuron in vitro initially sprouts several similar neurites that factors. ment is never neutral. Wiggin et al. After 18–24 hours one neurite expands its hedgehog and netrin. 1996). while the addition of plasma membrane components. Younger neurons regulating key activities. Branch formation along a neurite initiation and elongation. where reelin. From their birth immature neurons become polarized by asymmetry in local cues. including PI3 kinase. This result may occur when a growth cone “pulls” The previous section focused on the intrinsic mechanisms of in two directions (figure 1. or whether concentration of any of the Axons and Dendrites Neurons sprout axons soon after previously mentioned molecules or signals is sufficient to ceasing migration. outer marginal zone. This localized actin-based phogenesis in the developing human brain. morphogens. Less is known about the mechanisms of dendrite axons. The neutral motility may occur until microtubules enter an actin-filled environment of a tissue culture dish facilitates understanding nascent branch by transport or by polymerization of these intrinsic mechanisms. However. a protein involved in actin motility (Mandell gestational weeks (Ramakers. the axon. the developing brain. neurite branching. In the of axonal specification. a diffusible molecule kinase or other components of the mechanism. dendrites.5). adhesive protein laminin in the underlying extracellular Polarization of Neuronal Form A hippocampal matrix (ECM) of the ventricular layer. migrate past older neurons to reach the marginal zone. or dendrites are formed in two ways: by a growth specification. Once stable Neuronal Migration Immature neurons arise from microtubules are established. Neural migration stops at the complex. regulate dendritic characteristics. growth cone migration neurite is initiated by localized protrusion of filopodia or and turning. These newly born neurons migrate out others. part of the P-domain and associated C-domain may separate from the whole and establish an Regulation of neuronal morphogenesis in vivo independent growth cone and a new branch of the parent neurite. membrane. as early as the seventh week in the cortex. such as concentration of PI3 kinase activity Neuronal Polarization and the Initial Growth of in a neurite tip. the Par cues as they migrate upward. such as the MAPs tau and MAP1B. the in vivo environ- microtubules from the main neurite (Gallo and Letourneau.2. 1998). This neurite becomes the axon. 1996). the acquisition cytoskeletal. whether axonal specification always begins with the same upstream event. Acquisition of microtubules with mixed cone splitting or by a new branch sprouting from the neurite polarities may be important.2). This section will discuss the roles of extrinsic mole- mechanism is particularly prevalent in the branching cules and signaling events in regulating neuronal mor- morphogenesis of dendrites. as well as localization of shaft behind a growth cone. 1. the other neurites become activity of PI3 kinase in young neurons. it is a random focally pulling on a neurite or presenting adhesive proteins decision as to which neurite sprouted from a neuron becomes to one neurite will induce a neurite to become the axon. cortical plate in a wave of migration between 6 and 18 and GAP43. such as sonic extend slowly.. 2005). such as actin filament organization. and signaling components that of stable microtubules is key to forming a branch (figures 1. neurite shaft to create microtubule ends that can be moved into a nascent branch (Baas and Buster. produced by the surrounding growth cone and elongates significantly faster than the neuroepithelial cells. and guidance molecules. but cortical neurons in vivo always sprout their Thus extrinsic signals can influence the intrinsic mechanism axon in the same direction that the axon will grow.Mechanisms of Branching Branches of neurites. Caenorhabditis elegans. including the The Differentiation of Axons and Dendrites. 2004). triggers neurons to cease the tips of newly specified axons and are implicated in expressing integrin adhesion receptors. Microtubule ends in the main neurite may become distribution of axonal guidance cues in the environment of linked to actin filaments of the protrusion and be pulled into the developing brain shape these intrinsic morphogenetic the branch. Several molecules and pathways may be retain their initial polarization and encounter additional critical to axonal specification. specify axonal character. and transport and the upper layer II contains the youngest neurons. This axons. In a growth cone. 2005). and spatial and temporal patterns of 1999).2.

(From Tessier-LaVigne and Goodman. including slit proteins. that is. neurons. Immature cortical pyramidal a growth cone detects and responds to physical and chemical neurons first extend an axon toward the ventricle. but rather in a diate target to which the growth cone navigates. Several proteins have been identified as negative guid- Thus the opposite responses of axons and dendrites to ance cues. because without filopodial and ent (Whitford et al. neurons are attracted by Sema3A. so the “guard rails” to keep growth cones migrating on the proper axonal growth cone migrates away from the Sema3A source. growth cone turns or changes direction as it enters the next nation of Sema3A signaling and high cGMP levels in the segment of its journey. is divided into several segments. these opposite directions of axonal versus μm-diameter axon allows exploration of an expanded dendritic growth are regulated by the same extracellular search area 25 μm or more across. each ending at an interme- sion of membrane receptors for Sema3A. Other factors are implicated in regulating the initial direc. PI3 Sema3A are due to an asymmetric distribution of cytoplas- kinase is involved in axonal specification of mammalian mic signaling components in dendrites versus axons.. which grows toward the pial surface.their axon toward the netrin source (Adler et al. tion of cortical axonal growth. 2002).. Sema3A. Short-range cues on surfaces attract or repel migrating growth cones. When filopodial and molecule. of filopodia and lamellipodia from the growth cone of a 1- Unexpectedly. semaphorin 3A (Sema3A). 2006). The difference in direc. the path tions of these processes lies not in a local difference in expres. path. but they the pial surface and released to create an extracellular gradi. Growth cones integrate that growth cones come into contact with act to promote or inhibit information coming simultaneously from multiple cues during growth cone adhesion and migration. do not navigate accurately. This pathfinding occurs by growth cone navigation.7 Summary of the action of guidance cues that are ible molecules released from intermediate or synaptic targets that involved in growth cone navigation. Often these local difference in distribution of signaling proteins that intermediate targets represent a choice point at which a modulate levels of the cyclic nucleotide cGMP. Axons are repelled by Sema3A. 1996. If the path of a growth cone to its target is long.7). axons grow. while Sema3A signaling in the axon combined with migration. lamellipodial protrusions a growth cone’s search area is too while the subsequently formed apical dendrites of these small to localize guidance cues. The combi. axons follow stereotypical routes to their targets. perikarya. and several Figure 1. and thus localization of PI3 kinase in response to a local cue may both specify axonal identity and regulate Axonal Guidance Once sprouted from neuronal actin motility to control the direction of axonal initiation. acting like actin dynamics and activated myosin II contractility. which depresses ics are expressed adjacent to these pathways. The protrusion by an apical dendrite. Pathways for growth cone navigation apical dendrite promotes actin polymerization and dendritic contain molecules that promote adhesion and growth cone growth. produced by cells near lamellipodial protrusion is suppressed. followed features in its environment (figure 1. navigation. Long-range cues are diffus. Molecules that repress adhesion or actin dynam- low cGMP activates the GTPase RhoA.) 14 fundamentals of developmental neurobiology .

so growth cone corticospinal axons turn laterally to exit the dorsal migration depends on integrating the intracellular signals telencephalon through the internal capsule. from moving medially by expression of the repellent cues. Ncx. The intermediate other molecules are soluble.8 The trajectory of growing thalamocortical and corti. expressed in the subventricular zone (figure 1. Growth cones of corticothalamic and cone is detecting several guidance molecules. At the telecephalic-diencephalic boundary these cerebral cortical development corticofugal axons reach another choice point and split into two groups. The guidance in the developing CNS. 2003). axons emerging from the diencephalon and in the ventral telen. thalamus. growth cone adhesions. suppression of actin polymerization. The molecules lowing section describes specific features of growth cone or cells that mediate this first decision are unknown. internal capsule. Some molecules simply mark a path as positive adhesive contacts that promote actin polymerization and or negative without providing directional information. Netrin-1 is an attractive factor for plate 3. gan- cephalon.) (See in the ventral telencephalon. Th. are released by navigation zone is the first choice point for corticofugal axons. cones of corticocortical axons turn medially. of model vertebrate systems. cific receptor with specific signaling mechanisms. The expression of guidance molecules is and then turn. Semaphorins 3A cothalamic fibers involves multiple steps and both attractive and and 3C steer cortical fibers to penetrate the intermediate zone repulsive guidance cues. while give growth cones traction to migrate. and are distributed in gradients that provide direc. Figure 1. Most of the molecular internal capsule contains the attractant netrin-1. although At eight weeks the earliest corticofugal axons reach their common features of these mechanisms include disruption of first target.ephrinA’s.9 and plate 4). an adhesive retraction of entire axonal branches or segments (Guan and protein that binds growth cone integrin receptors to form Rao.8 and plate 3. both populations of fibers in the internal capsule. the intermediate zone. they are prevented human brain development is included (Ramakers. proteins expressed in ventromedial diencephalon. Ephrin-A5 is involved in sorting thalamocortical axons glionic eminence. 2005). face in response to a gradient of the repellent cue Sema3A. Each negative cue is detected by a different spe. while growth simultaneously triggered from multiple receptors. Growth cone navigation along major pathways during 2002). The fol.. but the timing of the events in As these axons traverse the internal capsule. expressed by the underlying tional information to growth cones.) letourneau: formation of axons and dendrites by developing neurons 15 . EphA4 in the thalamus and ephrin-A5 in the cortex related to each of these steps: Slit is a repellent that steers thalamic are involved in the establishment of topographic connections. neocortex. leading to growth cone collapse and sometimes extracellular matrix and contains laminin. Corticothalamic axons turn toward the thalamus. At any instant a growth ventricular zone. GE. hypothalamus. The intermediate zone is rich in contraction. attracted by Sema3C. slit-1 and slit-2. while corticospinal axons continue caudally.. Navigation of Corticofugal Axons As stated earlier. (From Uziel et al. and activation of RhoA to stimulate myosin II–mediated figure 1. IC. in the ganglionic eminence (Bagri et al. 2006. which along information about growth cone guidance comes from studies with laminin promotes growth through the internal capsule. Hyp. encounter the repellent Sema3A. as they targets. avoiding slit cortical neurons sprout their axons away from the pial sur.

and from the cingulated cortex. cones. hippocampus.9 Schematic diagrams of coronal sections through the levels. Corticospinal axons plate where they extend and branch. these although the callosal path may be “pioneered” by axons repellents are not expressed in the decussation area. The growth netrin. completing the decussation by cones of corticocortical axons are attracted by netrin-1. creating an axonal path that is corticospinal axons now respond to attractants such as followed by neocortical axons to the midline. turn medially in the intermediate zone (Richards. 2004). the axons reach the cortical sub- axons occurs in an interesting manner. 2002). ic. Regions depicted in green express both slit-1 and developing forebrain showing the trajectory of corticospinal (red). 2005). Ten Donkelaar et al. but growth callosum begins forming by 11–12 weeks and is well devel- cones do not enter spinal cord gray matter for several weeks. In humans the corpus The lumbrosacral area is reached by 29 weeks. This exuberant growth of axons followed by retraction of common that the first axons that establish a path become mistargeted axonal segments is a common feature in the “pioneer fibers” that are followed by subsequent growth development of many cortical circuits (Innocenti and Price. below the developing corpus callosum. Corticospinal axons continue toward the hindbrain until The corticocortical fibers that form the corpus callosum they reach the decussation area at 10 gestational weeks in make several guidance decisions after their first decision to humans (Ramakers. that bind actin-based protrusive activity from the axonal shafts. Axons express several Activation of Rho GTPases and ABPs induces localized adhesion molecules. form adhesive contacts that promote growth cone migration. The axonal segments that extend beyond the innervated Growth cone migration along previously extended axons is target are then eliminated via retraction involving myosin a major means of axonal growth in many tracts. and it is II. internal capsule. slit-2. target response to attractants released from their thalamic target. and thalamocortical (purple) axons in rela. caudal ganglionic eminence. to cross the midline. NCx..Figure 1. prevents corticospinal by repulsion from slit proteins expressed by cells above and axons from recrossing as they grow down the spinal cord. corticothalamic (blue). After navigating dorsally and into the Innervation of target areas of gray matter by corticospinal contralateral hemisphere.) (See tion to regions that express slit-1 (blue) and slit-2 (yellow) at selected plate 4. 2005. Although corticospinal axons were previously repelled from The molecules that guide these decisions are unknown. the midline by slit proteins and other negative cues. oped by 18–20 weeks. H. pro- week 17. cells release attractants and express adhesive ligands that or they may recognize early thalamocortical axons and grow specifically activate local regions along the afferent axons. along them to reach the thalamus.) Growth cones of corticothalamic axons may turn in initially extend beyond their target areas. neocortex. caudal to the decussation. slit and duced by midline cells. Renewed expression of midline repellents. including L1 and N-cadherin. 2002. remaining for several 16 fundamentals of developmental neurobiology . and channeled to cross the midline ephrin3B. homophilically to the same molecules on growth cones to followed by collateral branches that grow into the targets. CGE. (From Bagri et al.. Eventually.

2005).) (See plate 5. laminins. slits. 2002). which are not listed individually owing to distinctions mapping in chicks and rodents. The Sema3A induction of growth cone collapse. Once a group of axons reach their synaptic target.. they prior to the entry of callosal axons. For example. 2001). Some growth growth cones turn dorsally and migrate toward the cortex cones cross the ventral spinal cord and only then synthesize within the internal capsule. thalamocortical axons Lu. being attracted cones (Wu et al. that determine the topography of retinal inputs to the tectum ways arises from cell-type–specific differences in expression (figure 1. netrins. 2005). RhoA activity is necessary for by netrin-1 expressed by cells in the internal capsule. 24 weeks they fill the upper subplate and extend branches exploring for their correct cortical targets. in downstream cytoplasmic in an increasing gradient from the anterior to posterior letourneau: formation of axons and dendrites by developing neurons 17 .8). The names and/or distributions of in the individual members expressed and the precise distributions molecules known.Figure 1. and Flanagan. Sema3A rapidly stimulates (Lopez-Bendito and Molnar. By targets. or potentially able. Thalamocortical Patterning Axonal Distribution within Targets axons finally enter the cortex between 26 and 28 weeks. become organized into patterns that represent physiologically The preceding paragraphs have described how axons relevant topography or sensory parameters. preventing recrossing the midline (Brittis. weeks before sprouting collateral branches at 28 weeks into signaling activated by guidance cues. molecules. Molecules other than those listed are likely to mechanisms at each stage are listed. The gradients represent the participate. An interesting recent finding is that growth cone Thalamocortical afferent axons begin their navigation by responses to guidance cues may depend on bursts of local growing ventrally until they are stopped by repulsion from protein synthesis of receptors or signaling components within slit proteins expressed by the underlying hypothalamus a growth cone. this diversity of axonal path. 2003. 2006.e. spatial differences in the expression of guidance cues and their receptors by developing tissues and neuronal popula- Navigation of Thalamocortical Growth Cones tions. However. semaphorins. 2005. Within the internal capsule. keeping lateral in response to slit and express EphA receptors that mediate a repulsive response proteins expressed by the ganglionic eminence (Bagri et al.. The distribution navigate to their targets by detecting and responding to of retinal ganglion cells’ axons in their midbrain target (optic guidance molecules that regulate growth cone motility. and temporal and their appropriate final target regions of the cortex.) consensus distribution for a combination of related molecules (i. figure synthesis of the GTPase RhoA from mRNA within growth 1. and Gradients in the distribution of ephrins and their Eph immunoglobulin-like adhesion molecules are too few to receptors on cells across the optic tectum (or colliculus) and account for the complexity of neural circuitry (Yu and the incoming retinal axons and growth cones are key features Bargmann. Uziel et al.10 Mechanisms and molecules controlling retinotopic ephrin-A’s). which they follow toward their how growth cones detect guidance cues and integrate cortical targets.10 and plate 5). Much remains to be learned about meet corticofugal fibers... Thalamocortical axons penetrate the cortical complex signals to navigate to their intermediate and final subplate between 9 and 18 weeks in developing humans. Then the growth cones turn laterally. to control the dominant between species. to midline ephrins. It tectum or superior colliculus) is a model system in may seem that the relatively limited numbers of guidance understanding this process (McLaughlin and O’Leary. Ephrin-A2 and -A5 are expressed of receptors for guidance cues. 2002). ephrins. (From McLaughlin and O’Leary.

projection have allowed much progress in understanding the Thus intrinsic regulation of cytoskeletal and membrane patterning of developing neural circuits. The identification of signaling activity from the neutral tissue culture environment will form dendritic arbors cytoplasmic domain of ephrin-B ligands indicates that both that are reminiscent of their characteristic in vivo morpholo- ephrins and EphB receptors can activate cytoplasmic gies. 1998). In fact. 2002). The discovery of components combined with availability of extrinsic factors. As physiological events along axonal shafts can rapidly regulate described previously. esis. dendrite formation is intrinsic to the and their EphB receptors among retinal axons and tectal neuronal phenotype. stimulating growth cone repulsion. These activity. and that subsequent remodeling of factors. proteoglycans. so they stop and innervate the anterior tectum. the The patterning of inputs to a target depends on activities apical dendrites of cerebral cortical neurons are formed distributed along the afferent axons. inputs and interactions with axon terminals (Van Aelst and figure 1. Visualization of the morphogenesis of individ- the development of circuits in other regions (Flanagan. EphA receptors bind ephrin-A ligands and trigger cadherins. produced dynamics and myosin II activity to induce retraction or addi. at the pial surface. and decreased Rac1 and Cdc42 activities and increased RhoA neurotrophins (Lopez-Bendito and Molnar. Like the tectal axis involves gradients in the distribution of ephrin-Bs formation of axons. 2004). and corticocortical axons to terminate in the correct layer. actin filament and microtubule dynamics operate to drive lateral tectal axis. The discovery of gradients in expression of ephrins-A2 Generally. of dendrites. as described in the following paragraphs. because they are less repelled by the ephrin-A gradient. ephrin ligands. for example. axons. fish has revealed rapidly changing addition and loss of small In addition to the development of the correct distribution branches and arbors as dendrites interact with afferent of axons within a target.. Filopodia transiently extend from dendritic shafts and neurons with which they make synapses. expressing lower levels of EphA Development of dendrites receptors. the same basic mechanisms of signaling to regulate axonal targeting along the medial. as regulated by these and may be due to both environmental factors and intrinsic gradients. and more elaborately branched than by gradients of cell surface ligands and receptors was pro. Thus determined by the relative levels of EphA expression by dendritic arbors are critical to the processing of neural infor- growth cones. gradients in the distributions of ephrin-A and EphA recep. Other extrinsic proteins produced by tion of collateral or terminal branches along developing neighboring cells or afferent axons promote the formation axonal shafts (Gallo and Letourneau. the apical dendrites of cortical neurons activities of RhoA or Rac1 and Cdc42 to regulate actin are oriented by an attractive response to Sema3A. membrane. a neuron initiates dendrites after it is actively and -A5 confirmed Sperry’s hypothesis. that gradients of interacting ephrins and their receptors have However. The distances that The dendritic arborization of a neuron contains the synaptic retinal growth cones migrate along the anterior-posterior inputs to the neuron and is where synaptic inputs are tectal gradient of increasing ephrin-A expression are integrated before the initiation of action potentials. and nascent syn- lamina-specific manner in the developing cortex. This lag may be several days. shorter. orchestrates tors in the neocortex and thalamus. in addition to the from the leading process with which immature neurons growth cones. It has become clear engaged in axonal elongation. indicates the initiation and elongation of branched dendritic arbors. respectively. the for- similar roles in regulating axonal guidance and patterning mation of dendrites is a prolonged activity. extend to the posterior tectum. many of these contacts and 18 fundamentals of developmental neurobiology . that the initial distributions of axons. although dendrites are more This mechanism for topographic mapping of connections numerous.8). be determined by previous cell interactions. such as osteogenic protein-1 and neurotrophins. while nasal retinal growth cones. 2003). As described earlier. is not final. and signaling proteins. Similar mechanisms may operate in patterning Cline. axons must recognize the target axons. 2006. including apses may form. Local signaling by guidance cues or other had migrated from the ventricular lining of the cortex. Retinal mapping along the medial-lateral mation for behavior and other neural activities.tectum. The sites of dendrite initiation from a neuron may activities is necessary to create more precise neural circuits. due to expression of dendritic-specific cytoskeletal. different neuronal types in a cells. and the final of thalamocortical connections to their targets in the primary shaping of dendritic arbors depends heavily on afferent sensory regions of the cerebral cortex (Uziel et al. However. surface and extracellular molecules are expressed in a the dendritic filopodium may be stabilized.. and if contacts are made with axonal growth cones. posed by Roger Sperry (1963) as the chemoaffinity hypoth. Eph receptors. Several cell termini. Growth cones of molecular differences may provide cues for thalamocortical temporal retinal axons express high levels of EphA receptors. including osteogenic protein-1 (BMP7) and The accessibility and simple anatomy of the retinotectal neurotrophins BDNF and NT-3 (Whitford et al. such as changes in expression of specific cytoskeletal axons due to further cellular interactions and physiological proteins. ual dendrites in developing brains of living frogs and zebra 2006). the formation of dendrites.

other cellular interactions. The final shaping of arborizations of than in the visual cortex.or threefold and reaching nisms that regulate the orientation and rates of dendritic the adult levels by 1–2 years. of more dendritic filopodia and elaboration of dendritic These measures of dendrite elaboration in the developing branches.synapses are brief. 2004). New ing Golgi staining of fixed neurons. modulate actin filament dynamics that underlie the exten. cells. synapses are added. growth. guided by positive and negative in conjunction with synaptogenesis and the increased responses to surface-bound and soluble molecular cues. Synaptic activity is a factor in elongating. component. or the agrin receptor postnatal experience. may be a retrograde signal that stops ronal mechanisms that respond to extrinsic regulatory inter- axonal growth in synaptic regions. and physiological branches develop prenatally. electrical stimulation by axons. Yet. once innervating axons arrive in the cortical signaling that regulates actin filament organization. Human Brain Neurons begin to form dendrites soon while the actin-based motility of growth cones at the ends of after they initiate axon formation. while signaling at more mature synapses may gen. Total dendrite length of pyramidal Formation of dendrites begins before afferent axons arrive neurons in the visual cortex increases rapidly in the first few and involves interactions of intrinsic and extrinsic mecha- postnatal months. dendrite formation accelerates as a ical forces. Motor a dynamic flux of intercellular molecular signaling. cortex. Neural circuits arise by a morphogenetic process in which Nitric oxide. mechan- plate at 26–28 weeks. extend abnormally long distances across muscle surfaces. and letourneau: formation of axons and dendrites by developing neurons 19 . The roles of these synapses in regulating den. Much remains to be of axonal terminals is also dependent on interactions with learned about how axonal and dendritic shapes are sculpted dendrites and postsynaptic contacts. Binding of guidance on cortical pyramidal neurons by 12–13 weeks’ gestation. and postnatal growth involves activities adjust and refine axonal growth and branching dendritic lengthening by terminal growth of branches as within a target to achieve more accurate axonal topography. consistent with the greater dendritic and synaptic dritic growth may also change as the synapses mature. human brain are mostly based on anatomical studies involv- erate stop-growing signals to stabilize dendritic arbors. increasing two. compared synaptic activation at early synapses may stimulate formation to unimodal primary cortical regions. In the visual cortex most dendritic aptogenesis. Apical dendrites are present ronments for molecular guidance cues. tion. and transform to a presynaptic ending. as mentioned earlier. 2005). while after the first year most growth occurs by dendritic morphogenesis. Dendritic growth accelerates when axons arrive and synaptogenesis and dendritic growth proceed more slowly initiate synaptogenesis. These data are static and excitatory synapses contain NDMA receptors only. implicating MUSK and agrin in an Summary axonal “stop signal. stop. at age two the average dendrite length per neuron in the sion and retraction of dendritic filopodia (Van Aelst and prefrontal cortex is longer than dendritic length in the visual Cline. most dendritic growth occurs postnatally of intermediate targets. and activation of NMDA recep. which is released by dendrites in response to axons and dendrites are formed according to intrinsic neu- synaptic activity. branching.” The neuromuscular junction contains a laminin isoform. cone migration. actions with molecules. genesis. on axons and target cells. Addition of AMPA recep. and the unpredictable physiological activity of receptor-aggregating protein. In humans. as the result of interactions between interactions may signal growth cones to reduce their dynamic genetically defined mechanisms of neuronal growth and activity. turning. and fail to account for the dynamic activities of dendritic elonga- AMPA receptors are added later. physiological experience and activity of postnatal life. such examined most thoroughly in the visual cortex and prefrontal as ephrins and Eph rceptors. although dendrites are elongating processes allows exploration of local tissue envi- initially short and slow growing. synapto- axons growing on muscle fibers of mice that lack the Ach. The driving force for axonal and dendritic growth Dendritogenesis in the Prenatal and Postnatal is the advance of microtubules and associated organelles. and features of the developing organism. and branching. In the prefrontal cortex. elongation of branches. and retraction that are revealed from real- tors to synapses may be required for retention of synapses time visualization of dendrite growth and synaptogenesis in and stabilization of dendritic arborizations. During the first postnatal year the dendrites and axons depends on mutual interactions. and the terminal axonal and dendritic length of dendrites increases 5. MUSK. complexity in the more integrative cortical regions. The final shaping living embryos. Axonal growth and the release of neurotrophins and other factors from cones reach their synaptic targets by navigating to a series axons. agrin. By two years of age the total dendritic tors at nascent synapses may regulate Rho GTPases to length per pyramidal neuron is only half the adult level.to 10-fold by branching and branches may be retracted. and microtubule advance to locally direct growth result of synaptic contacts. Post. Retrograde synaptic over a period of years. cues to their receptors on growth cones triggers cytoplasmic However. S-laminin. that inhibits axonal growth. Syn- cortex (Ramakers. Axonal projections within a target are initially patterned Dendrite formation in the developing human brain has been according to gradients in the expression of molecules.

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cognitive correlates of brain structural maturation. MRI is ideal for use in developmental populations. which are reviewing the postmortem literature. In vivo neuroimaging methods younger age ranges. ter accuracy. work in the early 1980s charted the time courses of synap- they allow for visualization of changes occurring at the togenesis and synaptic pruning. Postmortem studies: Synaptic modification and myelination Much progress has been made in characterizing structural brain development during the past few decades. these neurons undergo dendritic brain morphology.2 Imaging Developmental Changes in Gray and White Matter in the Human Brain ELIZABETH D. Particular emphasis will be given to cortical gray postnatal. We start by process of progressive and regressive changes. His series of histological cortical surface and throughout the brain that are unbiased studies demonstrated that synaptic density is high at birth by the observable sulcal cortical boundaries necessary for and continues to increase throughout the first year of post- making the anatomical delineations required by volumetric natal life. their generalizability. that used volumetric methods. as recent advancements in our laboratory Human brain maturation is a dynamic and complex process have allowed for the measurement of cortical thickness in that extends well into adulthood. Huttenlocher’s pioneering matching (CPM). provide certain advantages. synaptogenesis. Both approaches have distinct advantages and safety. and Jessell. A major concern with postmortem studies is where studying individuals at multiple time points is neces. such branching and arborization. We will briefly review the experience-dependent plasticity. Synaptic density then shows a marked decrease 23 . As the newborn brain grows in highly intuitive and critical for assessing global changes in size and complexity. disadvantages. as it may help elucidate the specific neurobiological changes underlying the maturation of a variety of cognitive processes. Specifically. largely Prior to the advent of neuroimaging tools. myelination. reaching its maximum between 12 and 18 months studies. level with MRI. an issue of critical importance in developmental cogni. SOWELL Introduction matter and peripheral white matter differentiation across development. At birth the human brain earliest quantitative imaging studies of brain development contains on the order of 100 billion neurons (Kandel. changes in MR signal values that are only indirectly linked tive neuroscience. while we The main focus of this chapter will be on neuroimaging cannot directly measure structural changes at the cellular studies of normative brain maturation that have been per. Although these studies are Schwartz. despite the advantages asso- also have the distinct advantage of allowing for investigations ciated with performing in vivo MRI imaging in developmen- into the relationship between brain structure and brain func. demonstrating the throughout the brain and have advanced our understanding validity and compatibility of these methods. O’HARE AND ELIZABETH R. as voxel-based morphometry (VBM) and cortical pattern and ultimately synaptic pruning. sophisticated mapping techniques. Because of its relative mortem data. of the timing and localization of alterations in gray and white Brain development can be characterized as a dynamic matter that occur throughout development. millimeters across the entire brain surface with submillime- mental changes in brain structure is of fundamental impor. tal populations described earlier. In contrast. We conclude with a discussion of potential tance in the field of developmental cognitive neuroscience. researchers were because of the availability of noninvasive imaging tools such limited to inferring structural brain changes from post- as magnetic resonance imaging (MRI). Understanding develop. 2000). the spatial and temporal patterns of matu- formed with a variety of brain-mapping techniques. these techniques measure tion. These rational change observed in recent imaging studies reflect studies have allowed for the mapping of structural changes patterns that were observed postmortem. to cellular changes in the brain. due to the questionable normalcy of sary to characterize longitudinal maturational changes in participants studied after death and the lack of samples from brain structure and function. and then turn our influenced by both complex genetic programs and attention to the in vivo literature. Nevertheless.

Synaptic pruning in this region is offset relative to cognitive control (Carter. and not just to the effects of synaptic pruning owing to the effects of experience-associated synaptic and cell loss. Interestingly. Giedd and col- onstrated the progressive spread of intracortical myelination leagues have suggested that reductions in synaptic density into frontal and parietal cortices during the first four decades are unlikely to account for the large volume decreases in of life. Studies examining the patterns of myelination in the axonal myelination are the hallmarks of experience-based developing brain show that this process also follows a specific neural plasticity and are consistent with the principle of spatial and temporal pattern (Brody et al. In contrast. Schwartz. Postulated to be the tion is thought to progress from inferior to superior brain basis of the formation of cognitive networks that underlie regions and from posterior to anterior regions. Synaptic pruning then begins and contin. 1994). peak synaptic here could be on axons originating in the cingulate gyrus. Jessell. and Cohen. presumably cortical ribbon. increasing size of glial cells attributable to myelination is in part. cerebellum myelinates prior to the cerebral hemispheres. In primary visual cortex. changes observed in neuroimaging studies. Brody adolescence. Botrinick. and et al. fragmentary evidence for brain maturational changes in late In contrast.. evidence for a possible relationship between occurring in middle and late adolescence (Huttenlocher and improved functionality and increased myelination. Bunge et al. Thus neurons and synaptic connections during infancy and early myelination of the brain regions responsible for higher cog. childhood and adolescence. Furthermore.. the second and third decades of life (Yakovlev and Lecours. is still occurring neural activity via synaptic pruning that continues well into throughout adolescence (Yakovlev and Lecours. human brain are being myelinated. Furthermore. As dis- Dabholkar. nal connections that are in turn continuously changing with tuning of cognitive control and executive function (Cohen experience (Post and Weiss. synaptogenesis occurs more the first and second decades of life within the superior med- rapidly after birth and reaches a maximum at about 4 ullary lamina of the parahippocampal gyrus (Benes et al. 1982). the higher cognitive processes (Post and Weiss.. out development. vivo studies is the ability to relate changes in cortical struc- esis and synaptic pruning. childhood followed by activity-dependent fine-tuning of nitive functioning. the association cortices of the frontal and pari. Huttenlocher et al. 2000). 1999). This proliferation of myelination into the cortex gray matter observed throughout development and that the appears to result in gray matter “thinning. 1997). 1997. 1967. myelination show pronounced age-related change (Albert questions remain as to whether synaptic pruning or axonal and Knoefel. Myelina. because of the underrepresenta- etal lobes that are characterized by an extended period of tion of postmortem data from this age range. 1993). a major advantage of in In addition to the developmental processes of synaptogen. The work of Kaes in 1907 was among the first to illustrate Despite the characterization of the processes of synaptic this complex relationship between age and the myelination pruning and axonal myelination that are occurring through- of cortical regions known to subserve distinct cognitive func. Early work by Yakovlev Taken together. 1994). strated that the primary cortices in which the myelination Thompson. the postmortem studies that we have and Lecours demonstrated that myelination begins late in described illustrate that the brain is undergoing progressive the second trimester of fetal development and extends into and regressive age-related changes throughout development. the neurons of the developing ture with changes in cognition and behavior. with the most substantial decline indirect. That is. although pruning lasts longer. Histological studies yield only process is completed earlier show little age-related change. the relationship between postmortem find- tions. and Toga. Composite maps of cortical thickness in myelination contributes most to the gross morphological individuals ranging from 3 months to 97 years of age dem. this process involves the initial overproduction of and the occipital lobes prior to the frontal lobes. the extent of myelination relative to brain weight between tion.” Thus Kaes’s balance between the decreasing number of neurons and the work suggests that loss of cortical thickness with age is due. 2002). at which point synaptic density and indicate that some of the axonal myelination occurring in this region reaches adult levels.. a maturational period marked by the fine. selective specialization (Edelman. Concomitant reductions in synaptic density and increases in 1967). pruning.. prefrontal work of Benes and colleagues provides additional. cussed in the sections that follow. 2002). in certain brain regions was demonstrated by the work of 1979. This then leads to efficient networks of neuro- et al. 1997. ings and those from in vivo studies remains unclear (Sowell. The that of primary visual cortex. 1987). the dorsal frontal lobes. to an increased proliferation of myelin into the primarily responsible for determining the overall size of 24 fundamentals of developmental neurobiology . 1987). The authors describe the connectivity of this region ues to about 4 years of age. ultimately decreasing to about 60 percent of the Further evidence for an extended period of myelination maximum value attained shortly after birth (Huttenlocher. Fuster..between late childhood and early adulthood. months postnatal. this pattern Benes and colleagues who observed a 95 percent increase in of synaptic formation and elimination shows regional varia. 2000. 2004). a density in the prefrontal cortex is not attained until 3–4 years region known for playing a critical role in the regulation of of age. These postmortem studies of cortical width demon. Kandel.

As with the histological studies been reliably identified and manually defined. individual growth patterns.. et al. 2002). 1982) and of Yakovlev and Lecours (1967). volumetric studies also suggest regional the need for more accurate localization of maturational differences in the extent of gray matter loss during childhood changes.. 1996.. given that only gross lobar structures.. 1999. all seem to finding with the observation that the timing of gray matter agree that regionally specific patterns of gray matter loss loss had different trajectories depending on the brain region. 2004). the brain is subdivided into studies have reported an initial increase in gray matter separate anatomical regions via either stereotaxic coordi. et al. Snell. 2002).. et al. Gogtay et al. 1991). then declines during the adolescent and postadolescent et al. Trauner. white matter. the fact that the young adults had larger total brain volumes. Taken together. It may be that this nonlinearity in gray matter lobar region definition (Giedd et al. In contrast. Tallal (1990) reported that children (ages 8–10) had signifi. Volumetric studies Delis. Archibald. regarding the regional and temporal patterns of Although volumetric studies provide further evidence for cellular maturation.. gender. these studies demonstrate early work of Kaes described previously illustrates the pro. this was the first in vivo morphological evidence to support the Whole-brain mapping methods: Voxel-based morphometry postmortem findings of Huttenlocher (Huttenlocher. these studies are gray matter volume decreases during development have unable to precisely localize maturational changes in the been reported by several other groups (Pfefferbaum et al.. et al. et al. in frontal and parietal lobes. 1991. The relative contribu. 1996). Further. resulting in what appears to be cortical cortices of the parietal and frontal lobes.. Further- temporal and spatial patterns of synaptic pruning and more. 1999. These methods. Despite A second study by Jernigan and colleagues extended this differences in findings between research groups. Trauner. there is evidence to suggest that the observation of myelination across the brain. Reiss et al. studies did not measure synaptic density directly. Sowell.. or automated periods. depending on nates (Jernigan. in contrast to those reporting progressive gray matter loss cantly more cortical gray matter than young adults.. density that peaks between ages 10 and 12. cortical out child and adolescent development. volume change is due to methodological differences. Reiss et al... In the first quantitative have come from studies where the youngest subjects studied structural MRI study in normal children. methods were developed that allowed for the o’hare and sowell: imaging developmental changes 25 . In this approach. The earliest gray matter loss occurred in the deep motor this pattern appears consistent with what would be expected nuclei around early childhood and then later in the associa.. 1979. Trauner. 1999). (VBM) Huttenlocher et al. 1999). even in the presence of large Given postmortem findings of regional differences in the between-individual variation (Giedd et al.brain structures (Giedd. as those tion and volumetric measurements are then used to estimate studies reporting initial increases in gray matter have been the volumes of gray matter. Jernigan and were 4 years of age (Giedd et al. have 1994.. “thinning” during that time period. given the results from postmortem studies and given the tion cortices of the parietal and frontal lobes during early known pattern of cognitive developmental changes that adolescence (Jernigan. brain. A significant the focus of the remainder of this chapter.. Interestingly. the and adolescence. despite (Jernigan. 2004). Tissue segmenta.. Gray matter density manual definition of regions of interest (Giedd. with increasing age. thus far. and cerebrospinal longitudinal in design and have had more power to detect fluid (CSF) within each lobe or region of interest. developmentally related nonlinear age effects on gray matter is contingent upon the changes in gray and white matter volumes would be expected age range examined. continued gray matter loss and white matter gain through- Since the initial work of Jernigan and colleagues.. 1999. the ventral aspects of the temporal lobes change tions of myelination and synaptic pruning to the global less dramatically between childhood and adolescence (Giedd changes in brain size or cortical gray and white matter et al. Gogtay et al. highly significant decreases in gray matter along with con- liferation of myelin into the cortical ribbon during childhood comitant increases in white matter in the dorsal association and adolescence.. et al. Sowell. Vaituzis. 1991. 1996). et al. It is important to note that some studies have observed Some of the earliest quantitative brain imaging studies in nonlinear age effects on gray matter volume in various corti- children and adolescents used volumetric parcellation cal regions (Giedd et al.. To address described previously. Archibald. distributions observed across development may in part be these structural changes appear to be related to the changing elucidated by findings from brain-mapping studies that are cognitive capacities of children and adolescents. 1996).. positive correlation between frontal gray matter volume and performance on a verbal learning task was observed in a Anatomically based parcellation methods: study investigating brain-behavior relationships (Sowell. Reports of initial gray matter increase to show similar regional differences. Trauner. Although these occur during adolescence. occur during late childhood and adolescence. where the youngest subjects were 7 years old. 2002). Sowell. Furthermore. et al. 2001).

In a similar study. This is problematic because considerable variability in anatomical regions are likely not well matched across sulcal patterns exists across individuals and across cortical subjects.. this finding suggests a relationship between increased myelina- tion and development of cognitive functions (Paus et al. In contrast. 1999b). These maps are three- in frontal regions makes sense when one considers that the dimensional renderings of statistical maps shown inside the transparent cortical surface rendering of one representative sub- cognitive functions typically ascribed to the frontal lobes. adolescence. 2004. 2002). et al.1 and plate 6). Thompson. Areas in color represent clusters of gray matter density reduc- figure 2.. and adulthood. between childhood and adolescence.) (See plate 6.. et al. These methods rely on automated image reg.. 2000) to localize age-related gray matter density reductions between childhood and adolescence (Sowell. Modifying methods initially used to analyze functional imaging data. 1999a). with relatively little gray matter loss in effects. and subcortical regions (green) (Sowell. VBM methods are not without adults (Narr et al. 1999). ject’s brain. show pro. Thompson. 2000). location within the representative brains. Color coding is applied to each cluster based on its known collectively as executive functions (EF). (Luders et al. Thompson. cortical jects.. 1999b). Results from these analyses revealed that the frontal and parietal gray matter volume reductions observed in the volumetric studies of brain maturation resulted mostly from gray matter reductions in diffuse dorsal regions of these association cortices (Sowell. et al. and Toga. Thompson. A third study elucidated the full spectrum of structural brain maturation by using VBM to examine the pattern of maturation between adolescence and adulthood. Thompson.. The main advantage of VBM over volumetric parcellation methods is that it allows for the automated measurement of developmental changes in gray or white matter throughout the entire brain via spatial normalization of volumes into a standard space and the scaling of images so that each voxel coordinate is anatomically comparable across subjects. et al.. et al. 1999a.assessment of structural changes in brain tissues on a voxel- by-voxel basis. the pattern of cortical changes between adolescents and adults Figure 2.) Cortical mapping methods: Gray matter density regions. lengthy course of structural development characteristic of temporal lobes (blue).1 VBM reveals the full spectrum of gray matter density loss across childhood. Thompson. This postadolescent gray matter loss tion observed between these age groups. 26 fundamentals of developmental neurobiology . Diamond. mesial. the bottom panel shows the same maps for adolescent minus the parietal lobes (Sowell. 2001). however. ized without taking sulcal variability into account. Paus and colleagues used VBM to assess white matter changes in children and adoles- cents and observed significant age-related increases in white matter density within the left and right internal capsule and the posterior portion of the left arcuate fasciculus (Paus et al. tages over volumetric studies.. and shows the child minus adolescent statistical map for negative age orbitofrontal cortex.. 1999b) (see adult. parietal lobes (red). As these white matter pathways connect regions known to be important for speech and motor functions. our laboratory used voxel-based morphometry methods (VBM) (Ashburner and Friston. variability in children (Sowell. when brain volumes are normal- istration techniques to normalize brain volumes across sub. and between males and females shortcomings. The top panel was localized to large regions of the dorsal. 1999a). (Reproduced with permission from Sowell.. corti- cal changes were distributed in frontal and parietal regions (Sowell. 1997. et al. Clusters are shown in the tracted courses of development that appear to parallel the frontal lobes (purple). As described earlier. Thompson. this region (Fuster. Studies have demonstrated significant cortical sulcal Although the VBM methodological approach has advan. Thus. occipital lobes (yellow). 1999). 2004).

maps in figure 2. cortical point (Thompson.3 and plate 8 (Sowell.e. gray matter density was inversely correlated with brain Fuster. In addition to these observations suggest that the apparent thinning of evaluating local changes in gray matter over the brain o’hare and sowell: imaging developmental changes 27 . Sowell et al. and given that we reported a significant nonlinear decline in gray matter nonmyelinated peripheral axonal and dendritic fibers do not density with age. little work has been done to evaluate relationships between 2001). in contrast to the pronounced of interest at anatomically matched points across all subjects.. this tissue posterior region (perisylvian cortex) until about age 30 (see would have an MR signal value more similar to that of gray figure 2... these results show local brain growth in the same this issue is discussed later. although the precise variability and to improve spatial normalization. Thompson.. The cortices that are known from matter.. we observed Leonard. sulcal landmarks. postadolescent decrease in gray matter density characteristic and statistical analyses can then be used to help localize the of the dorsal frontal and parietal lobes. Leonard. characterized by during the postadolescent years. etal and frontal lobes (Sowell et al. we observed gray matter thickness increases in the left measure developmental changes in gray matter density in inferior frontal sulcus (i. gray postmortem studies. Sowell. This decline was most rapid between ages have normal white matter signal values on T1-weighted 7 and 60. Thompson. we observed gray supported by studies showing the time between childhood matter density reductions most prominent in the parietal and adolescence as a period of intense learning and modifi- cortices during childhood. et al. In a sample of 176 normal individuals tissue that has a gray matter appearance. highlight the combinatorial nature of regressive (synaptic manually defined in each individual. small increases in effects of age. histological studies to myelinate earliest. Rather. An increase in the amount of to create plots of linear and nonlinear effects of age on gray myelin could also result in a reduction in the amount of brain matter density. 2004). Later. 2002. changes in gray matter growth. 2003. these methods can account for interindividual differ. the primary VBM. et al. tions. Rosso et al. and was localized to the dorsal frontal and parietal MRI (Barkovich et al. Unfortunately. cation of language functioning (Sakai. on both the lateral and medial surfaces fibers in the peripheral cortices would not stain for myelin in of the hemispheres (Sowell et al. Thompson. this loss in gains in executive functioning (Luciana and Nelson. 2004). A reduction in the number of cortical synapses could changing brain morphology and changing cognitive func- result in the observation of reduced gray matter density. more linear pattern of aging than either the posterior tem- we would not see local brain growth during the same time poral language regions or the associative cortices of the pari- frame in the same cortical regions.. that is. showed a by regressive changes such as synaptic pruning or cell loss. 2005). et al.. 1988).. speculation that cortical thickening may be specifically jects described previously. et al.. 2003). white matter structure in the developing human brain.. regions that showed gray matter density consist of cortical thinning in the frontal regions typically reductions were also expanding. 2004). 2003). 2004). Because relationship between brain growth and gray matter density CPM allows for cortical anatomy to be matched across sub. related to gains in language processing. This unique pattern of gray matter a pattern of gray matter density change that was expected thickening specific to primary language regions leads to the given the results from the volumetric studies in the same sub. spatially and temporally concomitant with cortical thinning ences in cortical sulcal patterns. Broca’s area) (Sowell. Mega. namely. loss remains unclear.. nonmyelinated axonal association cortices. Thompson. The studies to be discussed here quantify local gray matter density between childhood and young adult- gray matter using a measure termed gray matter density. the in vivo findings of brain growth jects. as suggested in the ranging in age from 7 to 87 years studied cross-sectionally. CPM studies have used regression analyses (rather than brain shrinkage). Cortical pattern matching (CPM) methods were devel. 2002. These methods allow for the comparison of cortical features As mentioned previously. but some recent work from our laboratory addressing However. and would thus appear more like gray matter density gain occurred with increasing age in the left matter at a gross level in MRI. taken together. et al. regions where gray matter density reduction is occurring More recently. 1998. 2001. In contrast. 2002) (see figure 2. In summary.2 and plate 7).4 and plate 9). several different populations. cortex (loss of gray matter density) could also result from oped to address the problem of intersubject cortical surface increased myelination.. In a longitudinal study of normally developing chil- Our colleagues and we have used CPM techniques to dren. That is. and CPM studies described earlier was caused only visual and auditory cortices and limbic regions. Sowell. Furthermore. In the first of these. Interestingly. followed by a dramatic accelera. postmortem work by Kaes described earlier. Reporting on a sample of 35 indi. This notion is further viduals between the ages of 7 and 30 years. Thompson. If the loss of gray matter observed in the volumetric. are used as anchors to pruning) and progressive (myelination) changes in gray and drive fluid-warping algorithms (Thompson et al. et al. With CPM. as shown in the composite associated with these executive functions. hood have now been observed in bilateral posterior perisyl- This measures the proportion of segmented gray matter in vian regions in three independent samples of normally a small region of a fixed radius (15 mm) around each matched developing individuals (Sowell. during tion in gray matter density loss in the dorsal frontal lobes the adolescent and postadolescent period..

These are the contours drawn on each individual’s surface rendering according to a reliable. Thompson. In actual analyses. note that the upper sphere has a higher gray matter density than the lower sphere as it contains only blue pixels (gray matter) within the brain. Sulcal lines are shown where they would lie on the surface in the cutout region.2 Cortical pattern matching methods and gray matter density. Top left: Three representative brain image data sets with the original MRI. The lower sphere also contains green pixels (white matter) that would lower the gray matter proportion within it. written protocol (see also figure 2. In the blown-up panel. Top right: Surface rendering of one representative subject with cutout showing tissue-segmented coronal slice and axial slice superimposed within the surface. and surface renderings with sulcal contours shown in pink. and Toga. tissue-segmented images. Note the sample spheres over the right hemisphere inferior frontal sulcus (lower sphere) and on the middle region of the precentral sulcus (upper sphere) that illustrate varying degrees of gray matter density. (Reproduced with permission from Sowell. Bottom: Sulcal anatomical delineations are defined according to color.5).) (See plate 7. 28 fundamentals of developmental neurobiology Figure 2. 2004.) . gray matter proportion is measured within 15-mm spheres centered across every point over the cortical surface.

Figure 2. A total of 52 images from the 13 While gray matter loss in these regions shows a protracted o’hare and sowell: imaging developmental changes 29 . Gogtay and colleagues change suggest that loss of gray matter is most prominent in (2004) reported on a sample of 13 individuals between the the association cortices of the frontal and parietal lobes.05). While gray imaging sessions..05). Taken together. change). regions of greatest gray matter density reduction are statistically the A similar composite map for the adolescent-to-adult age effects is same as the regions with the greatest brain growth. Highlighted in red are for DFC. Highlighted in white are the between brain growth and reduction in gray matter density. and top et al. these CPM studies of gray matter density tive human brain development. showing that the relationship between In red are regions of overlap in the gray and DFC statistical maps. regions in the adolescent-to-adult contrast. reaching its peak around change that first appeared in dorsal parietal and primary age 50. The color bar represents corresponding in gray matter in the child-to-adolescent contrast (A). Thompson. the authors note that maturation of limit this variance and increase external validity and lower-order visual and somatosensory cortices occurs before generalizability. frontal cortex (Gogtay et al. Despite this comprehensive char. or DFC) and changes cence and adulthood (D). Composite statistical maps (top) for the age effects for gray matter density and the age effects for showing the correspondence in age effects for changes in brain DFC between childhood and adolescence (C) and between adoles- growth (defined here as distance from center. Shown in images in the lower part of this figure (left. In one of the first longitudinal mapping studies of norma.. sensorimotor regions between the ages of 4 and 8 years. ages of 4 and 21 years. loss over time revealed a shifting pattern of gray matter white matter volume first increased. matter density (P = 0. right. and CSF across the age range. we also plotted the total volumes of gray matter. and in blue is the probability map of all regions of signifi. Note the highly spatially consistent relationship the adolescent-to-adulthood years.) (See plate 8. indicating that the maps (gray matter and DFC) are nearly identical in many frontal change with age is in the same direction for both variables (i.3 Reductions in gray matter density are occurring in views) are the difference between Pearson’s correlation coefficients the same locations as brain growth. subjects were analyzed with approximately 2 years between white matter. and finally extended anteriorly into dorsal control for interindividual variance in brain maturation. Animation of the trajectory of gray matter matter volume declined continuously with increasing age. particularly in also shown (B). 2003). acterization of the effects of age on both local and global Gray matter loss then spread laterally and caudally in tem- measures of brain structure. The regions where the difference between correlation coefficients for shapes of the regions of greatest age-related change for the two the gray matter and DFC maps is positive. Shown in Z scores ranging from −5 to +5 for the difference between correla- green is the Pearson’s R map of all positive correlation coefficients tion coefficients for DFC and gray matter. (Reproduced with permission from Sowell. regions of significant negative correlation between DFC and gray cant gray matter loss (surface point significance threshold P = 0. and then declined. 2004). cross-sectional studies cannot poral cortices.) surface. 2001.. that of the higher-order association cortices.e. Similar to our findings Longitudinal studies are ideal for this purpose because they (Sowell et al. Very few regions of gray increased DFC change goes with increased gray matter density matter density reduction fall outside regions of increases in DFC..

Figure 2.. most prominently in right tory has recently developed similar methods by using the dorsal frontal and bilateral parietal regions. 2003). We with age up until approximately age 30 before a subsequent measured gray matter thickness in millimeters in a sample decline (Sowell et al. surements were taken. Jones. 2001). Notably. mately 0. 2004). In contrast to this pattern. our data (Fischl and Dale. the similarity of these patterns of results two years between scans. probably because of increased myelination in the A recent study by our group combined a longitudinal same anatomical regions. Shown is a surface rendering of a human brain gray matter density plotted on the x-axis and age (in years) plotted (left hemisphere.15–0. von Economo in his postmortem sample (von Economo. Thompson. 1929). Kabani et al.. course that extends into the postadolescent years. right is posterior) with scatter plots on the y-axis (Sowell et al.5 and plate 10). 2003). and thinnest in primary visual Studies of gray matter density changes are difficult to inter. Although the precise nature of of 45 normally developing individuals between the ages the cellular changes underlying these in vivo observations of 5 and 11 years. 2001). cortex along the banks of the calcarine sulcus in the medial pret because they must be reported as a percentage change aspect of the occipital lobe (less than 2 mm) (see figure 2. matter loss has a different trajectory in primary sensorimotor which automatically determines cortical thickness through- cortices. (See plate 9. Each subject was studied twice with remains unclear. and Aharon.30 mm per year. 2000. revealed statistically significant cortical thinning of approxi- 2000.... these out brain volumes with submillimeter accuracy (see figure patterns of gray matter loss are complemented by brain 2. Both maps revealed that cortex was thickest in Cortical mapping methods: Gray matter thickness the most dorsal aspects of the frontal and parietal lobes (approximately 4–5 mm). gray three-dimensional Eikonal fire equation (Sapiro. et al. the design with gray matter thickness measurements to map posterior temporal lobes show subtle increases in gray matter changes in cortical gray matter across development.) for gray matter density at various points over the brain surface. left is anterior. with ferent brain regions. The axes for every graph are identical.6 between one group and another (Sowell. Buchbinder. Miller et al. where it begins and ends earlier. Methodological advances now allow In addition to the striking correspondence of this in vivo for the measurement of gray matter thickness in millimeters data to that of Von Economo’s postmortem data. and plate 11). 2000. Our labora. growth.4 Plots of the relationship between age and gray matter The graphs are laid over the brain approximately where the mea- density reveal different trajectories of gray matter changes for dif. Leonard. The group average cortical thick- to those of postmortem histological studies portends their ness maps were remarkably similar to those described by validity. Significant 30 fundamentals of developmental neurobiology .

The correspondence of the millimeters). Furthermore. Cortical thickness. Thirty-five sulcal landmarks on the This is illustrated in the bottom right panel. surface renderings are flat.) anatomy of each subject with an average sulcal pattern derived for increases in cortical thickness were observed in canonical within individuals over a relatively brief time period during language regions of the temporal and frontal lobes (Wer. they allowed for the quantitative assess- ening was on the order of approximately 0.10–0. On the bottom right is a group average map tion. is then applied that aligns the sulcal of cortical thickness. Note the crosshairs in each map: while at slightly different average thickness value within a 15-mm sphere can be calculated locations in the image.7 and plate 12). respectively). These results high. homologous surface points). and they validate previous cross-sectional find- nicke’s and Broca’s areas.15 mm per ment of the magnitude of change in identifiable units (i. A complex deforma. groups of individuals. is calculated using the Eikonal fire equation cally delineated surface renderings are shown for four individual (illustrated in more detail in figure 2. these results confirmed cortical thicken- changes in gray matter thickness to previously described ing in posterior perisylvian regions and for the first time gray matter density changes is striking. revealed cortical thickening in the left inferior frontal lan- lighted that measurable cortical changes were occurring guage region.e. or warping transform. development.. defined as the 3 D distance (in mm) between the inner gray matter/ After sulcal patterns are demarcated. Surface subjects (i. CSF from cortical gray matter. year (see figure 2. gray-scale image volume is tions with the same relation to the primary sulcal pattern across shown in the upper left for one representative subject. In the bottom left the flattened sul. the crosshairs in all for subjects illustrated here). Using these methods. (See plate 10. o’hare and sowell: imaging developmental changes 31 . matter boundary. the subjects. ings.5 Cortical pattern matching methods and gray matter the group.e.. lateral and medial surfaces are identified and manually traced.Figure 2. a renderings (upper right) are automatically rendered for each subject local measurement of cortical thickness can be made in each subject using the signal value that best differentiates cortical surface sulcal and averaged across equivalent cortical locations in all subjects.e. they represent the same sulcal anatomy in and averaged across subjects to estimate cortical thickness within each subject (i. 3 D.. white matter border and the closest point on the outer CSF/gray tened to a 2 D planar format. This cortical thick. The skull-stripped. Given that the deformation maps associate cortical loca- thickness.6). Finally.

so the thickness measures are at a Color coding has been applied over his original stippling pattern. at the first scan. The brain surface is color coded according to the (C) gray matter thickness image where thickness is progressively color bar where thickness is shown in millimeters. 2004. Figures A through C are sliced at the same level in all similarities between the two maps. (Reproduced with permission three image volumes from the same subject. Thompson. Note the images were resampled to a cortical thickness map of von Economo (von Economo. et al. Our average coded in millimeters from inner to outer layers of cortex using the thickness map can be compared to an adapted version of the 1929 3 D Eikonal fire equation. to highlight the right (mm). voxel size of 0.6 Cortical thickness maps: (A) original T1-weighted vivo average cortical thickness map created from these 45 subjects image for one representative subject.) 32 fundamentals of developmental neurobiology . Leonard. 1929) (E). submillimeter level of precision.33 mm cubed..) (See plate 11. according to the color bar on the respecting the boundaries of his original work.Figure 2. (B) tissue segmented image. Shown in (D) is an in from Sowell.

Future work will combine tively global verbal intellectual abilities and that the structural and functional MRI methods to characterize the significant correlations were observed in the language-domi- specific relationship between these observed increases in nant left hemisphere. these findings were con- not surprising.8 and plate 13). decreases.. TD) and white (significant thickness increases. (Repro- color bar at the near right (ranging from t = −3. the only region showing increases in gray matter thickness in the What is the relationship between the changes in gray and left hemisphere. Sig. 2004). Thompson. we evaluated relationships between changes in gray gray matter thickness in left inferior frontal regions was o’hare and sowell: imaging developmental changes 33 . these findings represent the third observation of matter thickness and performance on a test of general verbal specific age-related increases in gray matter in the primary intellectual functioning. studies have begun to address this important question. 1991).0). language measures such as motor dexterity and strength. Leonard. 2004) (see figure ment than any other cortical region (Sowell et al. alized change in cortical thickness measurements.. increased earlier). Leonard. nificant values are overlaid in shades of red (significant thickness 2004. we expected improved hand motor skills to correlate In the same sample of 45 normally developing children with gray matter thickness values in the hand motor region. We expected that in gray matter gray matter thickening in the left inferior frontal gyrus. et al. 2002. In order to establish the changing cognitive capacities of children and adolescents? specificity of the relation between gray matter thickening in Unfortunately. 2. As predicted.. duced with permission from Sowell. Sowell et al.) As noted. et al. Color coding according to the color bar at the far right. we examined more specific cognitive func- functional maturation of language processes.Figure 2. 2003). Sowell. (Sowell. given that the task represents rela- of the language-learning process. turn. et al. the vocabulary subtest of the language cortices. studied longitudinally for cortical thickness change (described but not the left inferior frontal cortex. 2003. et al. In addition. it appears performance on this test in diffuse areas of the left hemi- that these regions have a more protracted course of develop.. little is known on this topic. which relate with improving phonological skills but not with non- have largely focused on correlating IQ measures with struc. Arrows point to three represents t values at each cortical surface point according to the regions of significant increases in gray matter thickness.. TI). 2007). Leonard. Thompson. drawn from three independent samples Wechsler Intelligence Scale for children (Wechsler. tions—phonological processing and motor speed and dex- terity—and their relationships to changes in cortical thickness Cognitive correlates of developmental changes in these same children (Lu et al.. would be associated with developmental white matter distributions that we have described and the changes in phonological processing..) (See plate 12. Greater gray matter thinning was correlated with better Thompson. Although the only regions to survive cor- That the structural maturation pattern is markedly different rection for multiple comparisons were the left lateral dorsal for brain regions critical for language processing is perhaps frontal and the left lateral parietal. sphere (Sowell. This we predicted that thickness change in this region would cor- section contains a brief discussion of these studies.00 to t = 3. given the complexity and protracted nature sistent with expectations. but a handful of the left inferior frontal gyrus and phonological processing.7 These maps show the statistical significance of annu. gray matter thickness in primary language cortices and the More recently. In tural changes in the developing brain. Thompson.

the average-intelligence group showed similar to the other findings of frontal lobe–IQ correlations a decline in cortical thickness throughout the ages of 7–19. parietal. was significantly correlated with children and adolescents. 2004). No positive correlations reached significance.) (See plate 13. That is. motor processing improvement. When examining all subjects. Regions in color represent et al. In vary with age. cal thickness (time 2 value − time 1 value) and change in vocabulary (Reproduced with permission from Sowell. The high-intelligence group showed a trajectory intermedi- 2005). while the high- 34 fundamentals of developmental neurobiology . variables in the anterior temporal cortex (Shaw et al. Leonard. 2004). Thompson. (Thompson. in adults. Studies examining the correlation between these analyses. the superior-intelligence group showed a marked increase in etal) gray matter thinning and vocabulary. assess gray matter and found a significant positive correla. 2006). older years.) significantly correlated with improving phonological pro. And thickness in the younger children. but not with improving motor processing. In contrast. not significant.. to a strong positive finally. Haier and colleagues (2004) used VBM to correlation in later childhood through adulthood. As described previously. and thicker in the superior IQ children in the frontal cortex (Haier et al.8 Brain-behavior maps showing the relationship negative p values. 2001. and modest negative correlations between these between gray matter thickness change and cognitive matura. suggesting that positive correlation in children in the anterior cingulate the relationship between frontal cortical thickness and IQ (Wilke et al. regions where greater thinning was associ- between vocabulary scores and cortical thickness. the decreases in gray matter thickness in the hand region of left authors noted modest positive correlations between IQ and primary motor cortex (see figure 2. and superior IQ groups. but not phonological thickness and intellectual ability in 307 normally developing processing improvement. frontal cortex was thinner in the superior IQ children in the tion between gray matter density and IQ in the lateral pre. These maps ated with greater vocabulary improvement. design to examine the relationship between gray matter trast.. In con. which is likely cortical thickness in the medial prefrontal cortex that peaked reflective of more general verbal IQ and thus is quite at age 11. 2004. and Williams. In a recent study. earlier years. Growth common to all studies were significant relationships between curves demonstrated that the superior-intelligence group frontal lobe structure and general intellectual functioning. A shift was observed from positively correlated with IQ most prominently in the orbi. Regions in white were show the p value for negative correlations between change in corti. et al. Shaw and colleagues used a longitudinal cessing. This cortical thickness in most of the frontal. Evidence suggests that relationships between intelligence the authors decided to further investigate their data by split- and gray matter structure may show regional differences that ting subjects into average. between cortical thickness and IQ with such a large sample. Toga and Thompson... they found a significant interaction between gray matter volume or density and IQ found a significant IQ group and age in the prefrontal cortex. and occipi- double dissociation illustrates a specific correspondence tal cortex. Chitins. negative correlations between IQ and frontal lobe cortical tofrontal cortex (Frangou. ate to those of the other two intelligence groups. tion in the left inferior frontal cortex. high. a brain region known Apparently surprised by the relatively modest correlations to be important for language processing. gray matter density was varied as a function of IQ level.. scores (time 2 score − time 1 score). In adolescents. had the most rapid rate of cortical thinning. While different measures and methods were used. Cannon. This result occurred in large part because we found significant correlation between frontal (and pari. 2003).9 and plate 14).Figure 2. that is.

That is. negative correlations with cognitive functions subserved by the work to date leaves little doubt that measurable changes those regions.) and average-intelligence groups had slower rates.. Increases in gray matter thickness in left inferior of Oxford University Press from Lu et al. while between thickness and motor processing (panel B).e. but not with motor processing.9 Pearson’s R correlations between changes in gray frontal regions significantly correlate with improvement in pho- matter thickness and phonological processing (panel A) and nological processing. Regions in decreases in gray matter thickness in primary motor cortex sig- white represent positive correlations with a threshold of p < 0. but Regions in red represent negative correlations with a threshold not with phonological processing. 2007. positive or negative). improved functioning is associated in gray (and white) matter tissues are linked to changes in with decreasing cortical thickness in regions that thin with cognitive abilities. nificantly correlate with improvement in motor processing. findings suggest that instead of intelligence correlating with depends on the cognitive function and brain regions total gray matter volume or gray matter thickness across the evaluated. A B Figure 2. and the work of Shaw and colleagues demon- age span. The work of Lu and colleagues shows that age (which cover a wide area of most of the dorsal and o’hare and sowell: imaging developmental changes 35 .) (See plate 14..05. regions While considerable work is yet to be done in connecting that show cortical thinning with development tend to show structural brain changes to changes in cognitive functioning. these correlations depend upon the age range strates that the time at which these brain-behavior relation- studied. These the direction of the relationship (i.05. Generally. ship evaluations are made is also critical. (Reproduced with permission of p < 0.

to the thickening of cortex. mortem material from the same individuals.5 T. 1999). M. Gilles... Friston... and future directions postmortem material in the child-to-adolescent age range. and adulthood. cortical thinning contin- ues. tion. 10:49–57. C. Animal models could also provide potential answers to these Postmortem studies have demonstrated that brain matura. As we discussed. J.. and K. Dudukovic. with primary expressive and receptive language functioning. This issue may be largely semantic in nature. Albert. cingulate and prefrontal cortex: Who’s in control? Nature Neurosci. tive abilities as assessed with functional MRI in an effort to it is becoming more apparent that synaptic pruning and provide an even greater understanding of the brain changes increased myelination contribute to cortical thinning during subserving cognitive development. tissue and NIH Roadmap for Medical Research Grant U54 that has gray matter signal on MRI in young subjects may RR021813. This dynamic sured. It is not at all clear from the post. The direction and pattern of these relationships matter along with concomitant increases in cortical white varies depending on the typical developmental pattern of matter across the dorsal aspects of the higher-order associa. Further funding myelination into the inner layers of cortex likely results in was provided by NIH/NCRR resource grant P41 RR013642 observations of “cortical thinning” on MRI. though it is likely more degenerative in nature. Neurosci. while most developmental struc. we could measure cortical thickness using MRI 3:421–423. E. the only definitive way to evaluate this would be to combine Cohen. increase in thickness throughout adolescence and young 1988. and not acknowledgments Support was provided by the National due to the same progressive changes that occur during devel. Gabrieli. Ashburner. J. and D. Oxford Univerity Press.. Changes in the changes in cognitive function have been unfortunately relative proportions of gray and white matter observed with sparse.e. hood. H. M. Voxel-based morphome- New and converging findings from several independent try—The methods. I. Vaidya. Thomason. 36 fundamentals of developmental neurobiology . and F. and C. brain region subserving the cognitive function being mea- tive cortices in the frontal and parietal lobes. M. Kjos. Institutes of Health (NIMH K01 MH01733 and NIDA R21 opment. Unfortunately. S. Neurol. While we cannot determine the structural changes with detailed analyses of changing cogni- cellular etiology of gray and white matter changes with MRI. Knoefel. Rev. may be occurring simultaneously in regions of the brain that 1987. Neuron by Kozorovitskiy and Gould in chapter 4 of this volume. 2002. Again. Gould et al. D. DA015878 and R01 DA017830 awarded to ERS. Radiology 166:173–180. 1994. and J. An autopsy study of myelination. E. Psychiatry 51:477–484. E. Exp. 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glial cells. Finally.3 Gyrification and Development of the Human Brain TONYA WHITE AND CLAUS C. A groove is created two identical stem cells with each mitotic cycle (Rakic. Thus this period results in an exponential growth in short-lived sulcus in the brain. with one daughter cell remaining as subcortical structures will spring forth from the rostral an undifferentiated stem cell. 2003). 1968). the theories surround. hypothalamus. These layers. The rostral region of the neural tube undergoes exu- anatomic or functional brain patterns. Swanson. It is the differentiation of the ectodermal layer that outer layer becomes the cortical rim of gray matter (GM) in forms both the skin and the central nervous system. Clusters of neurons along the midline of the ing gyrification are fascinating. with each stem cell producing Jessell. The walls surrounding the cerebral ves- of the characteristic gyri and sulci mainly occurs before birth icles become thick and form the lamina terminalis by the in a process known as gyrification. such as the brain stem or life. Many researchers who seventh week of fetal life (Destrieux. This life that the dividing cells begin to differentiate into one of mechanism. 1874. with little thought berant growth involving an overabundance of neural and given to how they develop. which describe the differentiation of embryonic precursor struc- will also be outlined here. In general. 2000). involves neurons mesoderm. tures. and. the neural The neural plate is the first structure of the CNS to progenitor cells located in the ventricular zone begin develop within the ectodermal layer (Kandel. These processes are likely driven by differential growth rates of the different embryonic territories. brain. and symmetric cell division. these processes are nested and dependent The classic concept of a “fate map” has been invoked to upon the other major neurodevelopmental processes. and Kakou. known as the endoderm. Little is ate into the peripheral nervous system. 2000). 2000. and ectoderm continue to undergo rapid cell formed via mitosis at the ventricular zone migrating along division and differentiate into the different organs of the radial glial guide cells in the outer layers of the brain. known about the mechanisms behind the emergence of these During the fifth week of fetal life. basal ganglia. a age. the neural crest cells The cerebral cortex of the human brain has a readily identi. remarkable variety of morphogenetic and particularly folding processes occur even at this early stage of brain develop- Brain development prior to gyrification ment. However. and the cortical and asymmetric division. The major components of gyrifica. This neural groove rapidly neuronal progenitor cells. The caudal region of the neural gestational age. which are frequently separated by early limiting sulci. It is not until the second week of uterine ventral regions of the neural tube in a specific pattern. they are potentially relevant for the thalamus. which has been described as the radial unit three different layers. HILGETAG Introduction with the formation of the neural tube will differentiate into the epidermal layer of the skin. 2000). study the brain utilize gyri as landmarks to define specific 1998). as biological form is ventral region of the neural tube differentiate further into closely linked to function. 1995. between the neural tube and the ectodermal wall differenti- fied characteristic pattern of grooves and folds. It is the primary goal of this chapter to describe terminalis. in the midline of the neural plate. the progenitor cells gradually initiate tube will later become the spinal cord. Before six weeks of fetal life. folds to become the stages and mechanisms of gyrification of the human the commissural plate (Rakic and Yakovlev. Schwartz. hypothesis (Rakic 1988. However. The dorsal region of the lamina localization. Pomeroy and Kim. known as gyri and sulci. Formation of the Neural Tube (Neurulation) The mating of egg and sperm is followed by rapid stem cell Neuronal Migration Neurons migrate out from the growth and division. at approximately six weeks closes to form a neural tube. and brain stem understanding the development of brain function and its (Pomeroy and Kim. tion take place primarily during the third trimester of fetal into specific adult brain structures. Velut. forming perhaps the first 1988). while the other daughter cell region. the cerebral vesicles grooves and folds. This body. or between approximately 26 and 40 weeks’ gestational the cerebral lobes (His. The cells within the ectoderm that are not involved matures into a neuron that migrates outward to the cortex. known as the lamina reunions. The formation begin to take form. 39 . Then. the adult brain.

with increasing complexity that continues during postnatal fication (Stewart et al.. Andreasen. several neuronal subpopulations show different dent (Verhage. 2002). their maintenance. In turn. Thus a certain level of growth and pruning allows for pursue a tangential migratory path into their target layers inherent plasticity during neurodevelopment and explains 40 fundamentals of developmental neurobiology . The effect of the tangential generations passing through the previously developed cells mode of migration on cortical morphology is likely small before reaching their ultimate migratory position in the gray or has only a local influence on the development of the matter of the cortex (Sidman and Rakic. 1988). strengthened through activity. which is a later process. when two regions. you $20 now.. The connection of these nerve cells area of the brain (Rakic. 1 cent. and Nopoulos. where division. resulting in a larger the thalamus and cortical gray matter meshes well with size of these structures. Chemical signals guide these layered cortex is influenced by the asymmetric period of cell developing dendrites toward their ultimate location. These pyramidal cells form connections with inter- During these two phases of symmetric (before six weeks) neurons that are located within the vicinity of their migra- and asymmetric (six weeks to 12 weeks) cell division. migrating into late-developing brain structures undergo a Andreasen. 2003) and thus may not be directly told his son at the beginning of the month. as well as disrupting the development of gyri. This developmental correlations between volumes of the thalamus and cortical principle has been called “late equals large.” If the son were to choose poorly understood. they extend asymmetric cell division. The cortical cortical layer. 1984. a decrement in cortical thickness apical dendrites subsequently extend additional branches. 1975). 2 death for gyrification and brain morphology that are as yet cents. Development of Connectivity between Cortical The surface area of the brain has a close association with and Subcortical Structures As the radial glial cells the number of radial units formed by symmetrical division migrate toward the cortical plate. The cell layers and. 2003). during the phase of As the neurons migrate into the cortical plate. these events can influence gyrification. path. 1979).6 million for a month with 31 days. These number of radial units equates with a larger number of lined projections migrate primarily into layer IV of the cortex projections to the cortical plate and thus a greater surface (Wise and Jones. and those connections that the mode of radial migration is mostly followed by pyra. 1939).. and so on). “I will either give involved in cortical gyrification. However. cell death is a potentially double the number of neural progenitor cells. 1995. there are potential indirect consequences of cell the amount each day for the next month (that is. Studies brain structures in a large number of different species (Finlay that demonstrate volume decreases in both the thalamus and and Darlington. (White. 1963). Thus the thickness of the six. This relation between longer period of symmetrical division. allows for communication between the subcortical and Since each round of mitosis results in an exponential increase cortical structures.3 million dollars for a 30-day month or 10. it results in a deletion of cortical apical and basilar dendrites (Juraska and Fifkova. 16 cents. 2002). 1974. 4 cents. Studies have demonstrated high impact on surface area (Rakic. 1995). one additional mitotic cycle would of the initially formed neurons. In particular. mitter. development (Conel. While these connections It has been found recently that the migration of neurons form in the absence of the release of neuronal neurotrans- into the cortex is not as straightforward as initially thought. This process can lead to the elimination of up to 50 percent Before six weeks of age. Levitt. the penny. 2000). with later (Kriegstein and Noctor. once formed.The migration forms an inside-out pattern. 1978). radiation is applied after six weeks. The principle has been verified for the present neurodevelopmental and neuroanatomic the developmental time table and corresponding size of understanding of thalamic/cortical GM connectivity. small tory path. (Rakic. in turn. while different types of cortical interneurons 2005). The vast majority of cortical neurons are GM rim consists of six layers of cells that have migrated in pyramidal cells that migrate along the predominant radial this inside-out pattern. midal cells. Such a direct relation between cortical in the number of progenitor cells. and Plomp. Sidman and Rakic.. see little traffic are eventually pruned (Luo and O’Leary. and double Nonetheless. reductions in volume of both the When the embryos of monkeys are irradiated during the prefrontal cortex and mediodorsal nucleus of the thalamus) symmetric phase of progenitor cell division. of the cortex. there is a may reflect aberrant patterns of connectivity between the decrease in total surface area of the brain. 1995). even when controlling for intracranial volume (White. synapses are formed (Sperry. or I will give you a penny now. 2005). and Nopoulos. A larger cell projections from the thalamus (Rakic. is activity depen- for example. 2004). he would have more than 5. perturbations can influence the thickness or the surface area Another factor affecting brain morphology is cell death.” as neurons GM.e. Maia. regressive event that occurs early in development (Cowan This point can be illustrated in the story of the father who et al. they meet with afferent along the ventricular zone (Rakic 1988. 1973). 1973). Striedter. 1995). small changes affecting GM and the thalamus would presume a volumetric relation the duration of symmetric growth will have a dramatic between the two structures. However. cortical regions (i. Connections are migratory patterns (Nadarajah et al.

and Yeshurun. owing to the larger surface to take detours around the additional wiring volume area of the body and need for a greater number of neurons (Chklovskii. the computational prowess of the human brain the relationship between body weight and surface area is appears linked to the overproportional size of its cerebral considerably greater in these mammals. Van Essen. These theoreti- to cover the sensory and motor domains of the body. would lead to very uneconomical wiring in the thickened sarily translate into greater intelligence. and Yeshurun. reflects an (Hofman. 1997. 2005. a thou- The elephant brain is four times larger. 2005. interneuron develop. and a complex inter. larger absolute brain size does not neces. This criti- gray matter and thus greater computational power. The smooth. This architecture includes the segregation of WM and GM there is evidence that one limitation in the enlargement of and limiting the thickness of the gray matter sheet. porpoises. meet with minimal consequences as compared with the same 2002). since connections within the cortex would need generally possess a larger brain. The cal threshold in brain size is likely related to constraints on phylogenetic increase in the surface area of the human brain other body systems and developmental events. however. At what point. 1995. 1998]. than the human brain. should allow a smooth human cortex with play exists between these processes that is as yet not com. and primate brains of up to 10 cm3 volume are generally developing structure (Finlay and Darlington. in concert with power of body weight across both primates and nonprimates the volume-saving folding of the cortical sheet. Brain weight scales to the ¾ connections within the white matter (WM). Dunlop. Thus the extra projections of intelligence when viewed within an environmentally required to link neurons in the additional cortical layers adaptive context. is about three times as large as the inner surface of the The development of the cerebral cortex requires an skull (Hilgetag and Barbas 2005. between the degree of gyrification and absolute brain size Greater surface area equates to a larger amount of cortical (figure 10. the surface area of the Theories of the ontogeny of gyrification human brain is approximately ten times greater. and Stevens. and Schüz. Toro and Burnod.. For example. whereas the human cortex is only twice as thick (Rakic. In addition. tripling cortical thickness. Therefore. and gyrification. Finally. 1999). Ruppin. orchestration between the processes of neuronal migration.why children with large sections of the brain removed may expanded laterally rather than vertically (Chenn and Walsh. in humans the surface area of the brain to the size of the pelvis and the birth process in humans is 1. 1989). The also be increased by adding to cortical thickness rather than formation of cortical and thalamocortical connectivity is cortical surface. 1995. optimal wiring and volume arrangement for the very dense phins have a disproportionately large brain compared to connectivity found in the primate cerebral cortex (Murre and their body mass (Allman. 1989). Welker. from not fully complete before gyrification. Ruppin. Given the formidable degree of connectivity among cortical neurons (each forming. Prosimian due to an extension of the developmental period of this late. These What mechanisms produced the convoluted human cortex? comparisons indicate that during evolution the cortex Was it merely additional symmetric cell division with white and hilgetag: gyrification and development of the human brain 41 . Schwartz. 2005). and dol. Sturdy. ment. seemingly only a minor increase in brain volume. yet the thickness of (Striedter. 1998). maximum birth size of the embryonic skull and its relation 1990). which the brain is related to the balance between brain and body is enacted through a lateral increase of the cerebral cortex energy demands (Armstrong. pletely understood. However. A larger animal will cortex. the number of neurons in the cortex could ping processes (Darlington. 2006. 1995). 1993) have demonstrated that this The phylogeny of gyrification idea is ill-fated. 1982). resulting in a convoluted human cortical sheet that resection in an adult patient.1 in Striedter. did cortical The most conspicuous feature of the human brain is the folding become necessary? It appears that gyrification is disproportionately large size of its cerebral cortex. Richman et al. 1990). about 5 to 15 mm. Schwartz. 1993). during evolution. humans. which is strongly related to absolute increases in brain size. Compared to macaque monkeys..700 times larger than in shrews. 1995). modeling studies (Murre and Sturdy. Schikorski. and dolphins have the greatest amount of cortical folding. subcortical and cortical connectivity. such as the has far exceeded growth in the cortical thickness (Welker. since the cortex and the intricate architecture of the cerebral cortex. and the brain of the sand or more connections with other neurons [Braitenberg sperm whale is five to six times larger. 2002). 1982). and Finlay. Zilles et al. all of which are temporally overlap. the cortex is only six times greater (Hofman. In this way. 1975. the volume of wire grows exponentially Although these mammals certainly have a considerable level with the number of neurons. on average. One cal studies support the idea that the segregation of brain can account for this relationship by normalizing brain mass tissue into components of cell bodies within the GM and by the weight of the animal. Since humans. brain is a costly organ with respect to energy metabolism. Theoretically. porpoises. while for larger volumes there is a close correlation result is a related increase in the surface area of the brain.

White et al. experimental white matter lesions in the developing primate tion. studies of monozygotic twins have interconnected regions closer together. However.. thus enhancing overall efficiency growth to specific regions of the brain (Le Gros Clark. 1975) and axonal-tension-based theories (Van Essen.. Welker. 1997. 1980. This 42 fundamentals of developmental neurobiology . course on average more tangential in the gyri (Welker. There have been found in a group of healthy adults (Magnotta is a sexual dimorphism in gyrification. structure to a brain with brain surface morphology and regional neuronal connectiv- convolutions that are characteristic of an adult brain (Arm. 1990). of gyrification. Naidich. Van Essen. strong et al. Toro and During the third trimester of fetal life. it needs to be kept in mind 1945) and mechanical theories of gyrification based on the that cortical folding due to the balancing of axonal tension physical self-organization of the brain (Hilgetag and Barbas.. excluding the traces into cortex..subsequent squashing of the excess gray matter into the et al. (Van Essen. is it possible that the folding patterns of the brain not brain (Goldman-Rakic. These include the theory of gyrogene. This finding implies that the regions that wire together. These changes continues to develop. by the neuronal connections is involved in the mechanisms ment of brain topology (Bartley et al. 1999. jections may deviate from the general shortening and 2005. whereas fiber pathways during the third trimester of fetal life. Richman et al.. known as the gray matter to be compacted within the given volume in a axonal-tension-based morphogenesis of the cerebral cortex.. 2006). Indeed. sulci are an expected outcome of brain changes that alter 2002).. then remains rela. tively constant throughout development (Armstrong et al. If tension produced demonstrated a strong genetic contribution to the develop. fire together. The age-related decrease in synaptic and on coronal slices of the brain by calculating the ratio dendritic arborization may result in decreasing the tensile between the outline of the cortical surface and a lissence. developmental changes that allowed not only for the increase A stimulating mechanical hypothesis was proposed by in surface area. specific genes have been found that are the connectivity between brain regions. only provide for increased surface area of the cortex. 1995). This concept. Histological studies of the neuronal pathways have the sulci). Bartley.. 2006. From this work on postmortem samples. the process of gyrification the sulci and greater curvature of the gyri. In addition. then changes in the patterns of the gyri and and Weinberger. cerebral cortex more strongly convoluted than the male It is a well-known neuroscience concept that brain cortex (Luders et al. 1995. or the theory that the gyri form as a result of active signals along axonal fibers. ity within a developmental framework. although two overarching theo. 2006.e. so that some theories can be further subdivided into those that involve projections may remain relatively long and connect distant differential growth patterns within the cortex (Richman regions of the brain (Hilgetag and Barbas. with the female et al. characteristic pattern? One need only study several brains postulated that neuronal connectivity during early neurode- within a species to notice the dramatic similarity in the velopment is involved in producing fiber tension that draws folding patterns. Toro and Burnod. 1994. 1999). cooperate volume difference between female and male brains is partly in brain function (Hilgetag et al. Dareste. that is. The mechanical straightening of fibers during development. they found that the neural fibers on average tend to traverse found that the gyrification index increases dramatically horizontal to the surface in the sulci. The axonal-tension concept has also been supported also that gyrification enhances the efficiency of neuronal by recent experimental findings in the primate brain as well processing within the brain? as modeling studies (Hilgetag and Barbas. imity.. 1997). is played out as a global tug of war. 2000). 1993. Goldman-Rakic and Rakic. 1975. Welker. remote changes of gyrification have been observed after Finally. and these studies support a link between from a lissencephalic.. local and related to disorders affecting gyrification (Piao et al. as we explore the mechanistic theories of gyrifica. maintaining this constant ratio. but also a mechanism to allow the newfound David Van Essen in 1997. the brain develops Burnod.. This arrangement contributes to greater compactness ries have emerged. given space? Or. Indeed. Thus another offset by a more efficient packing of the cortical sheet in advantage of the tension-based morphogensis hypothesis the brains of females. Since the brain nearly triples its along the line of average tensile would result in widening of volume from birth to adulthood. 1862). From a mechanical perspective. 1891. 2005). Zilles and colleagues (1988) Implications of the Mechanical Folding Hypothesis described a “gyrification index” (GI) that was applied to Combining the age-related differences in the morphology of measure the developmental trajectory of gyrification in the cerebral cortex with changes in neural connectivity is humans (Armstrong et al. Grant. forces that are involved in the morphogenesis of the cerebral phalic outline of the brain (i.. 1990). Jones. 2004). were there additional neuro. or smooth. alternatively. 1990). 1997. 1997). a release of tension 1995. 2004). is that regions that have strong interconnections and form The exact mechanisms underlying the gyrification of the functional circuits are maintained in relatively close prox- brain are as yet unknown. and Altman. Retzius. Thus individual pro- 2005. but 1984). Lohmann et al. of the brain and decreases the conduction time of neuronal sis. The GI was calculated intriguing..

cortical layers. Considering simple physical principles underlies the formation of cortical the complexity of neurodevelopment. partly oppos. resulting in the self- influences in neurodevelopment. neu. appeared to be strongly determined by genetic to the neurons’ migration.. pruning) are Gyrification During the first year of life. Moreover. folding. rons (unpublished observations). Brain weight peaks at approximately white and hilgetag: gyrification and development of the human brain 43 . the surface locher and de Courten. Reiss morphology of the brain has much greater variability than et al. however... 2006. 2006). 1996). coupled with the pronounced cortical plas- during the folding of the cortex influence the relative laminar ticity inherent in early development. the role of stochastic convolutions as well as cortical architecture. there are regional differences between more con- short cortical connectivity increases the global wiring length served and more variable parts of the cortical landscape of the brain. there is no such clear trend in the data from monkey of the brain. Thus the overall after birth. von Cramon. sulci (Lohmann. they cal convolutions. but interact at all stages of development. physical self-organization are not mutually exclusive pro- cesses. This study. and Nopoulos. Huttenlocher and Dabholkar. thickness of the cortex (White. monozygotic (MZ) or identical different cortical layers and areas. 1967). resulting in a larger ratio of thick. while brain size. White et al.e. supporting the phylogenetic differences between cor- Generally. For example. resulting in additional mechanical resistance however. which utilized a cross- overlap in the developmental timetables of migration and correlation algorithm to compare structural brain images. striate cortex (Huttenlocher and de Courten. 2002). and corti- friends are able to tell one identical twin from another. 1982. and Weinberger. While an admixture of long projections to mostly addition. modulate the changes thickness of cortical layers. and Postnatal Changes in Brain Morphology and the observation that some processes (i. it should not be ment changes take place at a rapid pace (Huttenlocher. Hutten- different in identical twins. 1996. Steinmetz and colleagues (1995) also demonstrated accumulation of cells in the deep layers.. neurodevelop- influenced by environmental factors. volume. there are more pyramidal neurons and glia in the degrees of asymmetry of the planum temporale.. surprising that certain aspects of brain development are 1979. Thus a dynamic interplay of genetics and are not completely identical (Machin. the volumetric brain measures. stretching and compression forces produced postnatal twins. but also for other surface measures contrast. 1997. Epigenetic deep layers of gyri than in sulci or straight portions of cortex factors are probable explanations. 2006). 1990. nonshared environmental influences that are present for For instance. it also contributes to a reduction of neural (Thompson et al. unpublished observations). Yakovlev and Lecours. by of the planum temporale. studied with and without dizygotic (fraternal twins) to may come into play as the cortex grows and cortical regions study the interplay between genetic and environmental are interconnected by axonal fibers. processes (i. the radial migration of late-maturing demonstrated that the majority of the morphologic variance neurons through the already existing deep layers in budding between the brain surface morphology of MZ twins was a gyri may be affected by lateral compression from the ongoing result of random environmental effects. or subcortical regions of the brain (Bartley. as there is potential gotic and dizygotic twins. Andreasen. ness of upper to deep layers in sulcal regions compared to The strongest evidence for surface pattern dissimilarities gyral regions (Hilgetag and Barbas. peaks by approximately the fourth postnatal month in the Jones. 1979). Heritability of Gyrification Numerous studies have genetic factors may underlie the timing of development of capitalized on nature’s clones. between monozygotic twins came from a twin study by ronal migration itself may be affected by the mechanical Bartley and colleagues (1997) that included both monozy- forces produced during cortical folding. 1987. not only for asymmetries (Hilgetag and Barbas. in cortical surface morphology. and potentially in an additional factors. Interestingly. Since parents and close organization of migrating neurons. there are not enough genes to program all the specific connections of all neurons and their synapses). 1999). It is possible that the greater a substantial contribution to many morphogenetic processes. and mechanical factors twins. and Steinmetz. folding process. For instance. 2001). In agreement with that MZ twins discordant for handedness exhibited differing this idea. which develop mainly the system (Kaiser and Hilgetag. which show significantly lower correlations than prefrontal cortex for different types of inhibitory interneu. 1997. ing constraints. Huttenlocher et al. In 2006).process would account for the long tail in the distance sulci of the brain are more highly correlated than the tertiary distribution of cortical projections (Kaiser and Hilgetag. Nongenetic factors tend to have a processing steps by providing long-distance shortcuts across greater influence on the tertiary sulci.e. which are predominantly It needs to be stressed. 2002).. Synaptic density midline. Measures of gyral and sulcal curvature of the efficiency of brain structure and function is determined brain are significantly less correlated in twins than is the by the simultaneous adaptation to multiple. 1987) and by Studies evaluating the gyral patterns in monozygotic twins approximately 12 postnatal months in the prefrontal cortex demonstrate that the deeper and developmentally earlier (Huttenlocher. that genetic factors and migrating tangentially. aspects of physical self-organization may make tical thickness and surface area.

1986. gyri and the sulci. Terry.. and Hansen. Giedd. 1994. Peters et al.. clinical aberrations of development based on current data... MRI studies have demon- 1984). Magnotta and colleagues (1999) showed gradual changes in namely. 1996. 1996. 2004. 2002. although the debate continues (Leuba and Kraftsik. and MRI studies have demonstrated only neuronal loss.... 1996). Haug et al.. 1994.. 2006)—both changes in et al. Trauner. 1986. This decrease in synaptic density is associ- a minor increase in mass after four to five years of age ated with decreased plasticity and is likely related to the (Pfefferbaum et al. Since this loss is mainly in older adults. Trauner. canceled each other out.. 2004. 1980. 2002. Gogtay et al. Sowell et al. Thompson. Haug. 2006. 1980. 2002). Mixed results have resulted from evaluating age-related 2001... 1997). Sowell. 2004. 1979. Trauner. with the gyri developing greater curvature age-related findings identified histologically have also been and the sulci developing less curvature. Armstrong and colleagues (1995) demonstrated that in the neuropil (Jacobs et al. Sowell. Cragg. at least in cific clues about past events that are based on current finds. Jernigan et al. 2003. (1955). 2004. into late adulthood (Caviness et al. 1991. 1996.... Since the original studies of Brody Giedd. Reiss et al. or becoming more shown using magnetic resonance imaging (MRI) techniques broadened with increasing age. 2002. 1994) to cortex (Anderson et al. 1985). who found that as many as half of the neurons in Sowell et al. 2003. Sowell et al. Histological depending on whether the sample was from postmortem studies have also demonstrated an age-related decrease in brains or subjects who received magnetic resonance (MR) cortical thickness associated with the changes taking place scans. et al. et al. Huttenlocher the thickness of the cortex and alterations in gyrification and colleagues (Huttenlocher. Devaney and early adolescence (Giedd et al. Sowell. 1997. 2004. Lenroot and Peters et al. and the cerebellum Johnson. Thompson. Sowell et al..... in the developing neuropil (Easter et al... 1979. durations of ultrasound (Ang et al. 2002). De Bellis et al. Henderson.g. More recent studies that utilized techniques to reduce strated reductions in the thickness of the cortex that corre- or control for brain shrinkage have not replicated the early spond with the decreases in gray matter volume (Sowell.. 2001). would be expected. 1999). colleagues did not specifically study differences between the Thompson. based on what is known regarding neurode- have been described during adolescence and adult life velopment and gyrification—e.. pruning of connections that have less functional efficiency fication during postnatal development have differed. 2003. little Using the analogy of an archaeologist piecing together spe- cell death appears to occur during adolescence.. Huttenlocher et al. 1998). loss occurs more in the frontal and subcortical regions (Giedd tion of neurons within the brain (Haug. The age of peak GM volume varies between been conflicting reports of the extent of neuronal loss in the studies and ranges from 4 years (Pfefferbaum et al. De Teresa. Sowell et al. the gray matter shrinkage resulted in the appearance of a greater compac.. 1994.. 1982) have reported substantial decreases in synaptic Clinical conditions can be broken down into primary dis- density in the middle frontal gyrus during adolescence and orders of gyrification (those that cause gross disruptions in early adulthood.. 1996. et al. 1998.. the recent reports of dis- (Huttenlocher. Giedd ruption of neuronal migration in rats exposed to long et al. the absence of the use of illicit substances.. findings. Reiss et al. 1996. studies that reported dramatic cell death apparently did not such that between childhood and adolescence there is greater account for methodological techniques that resulted in a gray matter loss in the parietal lobes (Sowell et al. so too is it conceivable to piece together the timing of specific Even in the absence of considerable neuronal cell loss. et al. greater shrinkage of younger brains. there have et al. ment involves primarily modulations within the neuropil. Haug et al. et al. Shefer. regions of the frontal and temporal lobes are lost. 1996. ing in late childhood or early adolescence and progressing thus maintaining a constant gyrification index.. changes in total cell counts of the cortex (for review see Jernigan and Tallal. developmental differences in brain structure and function For example. Studies of gyri. synaptic pruning and dendritic arborization.. Sowell. Tomlinson. 1973). 1996). This age-dependent whereas comparing adolescents to adults.. Pfefferbaum et al. The current consensus is that cortical neurons are Clinical conditions associated with abnormalities in generally preserved during adolescence and adulthood with gyrification at most a 10 percent reduction in neuronal numbers (Peters et al. 1984. and Gibson. Since Armstrong and (Giedd et al. 1999). measure the gyrification index.. 1982.ten years of age. tently demonstrated a decrease in gray matter volume start- which were opposite in direction. 1987). this decrease being without considerable the gyrification that are readily identified on imaging or 44 fundamentals of developmental neurobiology . 1983. The earlier There appear to be age-related differences in volume loss. Huttenlocher et al.. 1975. Alternatively. and Magnotta and colleagues did not Thompson and Nelson.... 1998). Sowell. 2002). appears to be one of the later-developing brain structures. 1990. The thinning of the postmortem brains maintained a constant gyrification cortical GM during late childhood and adolescent develop- index from birth through late adulthood. The brain curvature.. Giedd et al. it is possible that the opposite Cross-sectional MRI studies of development have consis- differences between the sulcal and gyral findings on MR.

. Vogeley et al. a malformation in which the gyri during normal aging and development using the GI are thicker and the sulci are less deep. phrenia have been mixed. histological differences between the sulci and the gyri there is a greater likelihood that the brain will show fewer (Welker. may produce enough tension within these deeper and colleagues (2004) found an increase in GI in the right layers to result in the development of some. 1923. Josephy. neuronal Utilizing techniques developed by Magnotta and col- migration plays an integral role in gyrification. Children with lissencephaly have severe developmental would support neurodevelopmental hypotheses for specific delays and mental retardation and are typically diagnosed disorders (Kulynych et al. Stewart. Stewart. 1988). Stewart. it is postulated that when the disruption in the peaked. This is evidenced by histological findings of hetero. albeit aberrant. Based on the neuronal migration takes place earlier (before 18 weeks). Gyrification With the emerging evidence supporting stream processes). 1975).. Radial and horizontal Several studies have emerged evaluating those at an migration of the deeper layers. whereas Jou gyrification. and polymicrogyria. 1923. Yates.. Vogeley et al.. although the actual thickness of the cortex is increased an increased GI in the right temporal lobe (Harris. 1923. it was postulated that these changes were gyri and sulci (i. meaning smooth. (Kulynych et al. Given the variability of the findings of these Caviness Jr. studies of 1975). Thus intrauterine events that alter gyrification characterized by an absence or reduction of the gyri and would be evidenced in an alteration in the GI.. Richman. 2005. Zilles et al. Van Essen.. meaning “thick”).. It is possible leagues (1999) that are able to differentiate alterations in the that the dilution of neuronal fibers within the thicker cortex. 2003) and the right cortex (Sallet (Bielschowsky.postmortem samples) and secondary alterations in gyrifica. and Caviness Jr. White and colleagues (2003) coupled with the increased failure of tangential neuronal found opposing changes in the gyri and sulci in the frontal fibers to adequately produce neural networks.. But within the first six months of life (Ross and Walsh. interestingly. 1995). whereas the gyri became more estingly.. 2001). subtle changes in gyral and sulcal include pachygyria (pachy stemming from the Greek word morphology that counteract each other would go undetected pachys. independently differentiate between sulcal and gyral changes Evidence shows that individuals with lissencephaly in cortical surface morphology. a full consensus has not been achieved regard- ing of the neurons within the cortex. demonstrating an increased curvature. Sallet et al. Harris. a tension-based hypothesis for cortical morphogenesis as the difference between a primary and secondary disorder (Hilgetag and Barbas.. Richman.. 1997).e. Whereas the gyrification index Primary Disorders of Gyrification Lissencephaly described by Zilles and colleagues (1988) remains constant (stemming from the Greek word lissos. be less pronounced (pachygyria). Richman. became more broad). 1944. schizophrenia. (i.. 1990). with several studies demonstrat- 1975). lissencephaly). 2003) and... Inter. and Caviness Jr. 1997. meaning brain) is an umbrella term that well equipped to determine alterations that occurred during describes a number of rare developmental malformations uterine life. of gyrification may only relate to the timing or the extent of there is a direct translation between changes in neuronal the specific neurodevelopmental insult. Whalley. Neuropsychiatric Disorders Associated with Altered tion (those that may influence gyrification through down. 1997). 2000). connectivity and gyral and sulcal morphology (White et al. and et al. and colleagues (2005) found a decrease in the left frontal white and hilgetag: gyrification and development of the human brain 45 . whereas between 18 and consistent with aberrant pruning under the tension-based 24 weeks the gross morphological defects of gyrification will morphogenesis hypothesis of gyrification. it is and enkephalos. control differences (Highley et al. 2004).. 2003.e. et al. substantially and the gyri and sulci fail to form. (Bielschowsky.. results in a and temporal regions in a group of children and adolescents lack of tension within the cortical surface. prior to an insult to the increased risk for developing schizophrenia. This then disrupts with schizophrenia. The sulci developed greater curvature the formation of sulci and gryi during brain growth. gyri and sulci independently.. ing a global decrease in the GI of the left cortex (Kulynych topic clumps of neurons in subcortical brain regions et al. 1997. This increase in thickness is related to studies and the clinical heterogeneity that is well known in the disruption in the migration and the subsequent spread. As would be expected from the disruption of neuronal gyrification in schizophrenia have also shown no patient/ migration. prefrontal cortex of patients with schizophrenia. Alternatively. from birth through adulthood (Armstrong et al. and thus sulci. 2003. CNS. the cortex is reduced from six to four layers. ing the specificity of neurodevelopmental abnormalities in Since the surface area of lissencephalic brains is reduced gyrification in schizophrenia. 2006. Studies in schizo- (Bielschowsky. and related disorders have an arrest of normal neuronal Most studies of neuropsychiatric disorders utilize the GI migration during the third to fourth month of uterine life to measure patient control differences. 2000). because the gyrification index does not differentiate between Malformations that are closely related to lissencephaly sulcal and gyral changes. Thus Magnotta and colleagues which results in a cortex with multiple small gyri and (1999) developed an image analysis algorithm that is able to shallow sulci. These distinctions define an arbitrary line.

an interesting theory proposes evaluating gyrification. 2002).. formation of connections. One hypothesis that may explain an increased GI in This hypothesis would account for gyri being functional patients with autism. there are significant temporal overlaps between dif- involves abnormalities in the minicolumns. the upcoming years will continue to exponen- disorders. The brain surface morphology continues to lobes. necessary scaffolding likely being constructed prior to this opmental trajectory in brain volume (Courchesne. Cells that line the ventricular zone change from sym. Redcay. the end of the second trimester. they were more pro. In a cross-sectional study of brain that regions of greater neural connectivity apply greater gyrification in patients with autism. logic conditions. knowledge of the complex processes involved with neurode- ated with the pathology within the onset and course of these velopment. and Finlay. there is a differentiation of cells within the to these questions will depend on a greater understanding of ectoderm into cell lines that are destined to become the cells developmental events. tially add to our understanding of brain development and gyrification. Alterations in brain size or gyrification may Dunlop. primary sulci begins near (VCFS).. although the brain has a ing schizophrenia than the general population. even into early to middle adult- Finally. individuals with velocardiofacial syndrome Gyrification of the deepest. 2004). changes of cells within the neuropil. when do specific corti- of the central nervous system. then the neural tant open question concerns the relationship between the tube. who have a nearly 30 times greater risk of develop. since Morphometric studies. nectivity tend to be drawn closer together (Van Essen. so that the processes of neuronal alter the volume of white matter passing through these migration. 2006). a better understand. an increase in GI has been demonstrated in hood. more subtle brain changes can be seen throughout with schizophrenia. however. forming first the neural plate. While the axonal-tension hypothesis sug- 46 fundamentals of developmental neurobiology . has only one study gyrification are unknown. and which aber- of highly complex processes. childhood and adolescence. distant brain regions and affecting processing speed and The most visible changes in brain structures occur during the integration of neuronal signals. Structural brain changes during adolescence and patients with Williams syndrome (Schmitt et al. Although the mechanisms underlying and Kennedy. Finally. many questions remain about the mechanisms and implications of the process of gyrifica- The development of the central nervous system and forma. which has been shown to have an altered devel. These processes begin in utero rations from typical development lead to the observable dif- and progress throughout the life span. such as neuronal migration. as reviewed here. formation of connections... showed a predominant lissencephalic character at the beginning of significant decrease in the GI in both the frontal and parietal the third trimester. During the first two ferences in brain shape in different patient groups? Answers weeks of fetal life. (For example. This time point is important. have demonstrated alterations during the period of symmetric cell division are systematic differences in WM as well as gyrification between more likely to influence the surface area of the brain. and normal subjects and patients with a variety of neuropatho- thus changes in the gyrification patterns. in addition to the reported decrease units with more efficient neural communication. and development of white matter in metric division to asymmetric division at approximately six the brain and the global and local degree of gyrification. The major changes in gyrification of the lobes (Schaer et al. The gyri becoming more steep and the sulci developing a broader direct relationship between alterations in gyrification and appearance. 1999). such that as the brain grows. These cells divide and multi. 2004). density Although the increases were global. human brain take place during the third trimester with the Autism.. matter fibers that course through the gyri (Casanova et al. 2006). For example.lobe. we found uterine life and the first few early years following birth. with the rate of pruning of synaptic and neuronal connections. young adulthood include a decrease in gray matter. However. Piven et al. time (Rakic. a narrowing of the gyral alterations in our young patients However. or the white ferent developmental events. Hardan and colleagues tension. what are the exact tion of the gyri and sulci in the brain involve an orchestration developmental mechanisms of gyrification. and right occipital myelination. the brain. and gyrification (Darlington. distribution. amount. tantly. 2002. Conclusions At the moment. cal areas and their interconnections form?) Another impor- ply rapidly. tion in the human brain. and an increase in nounced in the left frontal. 1997). These latter findings are associated with an subsequent behavioral changes for each of these disorders is increase of cerebrospinal fluid bathing the outer layer of an evolving area of research. An increased GI may reflect a regionally diminished change as well during adolescence and adult life. 1996). weeks of gestational age. Interestingly. right parietal. resulting in altered communication between interact and affect each other. Impor- in GI in individuals with dyslexia (Casanova et al. 2004. With the continued evolution of electrophysiologi- ing of the processes associated with gyrification of the brain cal and neuroimaging tools that are able to increase our may help us achieve a better understanding of factors associ. and gyrification likely gyral columns. areas of greater con- (2004) found an increased GI in the frontal brain region.

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hypothalamus. 2005. De Vries. Kaplan and Hinds the possibility of therapeutic application in cases of develop. were not adequately cell-type specific and thus widespread acceptance in the neuroscience community. We also examine several factors and conditions 1966. Gould. amygdala. diography and suggested the possibility that neurogenesis Adult neurogenesis in the hippocampus has been demon. a substantial but apparently smaller amount single-cell level. 1999). but can selectively label newly generated neurons. Barnea and the fact that cells undergoing DNA synthesis incorporate Nottebohm. and Bittman. This technique takes advantage of far.. In the olfactory bulb and the dentate that regulate neurogenesis in the hippocampus and consider gyrus of the hippocampus. Fowler et al. tia nigra (Altman and Das. taken up by cells in the DNA synthetic phase of the cell cycle. Studying adult neurogenesis also opens unequivocally identify them as neurons. and cussing the techniques used to quantify neurogenesis in the hippocampus during the postnatal period (Altman and Das. 1965. 2006. Weickert. adult brain. Luzzati The study of adult neurogenesis depends on methods that et al. 1998. Bedard. 3H-thymidine is Canellas and Garcia-Verdugo. Gould. Gravel. To further these goals. striatum. olfactory bulb. Johnson. 2005... and integration of newly gen- erated neurons need to be identified. including humans (Altman and Das. Polenov and Chetverukhin. Early histolo- these findings remain controversial. since some glial cells receive 51 . 1998. 2001). Gould. Altman. modifying both brain and behavior. 1977). Xu et al. at the ultrastructural level.. 1999). partially resolved this issue by using electron microscopy mental abnormalities. Most neurons in the adult mammalian brain are produced In this chapter. 2001. suggesting radioactively tagging the dividing cell and all its subsequent that it is a highly conserved process. 1998. this technique proved the young adult rat dentate gyrus every day (Cameron and useful for mapping mitotically active cell populations at the McKay. 1996. 2005. et al. we consider some of the key experimental during the embryonic period. et al. Eriksson et al. 2002. 1981. survival.. In contrast. and Parent.. Perez. Stable and specific. Bernier et al.. mammalian brain Fowler. Reeves.. or trau. and the factors that regulate the produc. but a substantial number of findings that led to the discovery of adult neurogenesis. severely limited the investigation of developmental or adult although the role of adult-generated neurons in the function neurogenesis. Huang.. When injected into an animal. Quantitative estimates progeny (although the signal becomes diluted with each sub- indicate that approximately 10. to demonstrate. The discovery of neurogenesis in the adult Zhao et al. and Wang. occurs in the olfactory bulb and dentate gyrus of adult rats strated in the brains of all vertebrate species investigated thus (Altman and Das. et al. despite excellent spatial reso- neurogenesis persists in the adult hippocampus has gained lution. differentiation. 1998. Adult neurogenesis is an important 1965). including throughout life.. dis- granule cells are born in the cerebellum. 1999. 2006). neurogenesis continues through. function and behavior. and Hinds. Runyan. are added to the adult rodent olfactory bulb and hippocam- The discovery of adult neurogenesis has already altered the pus. of neurogenesis occurs in the adult primate hippocampus While it was clear from the work of Altman that new cells (Eriksson et al. 1998. way the adult brain is viewed in terms of its potential for because light microscopic examination was not sufficient to structural change. with postnatal experience substantially neocortex. Zupanc. 1965). thymidine. and substan. 2002. 1969). the identity and fate of these cells remained in question. 1993. In 1965. and Saunders. that adult- matic brain injury. neurodegenerative disease.000 new cells are added to sequent division). 1999. the possible role of adult-generated cells in hippocampal out adulthood at relatively high levels (Altman and Das. the role that generated neurons in the dentate gyrus of the rat receive adult-generated neurons play in normal functional circuitry synaptic input on their cell bodies and dendrites (Kaplan must be elucidated. 2006. 1994. However.4 Adult Neurogenesis in the Hippocampus YEVGENIA KOZOROVITSKIY AND ELIZABETH GOULD Introduction tion. Adult neurogenesis under normal conditions has also example of a developmental neural process that persists been reported in multiple other brain regions. the idea that gists relied on methods which. Kaplan. 1965.. Reeves. Dayer et al. Reeves. Altman used 3H-thymidine autora- of neural systems and in behavior is still a matter of debate. 2003.

In contrast. the granule cell layer has been formed.. 1993). Yet new granule This method provides a sensitive means for assessing the neurons continue to be produced in the adult dentate gyrus number of adult-generated cells. One promising Although the existence of adult neurogenesis in the brains method involves infecting the new neurons with a retrovirus of rodents had been firmly established. produces cells with neuronal characteristics. As a result.. Chu-Wang. incipient hippocampus and come to reside in the granule For example. 1998. BrdU is an analogue of of both rodents and primates from progenitors located in the thymidine. Okano. most dentate gyrus neurons are produced during the first two postnatal weeks. 1993. gyrus. Pfaff. visualized. since it is an immunocytochemical method.. Numerous studies 52 fundamentals of developmental neurobiology . Zhao et al. whereas the adult recordings from the new neurons. al. tors continue to divide. 1990). development of 5-bromo-2′-deoxyuridine (BrdU) labeling the granule cell layer in the macaque forms during the pre- was a major breakthrough in the study of adult neurogenesis.. Altogether. establishing its occurrence in adult monkeys and itive evidence in support of adult neurogenesis in the dentate humans (Gould. Since the advent of BrdU labeling. granule neurons arise from hood. 1993). species and therefore of relatively little importance. lium in the wall of the lateral ventricle. 1999). The lack of interest in adult neurogenesis within the progenitor cells located in a discrete part of the neuroepithe- neuroscience community may have been partially attribut. as well as electrophysiological a remarkable degree of regeneration. BrdU labeling combined expressed markers of mature neuronal phenotype. 1981). it was therefore gyrus without undergoing final cell division. seemed incongruous with the concept of persistent neurogenesis in the adult mammalian Development of the dentate gyrus brain. because available autoradiography: (1) BrdU-labeled cells throughout an entire evidence suggests that many of the new cells die within weeks brain section (40 μm thick or even thicker) can easily be of their birth (Cameron et al. 3H-thymidine-labeled cells revealed that several thousand new granule neurons are were shown to incorporate retrograde tracers injected into generated daily in the dentate gyrus of adult rats (Tanapat the CA3 region (Stanfield and Trice. The observation that the adult brains of less a detailed morphological characterization of dendrites and complex vertebrates.. (2) the sensitivity of BrdU labeling can be amplified. in primates. cell-specific antigens used to determine the phenotype of 1978). Cameron and McKay. These advantages of the BrdU labeling method allowed for cell-type-specific antigens and combined thymidine label. Retroviral tools have enabled nomenon. Eriksson et al. immunohistochemical advances that enable staining cells. and Maderdrut. which is incorporated into DNA and can be hilus and subgranular zone. while 3H-thymidine autoradiography only allows for the detection of labeled cells in the top 1–3 μm of a tissue Hormones regulate adult neurogenesis section. Brain development in mammals was thought to be a temporally defined process. additional methods for porated into the hippocampal circuitry. 1985. 1999. which are incor. These studies showed that 3H-thymidine-labeled cells 1998. Reeves. These studies have and Gibbs. In addition. 2001). natal period (Nowakowski and Rakic. migrate across the able to the inability to find adult neurogenesis in primates. 1988). et al. 2002. such as fish and amphibians. researchers to reinvestigate the issue of adult neurogenesis ing/retrograde axon tracing were required to generate defin. During embryonic development. by the end of the second Methodological Advances Lead to the Discovery of week. 1999.. completed long before adult. Some progenitor cells gyrus of adult macaques were few in number and lacked the remain in the hilus and the subgranular zone of the dentate morphological characteristics of neurons. The majority of they direct axons to the major target site of developmentally these adult-generated cells express immature and mature generated granule cells. 1988). and cell pro- Hippocampal Neurogenesis in Adult Primates The liferation and migration decrease significantly. These progeni- concluded that they were most likely to be glia (Rakic. adult neurogenesis differentiate into granule neurons in the adult brain (figure was discounted as being specific to only certain vertebrate 4. In the rat. 2006). Kornack and Rakic. giving rise to daughter cells that Eckenhoff and Rakic. of neurogenesis in the adult brain. undergo axons from new neurons. tagging new neurons have been developed. The addition of these new immunohistochemically detected using specific antibodies. early discoveries did that drives expression of a fluorescent protein (van Praag et not succeed in encouraging the in-depth study of this phe. suggesting that et al. such as beta III–tubulin (TUJ1) and convincing evidence that the adult mammalian dentate gyrus neuronal nuclei (NeuN). such as with stereological techniques allowed for the quantification neuron-specific enolase (Cameron et al.synaptic input (Oppenheim. mammalian brain does not. 3H-thymidine-labeled cells in the dentate cell layer (Altman and Bayer..1). these studies provided neuronal markers. neurons to the dentate gyrus in adulthood reflects a turnover This technique has several advantages over 3H-thymidine of the adult-generated neuron population. and (3) the Steroid hormones play a well-known role in the organization technique is highly compatible with the immunolabeling of and activation of certain behaviors.

Collectively. 1992). the rate of granule neuron observed across the estrous cycle—the production of new production decreases.. dendrites. correlation between levels of circulating adrenal steroids and hippocampal granule neuron production is observed across Ovarian Steroids In contrast to the suppressive action of the life span.. Meaney. 1996) estrogen levels. adrenalectomized young adults (Cameron and McKay. Reeves.05 also alter the structure of the adult brain by influencing relative to controls. Removal 2005. E2 E2 + P4 Figure 4.. These effects account for a sex difference in during the stress hyporesponsive period diminish the rate adult neurogenesis. 1985.. while replenishing estrogen levels and Altmann. Sapolsky. Woolley et al. 1991. Experimental rapidly reverses this effect (figure 4. In the rat. The removal of estrogen by means of and macaques (Gould. estrogen affects the negative relationship between the levels of adrenal steroids survival of adult-generated cells in the dentate gyrus (Tana- and granule neuron production. Tanapat et al. neuron production (Schlessinger et al. kozorovitskiy and gould: adult neurogenesis in the hippocampus 53 . 1992).2). Removal of adrenal steroids by means of is temporary. Ovx Ovx Ovx giving rise to daughter cells that migrate into the granule cell layer + + and differentiate into granule neurons. 1990). Increases in glucocorticoids pat et al. Over the past few Treatment with progesterone 48 hours following the last two daily decades. structural development of the brain. Error bars represent SEM.. p < 0. Tanapat. 1999).. and Gould. the ovarian steroid known as the stress hyporesponsive period.. 1999). 2005.. which have proliferation in the dentate gyrus to the levels observed in been studied in depth. More recently.. 1999).. 1999).. Precursor cells residing in the hilus and the 0 subgranular zone of the dentate gyrus divide throughout adult life. with the adrenal glucocorticoid corticosterone results in a lation of adult hippocampal neurogenesis (Desouza et al. 4000 * Total number of BrdU-labeled cells in the dentate gyrus 3000 2000 1000 Figure 4. Ambrogini et al. 1991). during the first two postnatal weeks adrenal steroids on adult neurogenesis. decrease in these measures (Gould et al. synapses. whereas treatment supports the involvement of thyroid hormones in the modu. and progesterone. since under standard laboratory conditions. coincident with ovariectomy results in a decrease in the proliferation of increases in the levels of circulating glucocorticoids (Sapolsky granule cell precursors. and MeEwen. 1975. In addition to manipulations of glucocorticoids have confirmed this increasing the production of new cells. Sapolsky and 1999. estrogen. the production of new granule cells is greatest during proestrus. Some evidence also proliferation and neuronal production. 1986). when levels of circulating 2003). and cell survival (Sapolsky. the stage of maximal cells is further diminished in aged rats (Kuhn et al.2 Stereological estimates of the number of BrdU-labeled cells in the dentate gyrus of adult ovariectomized (Ovx) rats that suggest that these hormones affect behavior by altering the were treated with vehicle estrogen. In the rat. a natural fluctuation in cell proliferation is adrenal steroids are higher. adrenal and ovarian steroids were observed to alter the proliferation of granule cell precursors in the adult brain (Cameron and adrenalectomy in adult animals leads to an increase in cell Gould. 1999). a negative may act to suppress adult neurogenesis. low levels of hormone estrogen has been shown to stimulate the production circulating adrenal steroids coincide with maximal granule of new granule neurons in the dentate gyrus (Tanapat et al. but this chapter concentrates of circulating glucocorticoids in aged rats returns cell on the effects of adrenal and ovarian steroids. these observations illustrate that adrenal Adrenal Steroids Several lines of evidence point to an steroids are potent mediators of adult neurogenesis and inverse relationship between adrenal steroid levels and the suggest that stressful psychological and physical experiences proliferation of granule cell precursors. et al. Hastings.. Krey. 1994.. With aging. studies have demonstrated that steroid hormones injections with estradiol rapidly reverses an estrogen-induced increase in cell proliferation. During adulthood.1 Granule cell neurogenesis in the adult dentate gyrus of the hippocampus. This effect et al. 2005). First. Ormerod et al. such that female rats produce more new of granule cell production in the dentate gyrus (Gould granule cells than males (Tanapat et al.

long after the basal and stress levels of the main rat Gould. cant decreases in the proliferation of granule cell precursors in the sense that rats seek access to a running wheel. or 3 weeks thereafter. 6000 Experience regulates adult neurogenesis * 4000 Because the majority of neurons in the dentate gyrus are * 2000 produced postnatally. For example. using a variety of stress-inducing para. the main component of fox feces. controls. while at the same The effect of stress on neurogenesis is observed across many time enhancing neurogenesis by affecting cell proliferation mammalian species. neurogenesis reductions is not always simple. and Gould. results The relationship between stressful experiences and adult in an activation of the HPA axis accompanied by an inhibi. a stress hormone–independent rebound in cell proliferation Stress suppresses cell proliferation in the dentate gyrus of has been reported following stressor cessation (figure 4. 2005. 2006. most relative to LP and CC controls. this brain region has the potential to undergo functionally significant experience-dependent struc- tural changes during postnatal development and adulthood. that adrenal steroids are known to suppress the production results in continual suppression of cell proliferation and a of new neurons. The during the early postnatal period can have a very long. exposure to tri. these studies indicate that stress inhibits proliferation of granule cell precursors in male rat pups the proliferation of granule cell precursors during develop- (Tanapat. 2004).. 1999. as will be examined further later on. 2003). Error bars represent SEM. it is not surprising that exposure to the decrease in the volume of the granule cell layer (Fuchs et al. Cage control induced increases in the pool of immature granule neurons 8000 Large platform Number of BrdU-labeled cells Small platform may still exert an impact on hippocampal function. 0 The remainder of this chapter focuses on several experiences 2 hr 1 wk 3 wk currently known to regulate adult neurogenesis in the hip. methylthiazoline. The impact of stress on adult neurogenesis can sufficient to increase levels of circulating glucocorticoids in be additive over time.. possibility is that positive and negative stressors affect adult digm (Gould et al. after prolonged sleep deprivation. Stranahan. (Mirescu et al.. Stressful experiences ment.. factors that underlie the effect of stress on cell proliferation lasting impact on hippocampal neurogenesis. Estrogen. and a similar picture is observed in adult rats social context—after a brief period of running. 1994. while Roman et al. Mirescu et al. For example. ♦ p < 0.many of these new cells degenerate over time. 1 week. adult tree shrews show decreased neurogenesis differently. 2003. are not fully understood.. however. *p < 0. 1998). For example. 2006). While the stress-induced stress hormone corticosterone return to normal (Mirescu. 2006). 2006. adult marmosets demonstrate signifi. and Gage. and Gould. socially following sleep deprivation (Guzman-Marin et al. Galea. tion of the proliferation of granule cell precursors (Mirescu. van der Borght singly housed animals show a decrement in this measure 54 fundamentals of developmental neurobiology . and Gould. Khalil. 2004. In adult male rats. Gould et al. Galea. 1998). However.3 Reduced cell proliferation and adult neurogenesis function of the hippocampus. Rats subjected to 72 hours of sleep deprivation (small platform. rise in glucocorticoid levels downregulates these measures. Survival following BrdU injection pocampus and the implications of these findings for the Figure 4.. and Gould. During the stress hyporesponsive period. adrenal (HPA) axis fail to elevate circulating glucocorticoids. 1997).. Since running is a positive stressor. Collectively. layer of the dentate gyrus. glucocorticoid-induced re- daily maternal separation is associated with reduced levels duction in cell proliferation through an NMDA receptor– of neurogenesis in the offspring when they grow up (figure dependent mechanism is likely to play a role (Cameron and 4. and Gould. housed rats have increased levels of neurogenesis. one when exposed to the social stress of a resident intruder para. Sleep-deprived rats had lower numbers of BrdU-labeled cells in the subgranular zone/granule cell decreasing cell proliferation (see Mirescu and Gould. odors of an unfamiliar adult male rat also suppresses the 1997).05 for review). as well as in adulthood. as well as behavior. Peters. in a variety of mammals. wheel running increases the levels of circulating glucocorti- Peters. exposure to the odors of natural predators is et al. Galea. 2006). 2006). which does not evoke adaptation of the HPA axis. Tanapat. cage Stress Numerous studies have demonstrated that stressful controls) received a single injection of BrdU and were perfused 2 experiences alter adult neurogenesis in the dentate gyrus by hours.. digms. Kempermann. In addition. large platform controls.4) adult animals as well. and Gould.. 1997). Given stress. the effect of running neurogenesis after exposure to subordination stress (Gould on the number of adult-generated neurons is mediated by et al. (van Praag.05 relative to LP stressors that normally activate the hypothalamic-pituitary. 1998). coids in adult rodents (Droste et al. Chronic exposure to subordination male rat pups (Tanapat..3).

Stressors appear to regulate adult neuro. and Shors. Olariu et al. esis in the dentate gyrus (figure 4. and aged rodents (Kempermann. Khalil. The number of BrdU-labeled cells in the dentate proliferation and adult neurogenesis. Error bars represent SEM. but lower in single-housed runners compared to controls. In rodents. and were perfused in 2 weeks. behaviors that are likely to involve spatial navigation learning and. the hippocampal region. week. and the overall results genesis in distinct ways that may depend on the valence of have been mixed (see Leuner. One example is the striking relationship between experience and hippocampal neurogenesis in black-capped chickadees (Barnea and Nottebohm. Gould. black-capped chickadees that live in the wild retain more new hippocampal neurons than those that live in captivity. requires long-term exercise (figure 4. Others have shown that mice living in an enriched labora- tory environment maintain more new hippocampal granule neurons than those living in standard laboratory control cages.6 A longer duration of physical activity is required to enhance cell proliferation in socially isolated rats. 1997. Error bars rep- sleep deprivation received a single injection of BrdU 6 hours. thus. and adult neurogenesis in rodents. Separate cohorts Recovery period of individually housed rats ran for 3–48 days before being injected Figure 4. 2005). Additionally.05 relative to controls. and Gage. or 2 weeks later. 1994).05 relative to controls. Adult neu- rogenesis was enhanced after 1 week of recovery from sleep depri- vation. for the stressor and the social context of the experience.4 Lasting effects of prolonged sleep deprivation on cell once with BrdU. 1998). Multiple studies have addressed the link between learning and Gould. In animals living in standard labo- conditions associated with enhanced learning opportunities. We and others have found that the types of learning that require the hippocampus tend to increase the number of Learning Studies have reported changes in the number of new neurons in the dentate gyrus of adult rats (Leuner et al. Kuhn. these running on adult neurogenesis. 2006. 2006).. nutrition. review). p < 0. rats living in isolation eventually manifest the nant and subordinate animals living in a seminaturalistic running-related increase in adult neurogenesis.6) (Stranahan. p < 0. the influence of environmental complexity on the number of new granule neurons appears to be main- tained throughout the life span. Error the positive impact of social dominance on adult neurogen- bars represent SEM.5 Social context mediates the influence of short-term animals living in the wild and in a laboratory setting. p < 0. ratory conditions. 1 resent SEM. young adult. Rats received daily injection of findings present the possibility that increased learning oppor- BrdU and were sacrificed on day 12..5). It is possible that cells was greater in group-housed runners compared to controls. new hippocampal granule neurons in adult animals living in 2004.05 relative to controls.7) (Kozorovitskiy and Gould. Rats subjected to 72 hours of gyrus was increased only after 48 days of running. Cage control 10000 12000 Control Small platform * Runner * Number of BrdU-labeled cells BrdU-labeled cells in the 8000 10000 dentate gyrus 8000 6000 6000 4000 4000 2000 2000 0 3d 6d 12 d 24 d 48 d 0 6 hr 1 wk 2 wk Figure 4. affecting juvenile. 2004) might also relate to the differences in the opportunities for social learning that are available to domi- (figure 4. New neurons persist for longer periods of time during parts of the year when these birds engage in seed storage and retrieval. and activity levels differ between Figure 4. but this effect environment. social interaction. The number of BrdU-labeled tunities alter the survival of new neurons. many adult-born cells degenerate over kozorovitskiy and gould: adult neurogenesis in the hippocampus 55 . While many variables such as stress.

Dayer et al.05 relative to controls. Although attempts have been made to deter- mine whether task difficulty and hippocampal dependence are critical for the influence on adult-generated cells (Leuner et al. and cells in the dentate gyrus compared with subordinate animals (Sub) and cage controls (Con).8 Trace memory formation persistently enhances the increased the number of BrdU-labeled cells when compared with survival of newly born cells in the dentate gyrus. although not their learning tasks. and Thompson. or time points could easily miss when many newly generated granule neurons die signifi. measure. Dominant rats (Dom) had more BrdU-labeled in the numbers of new neurons (see Leuner. months (figure 4. One possible difference between the two sets of tasks is their difficulty. ing (Epp et al. Error bars represent SEM. 2005). these issues remain unresolved. This increase in survival persists for diminish the number of new neurons in the dentate gyrus. 2001. Gould. It is additionally possible that other types of cantly enhances the rate of their survival. after trace conditioning or unpaired training. Total numbers of exposure to unpaired stimuli at all survival times. BrdU doses. neurogenesis in the dentate gyrus alters only those cells that are produced within a specific time period prior to the learn- time (Cameron and McKay. 2006. Thus studies that have utilized differ- ing on hippocampal-dependent tasks during the time period ent paradigms. such as differences access to an enriched environment during the survival time after in schedules of BrdU injection and survival times. the effects of learning on adult neurogen- 6000 6000 6000 * 5000 5000 5000 * BrdU-labeled cells BrdU-labeled cells BrdU-labeled cells 4000 4000 4000 * 3000 3000 3000 2000 2000 2000 1000 1000 1000 0 0 0 Unpaired Trace paired Unpaired Trace paired Unpaired Trace paired 1 day 30 days 60 days Figure 4. A recent BrdU injection. such an effect.. 30. It Sub * is unclear what specific aspects of hippocampal-dependent tasks are necessary and sufficient for the enhanced survival of adult-generated cells. Electrophysiological studies have BrdU+ cells in the DG 5000 * shown that both hippocampal-dependent and hippocampal- independent tasks activate hippocampal neurons (Weisz. in press). 1984). 2 weeks after a single BrdU injection. Error bars rep- BrdU-labeled cells in the dentate gyrus of animals 1. for review). 7500 2004). other reports have either Figure 4.05 relative to study has verified that the learning-induced enhancement of controls. might production. p < 0. Some of these discrepancies can be difference was maintained in animals whether or not they had attributed to methodological variations.8).7 Status in the social dominance hierarchy influences failed to find such increases or instead have found decreases adult neurogenesis. long after the time that task performance obscuring the enhancing effect of learning on this brain becomes independent of the hippocampus (Leuner et al. Clearly. 0 Cage Enriched Unenriched In addition to studies finding enhanced adult neurogenesis with certain types of learning. training on tasks that do not require the Con Dom hippocampus does not affect the number of new neurons. Several tradi- tionally used learning tasks that require the hippocampus are 2500 more difficult to acquire than those that do not rely on this brain region. Trace conditioning 56 fundamentals of developmental neurobiology . in adult rats.. Clark. or 60 days resent SEM. In contrast. Train... p < 0. particularly those that are stressful. This Shors. 2006).

recent studies suggesting that be capable of exerting an impact on hippocampal function new neurons are activated by exploration and learning expe. which is impor.esis in the hippocampus are complex and likely dependent Parallel Changes in Adult Neurogenesis and on the age of the neurons and the particular learning task Learning Since new granule cells require time to dif- examined. ment with estrogen for more than four days results in Aside from the data showing that learning alters new enhanced performance on a hippocampal-dependent task neuron number and activation. Several studies have demonstrated that during the postnatal developmental period might be impor. This finding is consistent with the suggest that new neurons might be involved in learning. development (Overstreet et al. Second.. because they are The functional significance of neurons generated in the most likely to elucidate the functional consequences of dentate gyrus of adult animals remains unknown. some studies report decreases imply a functional utility for adult neurogenesis. Zhao et al. 1994. Squire and Zola. chronic increases in the factors that negatively regulate adult tant for learning and memory. increases in cell production to have a functional effect. sions).. changes in Although the exact manner in which learning alters adult cell proliferation are not likely to result in immediate neurogenesis remains unresolved. Krugers et al. 2006. for review. whereas sonable to consider a potential role for these new neurons chronic increases in the factors that positively regulate adult in learning. 1995. Gould. 1967. dependent tasks. 1992). 2001). suggesting that the granule “micro.. Weiss. and Praag et al. and Shors. 2005). 1996.. in performance during times of high levels of circulating ally rejuvenating population of new neurons seems well estrogen. their incorporation into the hippocampus. It should be noted passive membrane properties.. as well as for generated cells to extend axons is required for estrogen-induced consideration of the studies that do not reach similar conclu. It is likely that sufficient time for adult- Leuner. Chronic treat- 1998).. action potentials.. This substrate for learning in the adult (Nottebohm. In addition. impairments are not permanent. and synap. these behavioral changes were response to the neurotransmitter GABA they seem to observed shortly after stress and may likely involve other resemble immature granule cells generated during early cellular mechanisms.. 2002. although in their Thompson. 1998). 1997). survival may not be of sufficient magnitude to produce an observable functional impact. additional lines of evidence (Luine et al. 1965. 1973). the new neurons are likely functional consequences. conditions under Functional significance of adult neurogenesis which cell proliferation and survival are chronically enhanced or diminished are of particular interest. and Wojtowicz. Given changes in adult neuron production and survival. 2006). 2006. performance on hippocampal-dependent tasks. although adult-generated cells may altered by learning. the performance of animals ment of learning processes. dependent learning (Luine et al. to involve changes in neuron production. multiple studies attempting to interfere with Consistent with studies that have demonstrated a positive adult neurogenesis have found impairments in certain types effect of estrogen on the performance of hippocampal- of learning and memory tasks. several studies report a positive correlation between prior to four days after their production (Hastings and the number of new neurons and learning performance (see Gould. Kee. 1999). ferentiate and become integrated into circuitry. These stress-induced neurons” are morphologically well suited for the develop. favoring females. 1992. in spatial kozorovitskiy and gould: adult neurogenesis in the hippocampus 57 . the time suited for the proposed transient role of the hippocampus frame examined in many studies is likely to be too early in information storage (Squire. Snyder and Cameron. Elec. However. As in the case of acute stress studies. it is important to riences (Ramirez-Amaya et al. that previous work has reported that brief stress enhances tic inputs similar to the surrounding granule neurons (van hippocampal-dependent learning (Shors. Although estrogen treatment has generally been animals (Snyder. note that acute changes in cell proliferation and neuronal 2006). Subsequently. Bodnoff et al. observation that adult-generated cells do not extend axons First. granule neuron production are associated with enhanced Altman was the first to propose that neurons generated cognitive function. and the effect of learning on granule neuron production are associated with poor the number and activation of these new cells. which may found to enhance learning. confirm this hypothesis. Luine et al. observation is consistent with a possible role for adult- trophysiological studies of adult-born fluorescently labeled generated cells in hippocampal function: the deficit may only neurons indicate that the new cells eventually develop last as long as neurogenesis is impaired. chronic stress results in an impairment of hippocampal- tant for forming associations (Altman and Das.. it seems rea. It has been suggested Several studies have demonstrated that estrogen has a that new neurons positively contribute to the amount of positive effect on the acquisition of hippocampal-dependent synaptic plasticity shown by the hippocampus in adult tasks. In general. 1994. Nottebohm tested on a spatial task long after the termination of stress is suggested that new hippocampal neurons may be a cellular similar to unstressed controls (Luine et al. Altman et al. such as changes in synaptic plasticity. a sex difference. prior to complete maturation. 1989). A continu... 1996). As a result. Indeed.

neurogenesis in the hippocampus by inhibiting the process The production of new neurons can be inhibited by adrenal and examining the behavioral consequences. same criticisms made for similar studies of learning and Studies have also demonstrated a positive correlation memory. 2006. For example. important for certain types of learning and memory. Kuhn. experiences. genesis. and Shors. dendritic architecture. Furthermore. synapto. 1998). Achanta. by affecting either cell proliferation or cell survival. anxiolytic action of antidepressants in an animal model of tionship between new granule neurons and certain types of chronic stress. Although these findings are also open to the learning. and cell death these discrepancies involves the different methods used to are traditionally viewed as developmental processes. new neurons. 1996). The 58 fundamentals of developmental neurobiology . Some of the techniques that navigation learning in rodents on this task have yielded have been used to study the connection between learning conflicting data (Bucci. Similarly. 1996).. Taken together with the observation that females leagues (2003) have shown that focal irradiation of the produce more new granule neurons than males (Tanapat hippocampus inhibits adult neurogenesis and prevents the et al.. and Martinez. Gould. control the production of new However. 2006). synaptogenesis. another study demonstrated a sex In addition to assessing whether learning and memory difference favoring females in hippocampal-dependent are affected by ablation of adult neurogenesis. One reason for sion. learn better than males once the animals have been accli. Thus any behavioral changes observed after of new granule neurons produced in adulthood and the experiences that impact adult neurogenesis cannot be attrib. enriched environment living (Kempermann. the specific conclusions of these studies differ.navigation learning in rats has been reported (Perrot-Sinal reduce adult neurogenesis. and adult neurogenesis are treatment with the antimitotic Kavaliers. 1995. Chiba. than males. Fuller et al. campus related to anxiety regulation. the amygdala and prefrontal cortex It is evident that new neurons are generated in the hippo- have been identified as brain regions sensitive to experience campus of adult mammals. females adulthood (Shors et al.. and transgenic the former study demonstrate that although male rats ini. it should be noted that many neurogenesis is necessary for hippocampal function in learn- of the factors and conditions known to alter the number of ing and/or anxiety regulation awaits further investigation. fear conditioning and spatial navigation learning (see Cellular phenomena such as neurogenesis. both of which these experiments suggest that adult-generated neurons are act by altering cell proliferation. while others have observed no effect on context function. variety of species in which this process has been reported uted solely to the alterations in the number of new neurons. and Thus the definitive answer to the question of whether adult Gage. these data indicate an additional positive rela. including humans. steroids and stimulated by ovarian steroids. such as stress and learning. studies have learning as well. Previous studies of sex differences in spatial employed to assess learning. they suggest the possibility that structural plastic- between the number of new granule neurons and perfor. ity in the hippocampus is also involved in the therapeutic mance on hippocampal-dependent learning tasks following response of antidepressants. Collectively. also affect tively depleting the hippocampus of new neurons without other measures in the hippocampus—for example. The number and hormones. 2006. Fuss. Galea. neurons. However. females learn certain aspects of this task better confound in interpretation of these studies. Thus a sex difference in neurogenesis work on different timescales and vary in their reaction to the novelty of this task prevents females from effectiveness. and object strate by which hormones and experience alter hippocampal recognition. causing unrelated changes in other cell populations. as well as the different paradigms et al. axon exten- Leuner. The possibility that they affect other aspects performing well. and Gallagher.. Finally. for review). at least with regard to anxiety. 2002. suggest that new neurons are important for the function of this brain region. context ated granule cells may provide an important cellular sub- fear conditioning. dendritic development. 1997. Some have shown that decreasing adult neurogenesis impairs Collectively. 1999). either by affecting the proliferation of precursor including the development of new methodologies for selec- cells or by altering the survival of new neurons. the results of drug MAM. Studies carried out over the past several Blockade of Neurogenesis and Learning Several studies years have demonstrated that the production of new granule have attempted to determine the function of adult cells in the hippocampus can be modulated by hormones. and Ossenkopp. Santarelli and col- 1998). these observations suggest that newly gener- trace eyeblink conditioning. trace fear conditioning. the hippocampus is not the sole brain region affected by Conclusions experiential and hormonal treatments that affect adult neu- rogenesis. models with impairments in cell proliferation induced in tially perform better than female rats on the task. This study reported that females learn trace examined another class of behaviors involving the hippo- eyeblink conditioning faster than males (Wood and Shors. and dendritic spines. spatial navigation memory. After this performance confound is of brain function also remains an important potential removed. Methods for decreasing adult mated to the testing apparatus. global or focal irradiation. However.

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brain stem. Finally. 2006. KARINA QUEVEDO. and ventral subicu- tify pathways through which adverse experiences affect lum (Herman et al. AVP potentiates this process. parental loss. studies of children are increasingly employing and Cullinan. mechanisms through separated from a caregiver. in the bloodstream occur approximately 20–30 minutes after 1995. while the inhibitory inputs include the medial differences in stress vulnerability and resilience and to iden. interpretation of cortisol-behavior findings is often mpPVN is activated by means of signals relayed from the fraught with ambiguity. both to understand individual nalis (BNST). and the critical role that psychoso. For brain development. gene transcription and thus having long-lasting effects on 63 . we describe the anatomy stressors. see table 5. As depicted activity of the limbic-hypothalamic-pituitary-adrenocortical in figure 5. This The LHPA system is one of the two primary systems regulat. adrenocorti- these relations are complex and often dependent on context cotropic hormone (ACTH) is derived from the POMC and age. 2005). While the information in this chapter will Once released by the mpPVN. Shekhar et al. 2005). and the response tive and negative associations are obtained for the same would occur even if the animal were unconscious. and culminates in increased adrenocortical pro- see Cicchetti and Cohen. 2003. Herman research. 1997). sometimes both posi. in contrast.1. arginine vasopressin (AVP) from the medial parvocellular neglect. preoptic area. 1957. it CRH receptor 1 (CRH r1). region of the paraventricular nucleus (mpPVN) of the hypo- tional disorders and poor academic outcomes (for review thalamus. stimulating synthesis of the pro- should help researchers new to this area understand why opiomelanocortin (POMC) molecule. occurring at and childhood. prefrontal cortex. Cortisol binds to intracellular sympathetic adrenomedullary (SAM) system. Stressors in the form of abuse. context-independent physiologi- which can now be done using noninvasive sampling of cal stressors to the body such as hypoxia or infection—the saliva. Such psychological processing. TARULLO. Based on this inputs to the mpPVN (Gunnar and Davis. and poverty increase the risk of emo. will not be receptors throughout the brain and periphery. and Lewis. develop.. The LHPA stress response pathway begins with the on the developing brain (Levine. 2006). influencing covered extensively in this chapter because of space limita. we provide a very brief introduction the level of the limbic system and prefrontal cortex. For instance. As we will describe. secretion of corticotropin-releasing hormone (CRH) and for review see Levine. The other mammalian stress system. duction of stress hormones called glucocorticoids (cortisol in research on animals and adults supports the hypothesis that humans and primates. such as being chased by a predator or and physiology of the LHPA system. stimulating the synthesis and release of cortisol. In turn. 2004. the pituitary. ity and resilience. ences the signals sent to the mpPVN. the major hormonal product of the central amygdala and lateral bed nucleus of the stria termi- LHPA system in humans. CRH and AVP travel to not reduce the complexity of interpreting cortisol-brain. In this chapter. the activation of the mpPVN. 1997). where CRH binds to the anterior pituitary behavior relations in studies of human development. Processive target behaviors.1). molecule and released in pulses from the anterior pituitary.. such that peak cortisol levels ing mammalian stress responses (Stratakis and Chrousos. the initiation of this cascade is modulated by (LHPA) system plays a role in mediating the impact of an intricate network of both excitatory and inhibitory limbic adverse experiences on the developing brain. cascade is a rather slow process. BNST. systemic stressors—that is. corticosterone in rodents). require interpretation (process- which this system may impact brain development. Alpert.5 The LHPA System and Neurobehavioral Development AMANDA R. The excitatory inputs include the measures of cortisol. often through limbic circuits. 2002. AND MEGAN R. ACTH then enters the blood- LHPA anatomy and physiology stream and binds to receptors on the cortex of the adrenal gland. Herman and cial processes play in regulating its activity during infancy Cullinan. GUNNAR It has long been known that stress has significant impacts tions. Despite the ease of measuring cortisol. experience (Gunnar and Vazquez. ing) by the animal: assessing environmental threat and emo- mental changes in animals and children in the reactivity of tional significance by comparing the current situation to past this system to stressors. influ- to work on genes that may be important in stress vulnerabil.

and associated receptors Regions Associated Stress-Related Predominant 64 with LHPA Stress Behavioral Effects of Receptors of Expression of Response Secreted Agent Neurobiological Effects Symptoms Stress Interest Relevant Receptors Effects of Eeceptor Activations Hypothalamus Arginine Vasopressin Stimulates the release V1b Pituitary Increases sensitivity of AP to (mp PVN) (AVP)—just in of ACTH by CRH PVN modulating the actions of CRH Amygdala Corticotropin. 1. its release 1982) Cortex of the Glucocorticoids: Basal levels Sense of increased Acute: Mineralocorticoid Hippocampus Maintains electrical activity in adrenal gland cortisol in humans 1. Mediates 4. metabolism and if elevations release Higher affinity for (in primates) HPA rhythm corticosterone in energy utilization prolonged. neurobiological and behavioral effects. Anxiogenic and norepinephrine via 3. Mediates the fast fight-flight (POMC) in the readiness to its release Pituitary response anterior pituitary respond Hypothalamus 3. Binds Choroid plexus 2. Inhibits growth and MR binds reproduction aldosterone 2. (adrenal cortex) and other primates. Enhances synaptic increased increases at basal levels availability.1 Regions involved in the LHPA system: their hormonal products. see work by or de Wied (e. Mediates changes in ACTH releasing hormone production of arousal. Contains immune Glucocorticoid Pituitary Induces the termination of the and inflammatory (GR) Hypothalamus HPA activation responses Lower affinity for Hippocampus Reduces cerebral glucose 3. May promote recovery from 4. increases (MR) Frontal cortex neurons. Increases vasodilatation and synaptic plasticity avoidance and (II and III) Hippocampus diminishes blood pressure involved in memory decreased formation and social behavior learning Anterior pituitary 1. by Chronic: cortisol. Regulation of vigor followed. Adenocortico.. binds Facilitates cerebral glucose rodents 2. de sensitizes Wied and Jolles. response to stress. Stimulates 1. chronic: affinity for Cerebellum release (CRH) propiomelanocortin alertness and increases CRH Hippocampus 2. Table 5. Increases Amygdala to processive stressors release of startle 4.g. Some impacts via Acute or ACTH-R Cortex of the adrenal Stimulates the synthesis and fundamentals of developmental neurobiology (AP) tropic hormone retrograde passage chronic: gland release of glucocorticoids (ACTH) (derived from pituitary to increases from POMC) CNS. Augments Acute or CRH-1R: higher Neocortical areas 1. Increase is preferentially Olfactory bulb stress and adaptation mechanisms of related to with urocortins Amygdala 3. Dendritic atrophy cortisol. Stimulates the 2. and SAM system’s learning emotionality decreases nervous system immediate stress response Chronic stress levels release Outside the brain. Enhances neuronal trigger fear affinity for Lateral septal nuclei antidepressive responses excitability and anxiety CRH. Elevations in depressogenic effects the locus coeruleus amygdala CRH-2R: lower Subcortical areas 1. blood pressure. Mediates defensive responses 2. thus increasing and apoptosis at high Medial frontal cortex risk of neuronal death concentrations and other limbic Impairs synaptic plasticity and regions memory formation . synaptic plasticity underlying negative or in the central plasticity. Evokes anxiolitic and Hippocampus 3. binds Amygdala availability. 1.

Kwak et al. Within means of studying the influence of stressful experience on minutes. down-regulates CRH gene expression in the hypothalamus and POMC gene expression in the anterior pituitary. Rather. Once activated in response to a systemic or processive stressor. Basal cortisol levels peak about 30 are generally limited to measuring cortisol levels and must minutes after waking and gradually decline across the day rely on animal models to draw tentative inferences about to reach their nadir in the late evening. Romero. and the decline across the day becomes more researchers for assessing LHPA reactivity. The hippocampus and the amygdala are connected of sympathetic hormones (norepinephrine. cortisol binds to receptors in the anterior pituitary. and The hypothalamus is also a key region in the sympathetic adreno- amygdala are also reciprocally interconnected. activation of the LHPA cascade at arginine vasopressin (AVP).. with varying time courses and mechanisms. either directly or by way of limbic cir. Over the course of hours to days. The lateral hypothalamus activates nuclei in the ventral subiculum also have pathways to the hypothalamus by way brain stem. OFC. near the onset of what is occurring at the levels of the pituitary and hypothala- sleep (Daly and Evans. the developing brain. 2006). quevedo. Sapolsky. 1993). bed nucleus of the ticoids (cortisol in humans). level excitatory and inhibitory inputs. a number of methodological consider- al. The amygdala and medullary system.1 Schematic of activation pathways for the LHPA the mpPVN produces corticotropin-releasing hormone (CRH) and system. 2004). Interrogating the LHPA axis in the context of human devel- The LHPA system does not lie dormant between stress opment presents a host of challenges. thereby LHPA measurement in developmental research exerting a prolonged suppressive effect on ACTH secretion (Gunnar and Vazquez. and gunnar: lhpa system and neurobehavioral development 65 . In humans. have direct inputs to the hypothalamus. NE Locus coeruleus Spinal ACh Brain stem Anterior Cord NE cingulate Amygdala Hippocampus Hypothalamus Adrenal Orbital BNST Anterior pituitary Medulla EPI PFC POA CRH ACTH Cortex GC Ventral subiculum Cortico-Limbic Level Hypothalamic–Brain Stem Level Neural-to-Adrenal Level Figure 5.. which travel through the hypophysial the level of the medial parvocellular region of the paraventricular portal system to the anterior pituitary gland. that regulate release of the BNST. Over the past several at multiple levels by means of this signaling (see Dallman et decades of research. The anterior cingulate ACTH stimulates cells in the adrenal cortex to produce glucocor- (ACC). human development researchers LHPA circadian rhythm. 2003. and develop a more adultlike sleep schedule (Watamura Modulation and eventual termination of the LHPA stress et al. 1998). hippocampus. NE. For processive stressors. and epinephrine. mus (Gunnar and Vazquez. which releases norepinephrine to brain EPI) and parasympathetic hormones (acetylcholine. orbital frontal cortex (OFC). Cortico-limbic regions including the stria terminalis (BNST). and Davis. 1992).g..) physiology and behavior (de Kloet. 2000). inhibiting the LHPA axis stress vulnerability and resilience. the stress response is superimposed on an practical considerations. For systemic stressors. ACH). the mpPVN is pathways traveling from the spinal cord to preganglionic nuclei or activated by the brain stem. stimulating the pro- nucleus (mpPVN) of the hypothalamus depends on cortico-limbic. stable by 4–6 years of age as children give up daytime naps and Munck. and preoptic area (POA) all hippocampus and ACC maintain feedback control of the PVN. Ethical concerns also this circadian rhythm is evident by 6 weeks of age (Larson restrict the paradigms available to human development et al. duction and release of adrenocorticotropic hormone (ACTH). with areas involved in alerting. cortisol also ations have come to light. Pharmacologic tarullo. to the locus coeruleus (LC). amygdala. the adrenal medulla). to target organs (e. including the parabrachial nuclei. 1974. Because of ethical and responses. 1991. Thus developmental researchers are frequently response is achieved by means of multiple negative feedback interested in assessing LHPA rhythmicity and reactivity as a loops. as well as individual differences in hypothalamus. 2006). (Adapted from Gunnar cuits. The ACC. and hippocampus...

researchers interested in stress stress response (Dickerson and Kemeny. 1990). even samples collected following a psychosocial stressor.. such as collection context and time of day. this approach is misleading because the first sample is not Goodyer and colleagues (2000) noted that among adoles- a typical baseline measure: It reflects an LHPA response to cents at high risk for depression. develop- sample can prudently be considered “baseline.probes are rarely used with children. Legendre and Trudel. Second. design and the interpretation of cortisol results must take faceted dynamic processes affecting cortisol levels.. sample varying depending on the question of interest. Gunnar. Aggregating time-matched samples across three or samples is a complicated. There. 1992. consideration address the baseline problem. simply aggregating sample values. and often ethically Because of the LHPA diurnal rhythm. 1989. Because of the multi. Sampling on a single day is tively well defined procedure. more refined picture samples at the same time of day as the laboratory visit. While assessed in the laboratory. interpreting the unlikely to be sufficient to detect stable individual differ- significance of the cortisol values obtained from those ences. are suppressed upon arrival at the laboratory compared to Given these findings. berg. In a recent study by be paid to deciding when. at 13 ing cortisol reactivity in children have often compared a exhibited higher and more variable cortisol levels soon after cortisol sample collected upon arrival at the laboratory to awakening than did children of nondepressed mothers. 2003. van ability to probe the axis. time of day is approved psychosocial stressors do not reliably activate the another key design consideration. Lund. collection context. Gunnar et al. separation from a caregiver gener. ambiguous undertaking requiring more days provides a more reliable measure (Gunnar and consideration of many variables that affect the LHPA Talge. ally elevates cortisol levels. children whose mothers sample cortisol (Gunnar and Talge. 1996. at the design phase of a study.. with the best time to LHPA axis.. of the effects of early adverse experience on cortisol rhythm which is equivalent to animal researchers’ definition of base. in press.. However. and reactivity. when children are informing our understanding of the LHPA system. 66 fundamentals of developmental neurobiology . although elevations in response Latent state-trait modeling has demonstrated that the to brief separations are not always observed among infants maximum trait component occurs shortly after waking. another interpretive challenge. 1990.. hierarchical linear modeling to isolate variability may yield berg et al. Shirtcliff authority figures) sometimes are effective in provoking a et al. be informative. Larson. abnormally high morning cortisol levels across four days of ous. and how frequently to Halligan and colleagues (2004). 1991.g. Tottenham et al. while collection of salivary cortisol samples is quite found that older children (ages 9 and up) had higher cortisol straightforward.. Research between early and later childhood. 2007. indicating that there may be developmental differ. a richer picture of LHPA function than can be obtained by and Hertsgaard. the day-to-day variation itself may system. 2007). 2007). Spangler and Schieche. and Rasch. no one into account the time of day. making this a good sampling time for For older children and adults. However. First. 2004). particularly in identifying abnormal LHPA fore. 2005). evening. Conversely. view of the influence of cortisol and CRH on the brain.. For infants. the diurnal peak. careful attention must function and risk for psychopathology. Variability in cortisol levels from day to day presents Collecting salivary cortisol samples is a noninvasive.. The next section provides an over- Goozen et al. 1998). On the positive side. However. researchers allow for an extended interpretation of adult and animal studies is also challenging. human development researchers line levels as those observed when the animal has been left owe a substantial debt to the adult and animal literatures for undisturbed in the home cage. In contrast. period of acclimation to the laboratory context prior to there are somewhat less severe constraints on researchers’ collecting baseline samples (Gunnar and Talge. and variability in commonly use one or both of the following methods to cortisol from day to day. more severe stressors. Several studies have Thus. the use of statistical methods such as samples collected at home at the same time of day (Gold. cal issues constrain the techniques available to human devel- ences in response to the laboratory collection context opment researchers to probe the LHPA axis. Ethical and practi- 2001). reactivity may choose to sample in the late afternoon or the inconsistency of these mild manipulations in raising cor. Kirsch- models to inform our understanding of cortisol reactivity to baum et al. were clinically depressed during their first year of life.. they collect home of all these variables may yield a richer. when state components are higher and the system tisol levels in children necessitates a heavy reliance on animal is more responsive to stressors (Dallman et al. For reasons that remain mysteri. obtaining one or more coming to the laboratory. rela. infants and preschoolers often show cortisol levels that sampling predicted onset of depression in the ensuing year. Westermark. 2007). manipulations that involve a researchers interested in stable individual differences in threat to the social self (such as critical social evaluations by basal cortisol levels (Kirschbaum et al. after controlling for maternal depression postinfancy. Studies measur. However. where. at over 12 months of age (e. 1993).” Researchers mental differences in LHPA reactivity. meaningful assessment of LHPA function levels upon arrival at the laboratory than time-matched in children is a far more problematical and ambiguous home samples (Gunnar et al. undertaking than it might at first appear.

Influence of cortisol and CRH on the brain 1994. Romero. such effects. basal levels do play a crucial role multiple brain regions including (but not limited to) the hip. they support the ability to immediately respond to stressors making adjustments in the allocation of the body’s resources by means of the other stress system (i. For example.. 1952. 1991). and Dallman. Romero. 2007). see Gunnar and dehydrogenase. mediated activity in the hippocampus. 2000). 2000). 2000). Cortisol readily per. with the result that LHPA responses may 1993). These MR-mediated effects are classified as permissive because Cortisol targets tissues throughout the brain and periphery. Two characteristics of MR paratory effects. ing the mpPVN. Ingle. Similarly. MRs increase cerebral glucose avail- mineralocorticoid receptors (MR) and glucocorticoid recep. and Joels. These effects include dala. turning off stress-induced with glucocorticoid receptive elements (GREs) on the immune system responses and opposing impacts of stress- genome and modulates gene expression. and gunnar: lhpa system and neurobehavioral development 67 . Romero. 2006). and Munck. preparatory impacts of cortisol on CRH- are bound (de Kloet. we discuss the better-understood genomic effects the aftermath of a challenge (Sapolsky. quevedo. Cortisol mediates genomic effects by binding occupy GRs. and its activity influences imminent physical threats. MR to GR occupation (de Kloet. For example. However. and ers is that cortisol is a gene transcription factor that plays pituitary also serves to contain stress-induced activations of complex roles in modulating genes involved in brain devel. These receptors mediate different types of effects (Sapolsky. the fast-acting sym- in response to stressors in the environment that threaten pathetic adrenomedullary system. These opposing tarullo. that occur when cortisol binds to its receptors. and facilitating cere- bral glucose availability (Bradbury. Oitzl. chronically low and chronically high levels yield differential In addition to suppressive effects. As a result. in cortisol are much too slow to be helpful in responding to meates the blood-brain barrier. and Munck. taining the LHPA circadian rhythm.relying heavily on the human adult literature and on animal neurons will be able to respond to neurotransmitters. 80–90 percent of become more frequent and prolonged (Rosen and Schulkin. Cortisol operates on As cortisol levels increase in response to a stressor or at tissues through well-understood genomic mechanisms and the morning peak of the circadian rhythm. at typical basal levels. these recep. Akana. chron- effects they generate when bound and activated (Sapolsky. The opment as well as brain function (Gunnar and Vazquez. homeostasis. sion that influence the LHPA response to future stressors ity for these two types of receptors and the different types of (Sapolsky. Sapolsky. 2000). and Munck. ability. and Munck. One reason for induced catecholamine actions on neural systems). It may seem odd that MRs mediate cortisol inhibit hippocampal neurons. resulting in blunted cortisol responses to mpPVN maintaining a steady electrical current in the brain so that stimulation (Rosen and Schulkin. production in the mpPVN may oppose those in the amyg- mediated cortisol effects predominate. MR. in this basal range. GR- interest in the LHPA system among developmental research.e. amygdala. a hormone involved in salt-water facilitate memory formation by lowering the refractory balance. GRs also mediate pre- but similarly deleterious effects. in facilitating rapid responding to stressors (e. In the brain. which protects MRs from cortisol in the Quevedo. here. where cortisol interacts stress-reactive systems (e. orbital and medial cortical regions. ically high levels of GR occupation can lower the amygdala’s 1997).g. suppressive effects of these stress-induced cortisol elevations 2006). with deleterious consequences including dendritic that moderate levels of cortisol are most adaptive. and impaired learning and memory. long-term changes in gene expres- and GR account for this paradox: cortisol’s differential affin. Thus. in that they counteract the responses of other is translocated to the cell nucleus. prefrontal cortex. and Munck. If cortisol levels are An inverted U function characterizes the relationship chronically elevated. this ratio will tilt toward GR-mediated between cortisol and physical and behavioral health. because outside the brain. while GRs (de Kloet. effects. Romero. after which the hormone-receptor complex suppressive. Many GR-mediated effects counteract MR-mediated There are two receptors that bind cortisol in the brain. 1991). impairing synaptic plasticity effects in the brain. However. Sapolsky. hypothalamus.. cell death. Accordingly. while both atrophy. McEwen (1998) referred to this maintenance Romero. 1991). When MRs and GRs act in opposition to periphery. Cortisol has more than 10 times higher affinity for threshold for responding to threatening stimuli and activat- binding with MR than with GR (de Kloet. MRs are bound with cortisol while very few GRs in the brain 1998). 1991). Nongenomic effects of cortisol will be briefly described are thought to serve the function of restoring homeostasis in later. and memory formation. the LHPA axis in a process termed negative feedback..g. 1998). cortisol molecules relatively little understood nongenomic mechanisms (de in the brain will occupy the remaining MRs and begin to Kloet. while stress-related increases of stability through change as allostasis. one another. hypothalamus. MRs boost synaptic plasticity and tors bind aldosterone. is not sufficiently present in the brain. 2000). see for review Gunnar and Vazquez. and responses. the effect of cortisol depends on the ratio of MRs bind cortisol in the central nervous system. main- models. So. the enzyme 11 beta hydroxysteroid period of hippocampal neurons (for review. fight/flight pocampus. while GRs reduce cerebral glucose transport tors (GR). that is. GR-mediated effects tend to be to its receptors.

In primates. the maintenance of stability through change.effects make it very difficult to predict. LeDoux and Phelps. CRH-1 receptors are believed to mediate many of Watson. whether (Makara and Haller. 1993. with opposing influ- brane. 2000). the more apparent it becomes (Friese et al. many of the effects attributed to the LHPA system The relation of both very high and very low cortisol activity may have more to do with its releasing hormone. As with cortisol. ated by two receptors. However. 2001). stress-induced Munck. CRH receptors are located in regions involved in mpPVN. but also in the ences among species have been identified in the pattern of central nucleus of the amygdala and other fear. a priori. and nucleus tractus solitarius. 2000). tropin-releasing hormone (CRH). Sanchez. septum.and anxiety- distribution of MR and GR receptors. 2005). shaped relation between this neuroendocrine system and CRH and its associated receptors and ligands have a promi- healthy adaptation. ences and differential affinities for cortisol. chronically high cortisol that the HPA system has multiple and often contradictory levels. Evidence from nonhuman primates indicates rela. rapid nongenomic effects may exacerbate context of processive stressors. This multilayered system other cases. while also plentiful in the hippocampus and lateral (Heinrichs and Koob. implicating cortisol in cog. Recent evidence indicates that cortisol can suppression of eating.. To summarize. amygdala. 2000). Rosen and Schulkin. 1997. bed nucleus of the stria terminalis. Vermetten and Bremner. 1991). gulate cortex. but they hold promise for a much better appreciation multiple. such that an tions with their receptors. CRH has two primary (Sanchez et al. health at risk because of their immunosuppressive effects and the specific neural system being affected. et al. chronically low ity and context-dependent findings of cortisol-behavior cortisol levels can also be deleterious to physical and behav. 68 fundamentals of developmental neurobiology . high concentrations of receptors (1 and 2) that have distinct distributions in the MRs and GRs have also been observed in the prefrontal brain and appear to have opposing effects (Dautzenberg and cortex and other cortical regions.. have impacts on behavior and neural activity that occur too Notably. Slow. 2004. than with cortisol itself. Nongenomic.. the more that is learned exposure to chronic or frequent high levels of cortisol will about rapid nongenomic and slower genomic impacts of increase or decrease cortisol reactions to subsequent stressors cortisol (and corticosterone).. CRH-2 receptors are believed to mediate many of the veg- tion take many minutes to hours (Sapolsky. Hauger. 2004. cin- among other locations (Reul and de Kloet. central amygdala. autonomic. cortico- to poor physical and mental health reflects the inverted U. 2001). and The effects of LHPA activity also depend upon the loca. 2000). and locus coeruleus. are more broadly expressed. 2006. evidence is accumulating for faster-acting seem to enhance activity that is already occurring. Akil. CRH is tion of the MR or GR receptors within the brain. is emerging for these nongenomic effects includes evidence long-lasting genomic effects of cortisol in the brain are medi- that they involve specific binding sites in the synaptic mem. et al. are involved in modulating neurotransmitter interac. Davis. MR and GR. Additionally. 1985. Patel et al. the LHPA system affects the brain through stood. and etative effects observed in chronic stress (e. 2002. rather. MRs are related regions. appearing in the Similarly. Bale tively fewer GRs in the hippocampus compared to rodents and Vale. Vermetten and Bremner. while Effects of cortisol produced by impacts on gene transcrip. nitive and emotional regulatory function (López. the picture that stasis. Sanchez. they ing research area. impacts of altered amygdala-produced CRH can quickly to operate through genomic mechanisms and that be observed in the absence of robust activation of the LHPA are observed even in the presence of drugs that block MR axis or elevations in glucocorticoids by the adrenal (Makino and GR binding (see review by Makara and Haller.and anxiety-like effects of CRH (M. studies mirror the complexity and subtlety of the neuro- ioral health because not enough MRs will be occupied to physiology of this system. and may have particularly marked inverted U-shaped function characterizes the relationship effects on neurons that are active in response to the stressor between cortisol levels and healthy adaptation. In the consequence. Romero. In widespread impact on the brain. 1998). neuroendocrine responses to processive stressors. These effects do not appear to be specific. roles that depend on timing. can put the body’s physical roles in adaptation. In rats. In sum. orbital/medial prefrontal cortex. The complex- (inhibiting cytokine transcription). context. In an emerg- event. nent role in the organization of behavioral. M. Sanchez the fear. Davis et al. maintain the body in a state of preparedness to cope with Although studies with children must rely on measures of the stressors it will inevitably encounter (de Kloet.. rapid impacts of cortisol are not well under. and the CRH involved in behavioral impacts mainly confined to the hippocampus and lateral septum. cortisol. 1999)... produced not only by the hypothalamus. Differ. 1999. acting through GRs. yet cor- be the opposite of more slowly emerging genomic effects tisol and CRH have critical roles in brain development. Notably. 2004). 2006).g. 2002). is likely produced by these extrahypothalamic sites GRs. often contradictory mechanisms to promote allo- of the role of cortisol in adaptation.g.. rapid nongenomic effects have been found to of checks and balances is not fully mature at birth. and 2002). de Kloet. CRH also appears to have individual differences in adaptive responses to threat. appraisal and processing of psychological threat (e. 2000. As a nongenomic mechanisms of cortisol activity as well.

cortisol is required for neurogen. In fetal rats. and elevated LHPA activity with impaired negative decreases granule neuron proliferation in the developing feedback (see for reviews Matthews. and Nyirenda. Consequently. eration in the dentate gyrus is inversely related to cortisol maturely. 1999). 1992). by this placental barrier (Seckl. Exposure to chronic stress brain. Neurotrophic because GRs are expressed in oligodendrocytes.. which is administered to accel. First. white matter tract critical to cognitive and attentional pro- cesses. and have demonstrated long-term consequences of prenatal and Gottlieb. Prenatal DEX exposure is associated tisol impedes granule neuron proliferation indirectly through in adulthood both with impaired coping in adverse situations an NMDA-receptor-mediated pathway. 1993). 1995.. 1998). exposure to cortisol may be partially mediated by alterations Cortisol also affects myelination in the developing brain in the expression of neurotrophic factors. quevedo. which inhibits granule neuron (Welberg et al.. sure reflect prenatal programming of the HPA system. which allows even small variations in cortisol levels glucocorticoids to human adults to treat brain tumors also to have prolonged and widespread influences on neural results in white matter abnormalities. suggesting another potential side effect of high levels Vazquez. erate fetal lung maturation. ele- in adulthood and with elevated CRH in the central nucleus vated cortisol (or corticosterone) levels stimulate the hippo- of the amygdala. so cor- behavioral functioning. period of postnatal development. In human infants. Seckl and Meaney (2004) suggest that proliferation in the dentate gyrus (Gould and Tanapat. Elevating corti- in the hippocampus and cerebral cortex. and Gottlieb. in human to chronically elevated cortisol. and gunnar: lhpa system and neurobehavioral development 69 . 1975). 2004). Gould and Tanapat. and Thome. on the spread decrease in extracellular fluid concentrations in white timing of cortisol variations in relation to periods of brain matter (Minamikawa et al. granule neuron proliferation exposure to excess glucocorticoids. cortisol is a gene transcription of prenatal cortisol. they found that myelination was delayed in this Malberg. They also preserve existing neurons by preventing al. Schlessinger. 2001). 2001). neurogenesis continues even in adult- the effects of elevated cortisol on the pre. the long-term consequences of excess glucocorticoid expo. and Thoresen. tarullo. 1986. 2000). Most granule neuron precursors do not have prenatal glucocorticoids and long-term emotional and MRs or GRs (Cameron. Huang and associates (2001) apoptosis. Across the life span. development. elevated serotonin costerone during the SHRP by exogenous administration or expression in the hypothalamus. In rats. gyrus (Fuchs. DEX.and perinatal hood (Gould and Tanapat. but DEX is unaffected the CA3 layer of the hippocampus (Watanabe et al. it is difficult to disentangle the Tanapat. and development of neurotransmitter systems (Duman. Cowan. induced elevations inhibit neurogenesis. Galea. 1975). Uno. Wooley. of course. Therapeutic administration of synthetic factor.. and Gould. Whitelaw and dentate gyrus (Gould et al. Fetal DEX exposure has been basal corticosterone levels rise near the end of the SHRP linked to permanent blunting of norepinephrine expression (Schlessinger. and brain by exposure to an intense stressor (odor of a predator) stem. and myelination. neural apoptosis. 11β-HSD in the placenta helps to buffer the has been associated with decreased dendritic arborization in fetus from natural maternal cortisol. the glial factors are proteins that facilitate neurogenesis and synapto- cells that manufacture myelin sheaths in the CNS (Cintra et genesis. cell when corticosterone levels are low. for review see Gunnar and region. the medically prescribed sensitive to environmental influence throughout its extended administration of a synthetic form of cortisol called dexa. Specifically. Cowan. a major developing brain. Tanapat. The corpus callosum was selected as the focus of this Influence of cortisol and CRH during brain development study because it was hypothesized to be particularly vulner- able to the effects of repeated exogenous cortisol administra- Prenatally and postnatally. 2006). a prolonged suppressive effect on neurogenesis in the dentate 2000). administration and its prolonged period of myelination. Animal studies also suggest a link between Gould. Its structure and function are fetuses at risk for premature birth. DEX. 1999). These influences depend. Several lines of evidence document the effects The hippocampus appears to be particularly vulnerable of elevated cortisol on the developing brain. The deleterious effects on the hippocampus of chronic including permanent effects on GR gene expression. 1999. granule neuron prolif- effects of DEX exposure from the effects of being born pre. tion. specifically a wide- development. 1991. synaptogenesis. hippocampus. and impaired performance on hippocampally medi- flooding the fetal brain with an active and long-acting form ated learning and memory tasks (see for review Gould and of cortisol.We turn now to consider how these hormones shape the exogenous cortisol to sheep on the corpus callosum. gliogenesis. and in the dentate gyrus methasone (DEX) creates a natural experiment to examine of the hippocampus. 2000. Animal models are helpful in isolating these effects levels (Sapolsky and Meaney. peaks in the postnatal stress hyporesponsive period (SHRP). gliogenesis. 1999). 1994. and Flugge. In the dentate gyrus and other hippocampal examined the effect of repeated prenatal administration of regions of rats subjected to chronic stress (immobilization). Indeed. Huang et al... and slows down when division. a region instrumental in fear and anxiety campus to release glutamate. has the significant side effect of 1999). Also. myelina. tion as a result of its immaturity at the time of cortisol esis. As noted. Cleasby.

and processes of priming back nursing. ior influenced stress reactivity in the foster offspring. involving CRH-1 receptors may be related to the develop. it will be adverse effects in shaping the developing brain... rats. but also to species-typical variations in parenting during this period of particular hippocampal excitability quality. paired pharmacological inhibition of hippocampal CRH receptors with increased neurotrophin-3 (NT-3) mRNA. 2002).. Schmidt et al. however. In rats. mechanisms of neural plasticity known to mediate long-term ments of the stress response must also be involved (Smith learning. although to review current findings from the animal literature on effects our knowledge this has not been studied in relation to altera. 2002).. thus contributing to postna. Many Experiments with rodents illustrate how CRH mediates of these effects appear to involve regulation of MR and GR mechanisms of neural plasticity that provoke long-term development by means of alterations in GR gene expression. These variations within the normal range of maternal behav- ment of human stress-related disorders. tal processes of learning and memory.g. The mechanisms through which CRH influences development depend on the timing of exposure. 2003). nently and radically affects the density of hippocampal GR induced priming effects.. process (Uno et al. This has been convincingly demonstrated in studies of infant For example. The eleva. Here we impairs the development of the hippocampus. perhaps inducing long-term effects on learning and crucial neurodevelopmental processes and demonstrate that memory. the number of CRH-expressing regulation of the LHPA system (reviewed in Sanchez. While this study was conducted with dala resulted in long-term changes in the sensitivity of its adult rats. but other ele. activation of CRH receptors facilitated long. Excessive CRH 1989). experiences. synaptogenesis. as a decrement in BDNF expression also was observed in 2004). In parental care. disrupt neurogenesis. 1990). Notably. The authors suggest that corticosterone likely drome these rodents developed was correlated with cellular plays some role in the suppression of BDNF. particularly those involving variations in production as well as receptor density and distribution. 2004). 18 and then declines drastically to adult levels (Chen et al. Studies in both rats and nonhuman primates indicate that likely related to maturational changes in neurotransmitter early experiences. CRH also affects the Early experience effects in animal models developing brain. Rosenfeld. which The mechanism for BDNF down-regulation was less clear. 1995b) found greatly decreased typically show under stress did not occur in the context of brain-derived neurotrophic factor (BDNF) mRNA. variations in parental care occur on a continuum. to lay the groundwork for discussing the tions in BDNF activity as a potential mechanism in this findings on this topic from studies of human development. key indicators of parenting quality in the rat. 1995b). and Levine. For instance. Quality of parental care perma- acute stress (Blank et al. context-dependent fear conditioning in rats subjected to M. neurons and CRH-1 receptors peaks on postnatal days 11– In nature. of early experience. In addition to these cortisol effects. This down- expression of these neurotrophic factors. In the animal literature. such findings immediately raise the issue infants whose postnatal neural development is more compa. The repeated activation of the basolateral amyg- et al. Francis and colleagues (1999) cross- could make rodents prone to pathological outcomes. 2005). A recent study demonstrated that CRH tion in NT-3 expression was mediated by corticosterone.. tions in care such as peer rearing (e. Similar fostered the offspring of mothers who were at the high and windows of vulnerability may be present in the development low ends of the continuum of licking/grooming and arch- of the human nervous system.. and selective neuronal These studies implicate cortisol and CRH in a variety of survival. changes in limbic pathways involved in emotional disorders. it has implications for the effects of glucocorticoids neurons. can have long-term effects on reactivity and the rodent hippocampus. For the important to replicate these findings in nonhuman primate developmentalist.. the enhanced learning that rodents expression. increase the rodent’s stress vulnerability (Rainnie et al. The anxiety-like syn- chronic stress. Because glucocorticoid effects can vary depending distortions in levels of these hormones can have persistent on species and developmental status. As further evidence of CRH. Experimental manipulations have yielded evidence that the 2001). By altering neurotransmitter GABA (Rainnie et al. chronically elevated regulation of inhibitory mechanisms resulted in chronic cortisol (in primates) and corticosterone (in rodents) could amygdalar hyperexcitability.. research on this issue dence that exposing the fetal rhesus monkey to dexamethasone has a long history (reviewed in Levine. thereby shaping LHPA reactivity in adulthood 70 fundamentals of developmental neurobiology . This abundance of CRH neurons is believed to developing LHPA system is sensitive not only to gross devia- enhance synaptic transmission.Smith and colleagues (1995a.. hippocampal GR expression increases through- term potentiation in the mouse hippocampus and enhanced out development (Suchecki. there is already evi. including reduction of spontaneous inhibitory syn- on the dentate gyrus and other hippocampal regions during aptic potentials and reduced expression of the inhibitory their extended period of postnatal development. A potent CRH receptor agonist was chronically the dentate gyrus of adrenalectomized rats exposed to infused into the basolateral amygdala. 1995a. 1993. (Blank et al. Champoux et al. of the neurodevelopmental consequences of early stressful rable to human development. induces long-lasting cellular changes in the amygdala. 2006).

In the absence of sensitive. Coplan et al. 1996. responsive caregiving buffers the LHPA system phase could therefore represent a sensitive period for social during the first few years of life. social experience is also one of tial long-term consequences for LHPA basal levels in the the major sources of stress that challenges the immature wake of early social adversity. 1992). in nonhuman primates. 2005) traced these effects to the role of parental related mechanisms. Disturbances in parental care also in cortisol to mild stressors such as childhood inoculation produce persistent increases in CRH activity that. It is not yet known whether LHPA axis.. 2006). preventing or mitigating experience to shape MR expression in primates. and gunnar: lhpa system and neurobehavioral development 71 . it is not clear whether these are mediated in the Social experience and LHPA regulation in human same way as in rodents (see Sanchez. 2001). on the LHPA system. and this resistance to producing elevations in cor- the absence of elevated corticosterone. 2001.(Meaney and Szyf. although LHPA reactivity in young humans appears to be functionally long-term changes in basal cortisol levels have been difficult equivalent to the stress hyporesponsive period (SHRP) that to observe in nonhuman primate studies of disturbances in occurs in rat pups from postnatal days 4 to 14. On the positive side. development 2001). some of the effects of early experience on brain ity to mild stressors declines precipitously. with poten. 2005). Gunnar to co-occur with disturbances in parental care (Baram et al.. For example. tive. Pryce and colleagues (2005) posit that the weaning sensitive. 1997. These tion are highly vulnerable to cortisol elevations and long- findings exemplify the ubiquitous challenge in translational term disturbances in LHPA regulation.. Ladd.. weaning. 2001). cortisol elevations. there is evidence of chronic increases in cere. 2001). inform hypotheses about LHPA regulation in the complex Although long-term impacts of variations in parental care realm of human social experience. hyporesponsive period in the rodent. would be capable of tisol at least at the mean or group level persists through the the deleterious impacts on hippocampal development noted toddler and preschool years (de Haan et al. Broderson. This period of blunted 1997. while extended behaviors and heightened reactivity of the LHPA and sym- parental separation and low nurturant parental care result pathetic adrenomedullary (SAM) system (see review. child maltreatment. Finally. One species of New World monkey shows a The sensitivity of the developing LHPA axis to social experi- developmental peak in MR expression coinciding with ence is both an asset and a liability. The LHPA system is immature at birth. 1996). social experiences con- 10. even in injections. LHPA reactiv- Notably. Larson et al. or social depriva- are more closely evolutionarily related to humans. However. 1997). if maternal care- aging conditions (e. function and reactivity continue to evolve throughout child- In rats.. peaking in the hippocampus around postnatal day this extended period of development. 1998... 1998. despite the fact development may operate by means of CRH rather than that behavioral distress in response to these same stressors through modulations of glucocorticoids. exhibiting marked elevations in cortisol and ACTH in At the same time. not elevate corticosterone do increase CRH activity in the By 12 months of age. and Plotzky. For rat pups.g. postnatal levels of GR expression do not appear to vary developmentally. These animal models have helped to care in regulating methylation of the GR gene.. perturbations that do et al. they illustrate the rich potential of preclini. 1995). the SHRP is mediated by sensi- compared to those whose mothers enjoyed predictable for. tribute in important ways to shaping these brain circuits. In elegant work. Ladd. responsive caregiving. During the stress continues to be observed (Gunnar. Krueger. hypothesized to shield the developing brain from potentially bral spinal levels of CRH in rhesus monkeys who had been damaging elevations in corticosterone. in fewer hippocampal GRs and prolonged LHPA reactivity Sanchez. et al.. reared by mothers foraging under unpredictable conditions In rats and humans alike. responsive care. receptors toward those that mediate fearful or anxious cient feedback regulation of the LHPA axis. which is parental care. and Plotsky. quevedo. who maternal separation.. species-specific or more broadly applicable (Sanchez. Highly nurturant parental care disturbances in parental care shift the balance in CRH increases hippocampal GR density and leads to more effi. young children faced with psychosocial stressors such as mative to replicate the study with Old World monkeys. and LHPA basal and therefore do not appear sensitive to social experience. marked increases in tarullo. research of determining whether observed phenomena are Human newborns have a highly reactive LHPA system. 1998. Thus early rearing expe- to processive stressors (for review see Gunnar and Vazquez. 1993). humans share this MR-sensitive period. Meaney and colleagues (see Meaney impacts on brain and behavior through multiple LHPA- and Szyf. Lewis and Ramsay. Furthermore. early giving is sufficiently disorganized. Over the course of the first year of life. 1996). It would be infor. Nachmias et al. During period. and parental separation have been observed in nonhuman primates. MR density is highest during the early postnatal hood (for review see Gunnar and Donzella. Brunson et al. it is difficult to observe mean increases brain (Smith et al. and is sensitive to early social experience (Vazquez et al.. riences in rodents and monkeys may produce long-term 2006). response to stressors such as well-baby physical examina- cal models to explicate the mechanisms of social influence tions or childhood inoculations (for review see Gunnar.

2000. in press). Findings from animal research indicate circuits to activate the axis. 2003. Nachmias et al. 2001b. 2001). Cicchetti caregivers as a coping resource in stressful situations (Main and Rogosch. yielded evidence of elevated basal cortisol levels for at least 1993). with low basal cortisol levels and blunted LHPA axis has yet to be conducted in humans. LHPA axis with significant. Gunnar.. sive caregiving by the attachment figure is believed to result These blunted or low early-morning levels may reflect in formation of a secure attachment bond (Sroufe. Finally. as in the 72 fundamentals of developmental neurobiology . toddlers become highly vulnerable to activation of the observed depend on the methodology employed—that is. et al. 1995. basal cortisol levels. 1992).. however. In humans. maternal separation did result delays at adoption had elevated early morning cortisol levels in significant increases in cortisol for 9-month-olds when the when studied an average of 6 years postadoption (Kertes babysitter was instructed to be distant and perfunctory et al. removed from maltreating parents often exhibit extremely toddlers with a disorganized/disoriented attachment status low or blunted early-morning cortisol levels (Bruce et al. and sometimes large. and Levine. These findings raise the specter of LHPA axis is observed depends on whether or not the adult increased risk for psychopathology in genetically vulnerable is suffering concurrently from a clinical affective disorder children deprived of sensitive. 1993). Gunnar. order or depression. This disorder comparison group (see for discussion. a blunted diurnal rhythm in cortisol. Specifically. sensitive. 1993. and babysitters. 2001a. treated children showed a rise in cortisol levels across the sive alternate caregivers. cally stressed and neglected rhesus monkey infants (Boyce Rosenfeld. depressed mal- Studies with children have shown that sensitive. elevated basal cortisol pattern of behavior often associated with maltreatment in levels have been reported for physically or sexually abused which toddlers are ambivalent about whether to approach children who have internalizing disorders when studied or avoid the primary caregiver and are unable to use their months or years after rescue (Carrion et al. 2004)... Among adults.or hypoactivity of the context of disrupted care. Short. 2000. Fisher ries have been careful to employ a nonmaltreated affective et al. et al. 1983). or both).and cortisol responses to many psychosocial stressors (Yehuda long-term functional consequences would likely depend on et al. However. Gunnar et al. 1996. children exposed to deprived rearing precisely mirror the effects observed for adults with these environments (such as orphanages or neglectful homes) have disorders who do not have a history of maltreatment during blunted early morning cortisol levels and do not show the childhood. orphanage- cortisol elevations to mild stressors even when the mother is adopted children who were the most severely affected by absent (Dettling et al. 1994. such as child care providers and day instead of the expected decline (Hart. Broderson. changes in the LHPA axis and in stress-related neural activ- and securely attached toddlers do not exhibit cortisol eleva. 2006. (Gunnar et al. van Ijzendoorn et al. Childhood maltreatment effects do not function.. However. the precise effects giver. Studies of adults maltreated as young children also tend back of the immature LHPA system’s dependence on social to confirm the long-term consequences of maltreatment on regulation: When deprived of a sensitive. may be particularly stress vulnerable. and Nemeroff. Carlson and Earls... 1992).. responsive care. 2006). Spangler and Schieche. while depression is associated with elevated the frequency and chronicity of LHPA elevations. 1991). In contrast.. Unlike securely 2000. toddlers ment figure (Ahnert et al. attached toddlers. On the whole. De Bellis et al. prospective research on the func. 1999). 2002. recently adopted from an orphanage or other institution and Nachmias. are also able to buffer infants and toddlers from Cicchetti. Spangler and those studied soon after placement in foster care after being Grossman. whether hyper.. although conclusions remain tentative because typical decline in cortisol levels over the course of the day not all studies of adults with childhood maltreatment histo- (Bruce et al. 2006). over time. result tions to mild stressors while in the presence of their attach. Disorganized/disordered attachment behavior is a some of the children. 1996.. In addition. increases pharmacological probes that activate specific levels of the in cortisol to even mild stressors (for review see Gunnar and axis versus processive stressors that rely on cortico-limbic Donzella. However. orphanages or rescue from abusive parental care have often tions (Hertsgaard et al. PTSD is associ- tional consequences of disrupted care for the developing ated. under review. 1998).. response care during the and on the nature of that disorder (posttraumatic stress dis- toddler years. particularly for long-term consequences of chronic cortisol elevations in the processive stressors. Dozier et al.. Gunnar. In two studies conducted at day camps. 1997). Plotsky. For example. Young children chronically subjected to inadequate or and hyperreactivity of the LHPA system to stressors disrupted care tend to show dysregulation of basal LHPA (McEwen. 2004.. 1999).corticosterone are observed even during the SHRP (Suchecki. Heim. Gunnar et al. 1995.. 1996. For example. Kaufman. 1990. 2005). These findings reveal the major draw.. Sanchez. 1997. anomalously. and Solomon. and Johnson.. in increases in basal cortisol levels. Kroupina. However. activity of the LHPA system. respon. McCormack et al.. 2001). Spangler and Grossman. ity in limbic and cortical regions that will.. disorganized/disoriented toddlers show studies of such children many years after adoption from high cortisol levels in response to repeated maternal separa. flattening of the diurnal rhythm is also observed in chroni. their preadoption experiences as evidenced by severe growth in a laboratory manipulation. respon.

This group difference between children and adults in peer interactions are becoming increasingly salient.. LHPA stress responses and resulting in increased stress vul.. the in prevalence of affective disorders around midpuberty magnitude of cortisol increases over the course of the child. Gunnar and Quevedo. but they LHPA reactivity to laboratory tasks raises the question of are still in the process of acquiring the social skills to negoti. it is often challenging psychosocial threat (see Heim et al. 2000. the transition to adolescence.. influ.to four-year-old children show a rise in be effective with adults either (see review. as a group. Researchers have employed a variety of and Nemeroff. 2004). the period of relative stress hypore- et al. even when their behavior is such the adolescent perceives and processes threatening situa- that it would provoke negative or hostile responses from tions. 2001. Long hours in the challenging peer patterns. While increases in cortisol across the child-care day have and problems in regulating ACTH and cortisol responses to been observed in a number of studies. combination of these factors. the significance for later development of the small but fre. early and middle childhood. such that.. 1997. and gunnar: lhpa system and neurobehavioral development 73 . LHPA Tanner stage 3 (Halligan et al. individualized care responsivity may reflect maturational changes in the biology from child-care providers show little or no evidence of day. These data tend to support based studies. 2000. 1998. and effective laboratory stressors emerges around 12 to 18 tizes brain circuits to perceived environmental threat. 2004). Walder. an those rated as less socially competent and less capable of alternative but not inconsistent hypothesis is that as children emotion regulation (Dettling et al. close. others. experience remains one of the most significant sources of such as exposure to challenging cognitive tasks. 2000. 2001. The association of puberty with heightened LHPA dren who receive sensitive. Even for typically developing children not exposed to the but with little success in provoking a mean or average extreme adversity of maltreatment or deprivation. at around the period when an adult with whom the encing the frequency. what accounts for the transition from child to adult reactivity ate those interactions. and animal children aged 5 and older do not show these increases in models indicate that estrogen stimulates LHPA activity cortisol across the day in school or other group care settings (Netherton et al. girls who had reached midpuberty had tarullo. 2000)... amplitude. While some of these putative stressors. or some atypically low basal ACTH levels (suggestive of down-regu. 2004).. Watamura et al. Thus it is not surprising that sex (for review see Gunnar and Quevedo. 1999. 1999). months. 2003. 2004. Dickerson and cortisol levels over the course of the day when attending Kemeny. As further evidence that the developing sponsivity of the LHPA system in humans slowly draws to a LHPA axis is under strong social regulation by adults. 2007). Schmidt et al. In one study. chil. or an interaction between biological maturation and peers (Dettling et al. and tory capacities of the LHPA system (reviewed in Gunnar and that this heightened responsiveness may help explain the rise Donzella.. When care day is greatest for the children who are least skilled at one takes a longer developmental perspective. a history of maltreatment increases the children which facilitate successful peer interactions. responsive. particularly morning research area will be the possible interaction between varia. (Spear. Several researchers have suggested that with environment of child care may strain the emerging regula.. Shirtcliff et al. lation in response to chronic CRH drive on the pituitary). Gonadal steroids influence the LHPA system. effective stressors among adult subjects (L. Indeed. but not on the days they are at home licly about one’s most embarrassing moment. such as the threat of speaking pub- full-day child care. Netherton et al. would not stress. For children of this age.. Two studies have found that the timing of this increase in tions specifically affect development over and above the morning levels is linked to pubertal status. differences in LHPA functioning also emerge around Tanner mental change may reflect the improved social skills of older stage 3. There is increasing evidence that reactivity of the LHPA quent cortisol elevations observed in less sensitive and system and its relation to social experience change during responsive day-care settings. sensitivity to child care is age specific. of the LHPA axis. Basal cortisol levels. 2006). and Donzella. This develop. 2000.. Netherton et al. increase from ages 6 to 17 (Kiess et al. Legro tions in parental care and variations in child care. fit criteria for (Dettling. Gunnar move into adolescence. quevedo. and Reynolds. 1999.. As noted. and adolescence. in press). experience-driven alterations in how care cortisol elevations. or likelihood of abnormalities in the cortisol daily rhythm. 1995. Tout et al.studies of children. and duration of future child has a secure relationship history or even a sensitive. 2001). Another et al. 2004. this important question is cur. stressors in studies with preschool and school-aged children. Walker. 2003. 2001). A key consideration in this pubertal changes. responsive unfamiliar adult can buffer reactivity of this neu- nerability and elevated risk of internalizing disorders (Heim roendocrine system. social increase in cortisol. puberty the LHPA system becomes more responsive. the problem of identifying ethical the hypothesis that chronic stress during development sensi. likely in connection with rently under active investigation. 2004).. While we do not yet understand experience. Many two. Gunnar. 2003). reviewed to find stressors that reliably increase cortisol in laboratory- in Tarullo and Gunnar. levels. including negotiating social interactions: those rejected by peers and infancy. 2007).. challenge will be determining whether these cortisol eleva. improved LHPA self-regulatory capacities. occurring around impact of being in a lower quality child-care setting.

and current neurodevelopmental status. 11. ing internalizing disorders (Kagan. ences. At this point. there are no differ- employ the developmental psychopathology concepts of ences in cortisol levels for behaviorally inhibited and nonin- multifinality—that is. ability to stressors by reducing the child’s ability to use sleep 1987).. it is unlikely that these changes involve only responses of the LHPA axis at different points in develop- the LHPA system. but if the child-care provider is not 74 fundamentals of developmental neurobiology . Notably. Walker. For instance. see Dickerson and Kemeny. avoidance of novelty. To explore individual differences in LHPA develop- it is not clear whether these changes reflect alterations in the ment. For instance. multiple outcomes from the same hibited children in the presence of a sensitive.and pre. but these two children may have arrived at that outcome pubertal 13-year-olds failed to exhibit increases in cortisol to by very different pathways (equifinality). and vigilance— Thus. responsive care buffers tive right frontal EEG activation (Fox et al.higher cortisol morning levels than either midpubertal boys end point (see Cicchetti and Tucker.. Other systems involved in reactivity and ment. for further dis- or prepubescent girls and boys (Netherton et al. but inadequate care leaves young children Reznick. 2001. LHPA hyporeactivity. 9-. low vagal tone. at the individual level. Wewerka et al. consistent with elevated amygdala activity: The amygdala sol and CRH can have long-term detrimental effects on activates the sympathetic nervous system (raising heart rate). Elevated levels of corti. severe early social adversity may laboratory stressors increases with age and pubertal status lead to LHPA hyperreactivity. inhibits the parasympathetic nervous system (lowering vagal ability. Walder. cussion of these concepts). a decrease different points in development. that influence is filtered olds and 15-year-olds showed significant elevations in the through the lenses of an individual’s genetic predispositions range typically noted in studies of adults (Wewerka et al. LHPA reactivity. how genetic predispositions and social experience interact at tions in psychosocial regulation of the axis. and Snidman. Kagan. prolonged LHPA stress responses.. opmental path of the LHPA system. A starting point in this in the capacity of parental presence and availability to buffer analysis may be to consider interactions between stable indi- its activation. which explore individual factors that may interact with experience would lower the threshold for perception of threat and result in shaping LHPA development. experience in predicting differences in basal and stress Furthermore.. and sends projections to the right frontal cortex. a postinstitutionalized child several years after adop- that employed the Trier Social Stress Test (the stressor tion may have LHPA function that closely resembles that of shown to be most capable of elevating cortisol in studies of a child who has experienced low social adversity throughout adults. For example. 2002). 1998). it can be useful to activity of the LHPA axis. The developmental 2007). LHPA hyper- difficult to predict. and Reyn. at the group level. Sensitive. developing neural circuits. 1988). As further evidence of the biological ment. In contrast. Reznick. shyness.. Here we use behavioral inhibition as an example. we will likely need to learn a great deal more about axis and its regulation by cortico-limbic circuits or altera. This physiological profile is vulnerable to LHPA dysregulation. and greater rela- double-edged sword. However. we have some understanding of demonstrates moderate temporal stability and a significant the relation between social experience and LHPA develop. 2001. regulation of stress may also undergo developmental changes Behavioral inhibition has received extensive research around the same period of time (see Gunnar and Quevedo. apparently normal LHPA function (multifinality). responsive starting point—and equifinality. Temperament and genes The body of evidence on this topic indicates that behav- ioral inhibition interacts with social context in predicting In considering individual variability. Thus. Con- olds. fearfulness. in the one study versely. we activity increases CRH activity in the amygdala. 2004). extremely inhibited children the first years of life. 2001. 1994. Behavioral inhibition—characterized by acute as a stress regulator (Dahl and Lewin. life. Both psychological and physiological changes vidual differences in temperament and children’s social associated with the transition to adolescence may be involved. and Snidman. that is. 2004). multiple paths to the same child-care provider. exposure to chronic. heritable component. LHPA outcomes of tone). 2007). including increased stress vulner. both pubertal 13-year. a fact which can be considered a exhibit elevated heart rate. In the final section of the chapter. while early this stressor task. in different individu- Several studies have also noted that cortisol reactivity to als. 1998). The LHPA system is under strong social regulation in basis of behavioral inhibition. paving the way to development of an anxiety disorder (Rosen and Individual differences in LHPA function: Schulkin. It has exposure to early social adversity are heterogeneous and been hypothesized that in inhibited children. in more frequent. These changes in the LHPA axis in human children implications of social adversity also depend in part on the parallel changes seen in rodents at the end of the relative broader context of concurrent and subsequent social experi- stress hyporesponsive period (Vazquez. although they all reported being stressed social experience exerts a profound influence on the devel- or anxious during testing. there are well-known changes in sleep this temperamental category are at increased risk of develop- around the pubertal transition that may also increase vulner. attention because the 5–10 percent of children who fall in 2007). or (Klimes-Dougan et al.

.. a functional poly- of developmental research on stress and stress vulnerability morphism has been identified in the length of the serotonin in the near future... We do not influence reactivity and regulation of the LHPA system and intend this discussion to be exhaustive. more temperamentally inhibited exposure to corticosterone decreases BDNF expression in children do exhibit higher cortisol levels (Dettling et al.. the low- cortisol (Bruce et al.. version is associated with decreased serotonergic function duced in high levels in the hippocampus and cortex. 1996b). these effects were expressed only in and synaptic transmission. Inhibited children may be less able to regulate LHPA ment—appear to be associated with this BDNF polymor- responses to familiar stressors (for review see Gunnar and phism (Cheng et al. 1995a. and gunnar: lhpa system and neurobehavioral development 75 . 2005. Reznick. 2006). In these situations. to the type of gene research that will likely alter the nature In both human and nonhuman primates. 2006.. 2006). The Met considered an adaptive response to provide resources to allele appears to reduce the efficiency of BDNF regulation cope with the challenge. 2002. On the whole. with impacts on hippocampal and cortical year. such as (Duman. and its reduced expression may 2000). such as that involved in the encoding of new infor. provoke cortisol increases in securely attached infants or in Thus glucocorticoid-induced decreases in hippocampal bold infants regardless of attachment status.. Which genetic from knockout mice studies to human development.. de Haan frequency Val/Met and Met/Met genotypes should be asso- et al. BDNF down-regulation has been linked to the ated with an elevation in cortisol (Nachmias et al. of insecure attachment and behavioral inhibition is associ. increased in probability by histories of stress during develop- 1998). espe. 1987.. Green et al. BDNF increases neuronal excitability serotonin. we might expect that individuals porter gene are hyperfearful and exhibit exaggerated with particular genetic polymorphisms may be at risk for increases in corticosterone to processive stressors (Ren- altered LHPA activity under certain conditions and given Patterson et al.e. Vazquez.. However. problems. Theoretically. 1998). Rybakowski et al. this polymorphisms may be relevant? Here we will review several latter study does suggest that both the serotonin system and that are receiving attention in research on stress and stress neurotrophic factors may be important in regulating the vulnerability: genes involved in regulation of brain-derived development of stress reactivity and regulation.sensitive and responsive. This pattern would be consistent with 2004.. There have but did not differ from other adults in response to a novel been studies using mice with homo. E. In humans.. Schmidt and Fox. parental depriva- activity. 2002). early in a new school (less trafficking). there have been no studies of the effects of glu- (1996a. there is increasing evidence that genetic polymor- serotonin (i. while exposure to a frightening toy does not contribute to dendritic atrophy (Smith et al. those involved in regulation of Indeed. 2002). in predicting LHPA activity cautions against expecting that Chourbaji et al. in which highly anxious adults were more cocorticoid infusions in human adults with the Val/Met likely to show a cortisol response to familiar daily hassles. Additionally. 2002. 2006. predominant Val/Val genotype.. the serotonin transporter gene). tent with evidence that bipolar disorders. Parsian et al. the combination BDNF have been related to stress-induced memory deficits. and several phisms affecting the efficiency of serotonin regulation do genes that operate within the LHPA system. increases gene transcription of BDNF (Hartmann rearing has been shown to reduce cerebrospinal levels of and Lessmann. 2002). However. genotype versus the more efficient BDNF allele. In nonhuman primates.. Chronic serotonin transporter gene (Bennett et al. inhibited temperament predicts higher home levels of morphology (Cheng et al. 2005). Similarly. a common single nucleotide polymorphism or adjusting to a new school year (reviewed in Gunnar and (SNP) in the BDNF gene has been identified that results in Vazquez. but merely to point moderate the developmental impact of adverse experiences. 2005).. Shirayama et al.and heterozygous laboratory stressor. the rodent hippocampus. and thus plays a critical role in those peer-reared animals with at least one short copy of the facilitating neural plasticity (Alder et al. entrance into a new playgroup. suggesting difficulty in terminating the LHPA ciated with greater vulnerability to chronic stress than the response following removal from the novel context. To our studies of adults conducted by van Eck and colleagues knowledge.. main effects of temperament are not observed in liorate stress-induced reductions of hippocampal BDNF the proximate LHPA response to novel stressors. Tsai et al.. 1995b). The question is. there is evidence that genetic predispositions will exert main effects on activity of BDNF knockout mice that also lack the serotonin trans- the LHPA system. neurotrophic factor (BDNF).. transporter (5HTT) gene (Bennett et al. Its short BDNF is a protein involved in neural plasticity and pro. tarullo. quevedo. 2006). a rise in cortisol may be a valine (Val) to methionine (Met) substitution. there is little The interaction of behavioral inhibition with social context evidence that BDNF knockouts are more stress reactive (e. laboratory manipulations. This hypothesis is consis- ited children also have elevated basal cortisol levels. knockouts of the BDNF gene. and some antidepressants ame- Generally. 2003).. 2003). L. In contrast. pathogenesis of depression. Rather. Likewise. Neural (Holden.. Inhib. substance abuse cially levels obtained early in the morning (Buss et al. tion in the form of peer rearing as compared to mother mation. and Snidman. 1999.g. and mood disorders—all disorders that are Kagan. 2001). 2004). While it is difficult to extrapolate certain rearing histories. Davis et al. 1996). 2003.

relative to mother-reared monkeys. the development of individual differences in vulnerability to Patterson et al. and Shinitzky.. In the last several ment of depression. Recent research adverse experiences on the developing brain. Results to date. their impact short copies of the serotonin transporter gene. and at least one recent study associated tonin regulation. and there is growing evidence that the variations in the region of the CRH gene with panic disorder effects of elevated glucocorticoids operate. As noted earlier.. system. it may provide new toms were most evident in children who carried both the avenues through which to comprehend the role of experi- MET allele of the BDNF polymorphism and the short copy ences in shaping the development of individual differences of the serotonin transporter gene... age 25 increased among those who were maltreated as chil. Nev- to G) in the GR gene. As repeatedly noted in this section on individual differ- dren. 76 fundamentals of developmental neurobiology . but the ER22/23EK carriers had a faster this effect is exacerbated in monkeys carrying at least one clinical response to antidepressants (van Rossum et al. the study of stress and development may help us understand acted to enhance stress reactivity and fearful behavior (Ren.. 2004). This statement may also be true for stress. but it is not likely to reduce the importance of research human development. and thus children’s vulner- serotonin transporter polymorphism. speculate that activity of this system may have helped to neglect. and parental loss are associated with emotional dis- mediate the gene-by-experience impacts on the develop. orders and lower academic achievement. Impor. these two genes in combination increased depressive symp- toms in maltreated but not in nonmaltreated children Conclusions (Kaufman et al. significantly on the brain likely depends on whether the child experiences increasing their risk for developing affective disorders (Caspi significant stressors during periods of rapid brain develop- et al. 2006). Toister-Achitiv. which children have during childhood. 2006). in adults and behavioral inhibition in children (Smoller through promoting synthesis of the serotonin transporter et al. Again. children who have been severely their effects are moderated by the care and experiences maltreated may exhibit chronic increases in cortisol. the effects of which are not yet fully ertheless. 2005). 2006). In many cases. Risk of depression by ability to stressors. sive episode. Unfortunately. so we can only the developing brain. at least in part. of these polymorphisms will affect the development and als who were maltreated as children was moderated by the regulation of the LHPA system. As noted. Stressful life events including abuse. neither temperament nor genetic variations appear to individual carried one or two short copies of the serotonin have deterministic effects on development. based on the accumulation of both animal and understood (van Rossum et al. However. none of the studies examining gene-by-experience interactions for maltreated It is well established that stress has considerable influence on children included measures of LHPA activity. peer-reared monkeys has found that homozygous carriers of both these polymor- exhibit greater increases in LHPA reactivity to the stress of phisms had an increased risk of developing a major depres- separation and single-case housing for several days. on childhood experiences. transporter gene. in at least one study. cortisol and corticosterone are known to affect sero. Notwithstanding Several polymorphisms have been described for the GR the ease of introducing measures of salivary cortisol into gene. there is ample reason to expect that this polymorphism is related to glucocorticoid resistance and neuroendocrine system plays important roles in brain devel- consists of two linked nucleotide changes resulting in GR opment and functioning and in mediating the impact of receptors that have less affinity for cortisol. Several polymorphisms in the CRH gene have also tantly. suggest that many (2003) that the increase in risk of depression among individu. the impact of in stress vulnerability and resilience. These are only a few of the genetic polymor- (Tafet. 2003). In addition. however. ences in stress vulnerability and resilience. The BclI studies in child development. These findings phisms that are currently being explored in LHPA-axis- may partially account for a report by Caspi and colleagues relevant genes. short serotonin transporter allele (Barr et al. 2005). been identified. decades. Some of these genetic dif- in turn may influence serotonin regulation and expression ferences may affect reactivity and regulation of the LHPA of the serotonin transporter (Cicchetti and Toth. while others may moderate the impact of LHPA These effects may be amplified in children with one or two reactivity on other neural systems. Introducing genetics and candidate gene analyses into impairment in both serotonin and BDNF regulation inter. 2001). in knockout mice models. ment.. Rather. depressive symp. Regardless. The ER22/23EK human studies. 2005).. researchers studying child development have Another class of genetic polymorphisms that may play a increasingly turned to measuring cortisol as a means of role in individual differences in stress reactivity and the examining the potential role of the LHPA system in mediat- impact of early stressful life events involves variations in ing these impacts and in helping to explain individual differ- genes directly involved in activity of the LHPA system. but the increase in risk depended on whether the ences. including the BclI and the ER22/23EK. the complexity of the neuro- polymorphism has been associated with hypersensitivity to physiology and developmental psychobiology of the LHPA glucocorticoids and consists of a single nucleotide change (C system belies simple interpretation of cortisol findings.

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This also seems to be true for nongenetic alterations in development. that many molecules exhibit pleio. laminar and columnar organization that is assembled during 2004). brain functions. beginning prenatally and lasting through adolescence The cerebral cortex mediates higher cognitive functions and in the central nervous system (CNS) of all mammals. STANWOOD AND PAT LEVITT Introduction likely targets. Levitt et al. contribute impact that an altered neurochemical environment may to the remarkable phenotypic diversity of the nervous system. give rise to tissue patterning. have on histogenesis. These developmental milestones are ment. The Basics of Brain Development Temporally oping cells to respond to those signals. oligodendrocytes. such as prenatal exposure to The development of the brain relies on the spatial and tem. 2004). neurons. Defects in cortical develop. layered structure that exhibits very similar features across its D. by contact-mediated and diffusible effector substances. development in well-defined temporal and spatial patterns. all neurons and macroglia in a well-controlled proliferative tion.. by expression of spe. neural tube. both neurons and glia (Campbell and Gotz. Levitt. Transcription contribute to the formation of all brain structures from the factors. 2005). and glia also larly susceptible to modifications by exposure to drugs of undergo naturally occurring cell death. overlapping events.1. Both the availability of molecular signals and the ability of devel. and forms of mental retardation tangential extent. Synaptogenesis is a temporally extended developmental event.. The molecular and cellular bases that tie develop. Andersen. It has been suggested that developmental anomalies in cortical development underlie certain types of Cerebral Cortical Histogenesis The neocortex is a six- psychopathology. and later to form astrocytes and of neural development. such as schizophrenia (Weinberger. In the rat. Progenitor cells. but we know that influences on cell-cell development occur in all mammalian species. 2005). Eagleson. poral regulation of cell-cell interactions that are controlled 2000. is critical in the formation of synapses between specific target and homeostatic information. 1999. therefore. radial glia. cell adhesion and guidance molecules. and neuro. 2001. are essential to ontogenesis. In this chapter we describe research Glial cells differentiate early to form specialized migra- findings that implicate monoamine systems in the regulation tion guides. performing very dif. however. establish appropriate quantitative relationships between projection and target neurons and between neurons and Fundamentals of cerebral cortical development glia. grouped in five major categories. and Powell. can have a profound impact on mature described schematically in figure 6. cific receptors. serving as regulators of distinct cellular neuroepithelial cells serve two purposes: precursor cells for functions at different times in development and adulthood. together with the appearance of features of brain development to understand the potential polarized structural features (axons and dendrites). 1995. 2002. histotypic organization. populations of neurons. 2004. 1997. 1993. process. toxicants. and during development (Lauder. situated trophic factors all have been established as mediators of along the forerunner of the ventricular system. Thus all functional areas have repeated and autism (Charman. and circuit forma. migration of postmitotic neurons from their place of origin to ferent roles in cellular communication in the mature brain their final resting position (Noctor et al. mental defects to cortical dysfunction in these disorders Very similar temporally ordered patterns of cortical remain unknown.6 The Effects of Monoamines on the Developing Nervous System GREGG D. It is clear. we focus on several specific gene products that. with the peak of 83 . These neuromodulators are particu. or drugs of abuse (Trask and Kosofsky. Here.and postnatal appears to be a normal developmental mechanism to development. 2005). Progenitor cells of the germinal matrix. 2002). Neuronal differentiation involves the expression of Herlenius and Lagercrantz. which is responsible for the integration of complex sensory. motor. Huttner. Recent evidence suggests that specialized radial tropic activities. Stanwood and Levitt. a complex process that abuse and psychotherapeutics during pre. stress. interactions that mediate specific developmental events are total gestation is approximately 21 days. and a radial scaffold to guide the directed nized as exhibiting multiple activities. Gotz and Neurotransmitters and neuromodulators are now recog. Lewis and Levitt. Kriegstein.

Abbreviations: E. eration of topographic axon projections. Levitt. proliferative zone. Some elements of cell stones in the forebrain. 2003). differentiation and synaptogenesis occur over protracted periods of aggregation. and in the formation of precise sensory organization and a minimum of connections are already maps within specific layers of the cerebral cortex (Kanold formed. and myelination begins (figure 6. cerebral cortex. This so-called inside-out settling pattern is a hallmark ting the preplate is an important first step in establishing of cerebral cortical formation and allows one to define the 84 fundamentals of developmental neurobiology . Neurons arising from the proliferative zone along the The first neurons produced are actually not located in the ventricular surface of the dorsal telencephalon (dorsal forerunner of the cortex. migration. In the mouse. CP.1 Schematic representation of developmental mile. depicting proliferation and migration. basal fore- Neurons and glia are produced from proliferative zones. In the mutant (E) 16. age in months after left. such as the (Figure is modeled on Rakic. W. P. ficial. Bf. and mouse reeler. which eventually is split into radial glia to reach the cortical plate. and corresponding days in the rodent brain are on the right.1 and plate 15. 2003). marginal zone. circuit formation. Th. embryonic day. CC. The process of split.) subplate in the cerebral cortex. this process is abnormal and the cortex is disorganized. PZ. et al. to specific locations in the brain. cortical plate. targets for subcortical axons from the thalamus.. and a brain. By the third trimester. total gestation is about 19 days. basic of the cerebral cortex. TC. These beginning by the end of the second month of gestation and neurons aid in the guidance of axons to correct target regions peaking prior to midgestation. SP. but rather form pallium) attain a bipolar morphology and migrate along a structure called the preplate. thalamus. In humans. time and peak after birth. cerebral cortex. birth.Figure 6. neuron production. mate times of each event in the human brain are labeled on the postnatal day. M. corpus variety of physical and chemical cues contribute to their migration callosum. with neurons born a subplate and a supraplate in the marginal zone by the first early residing deep and those born subsequently more super- neurons destined for the cortical plate. The approxi. Transient structures. age in gestational weeks. 1995. MZ. in which expression of the reelin gene is defec- E15 corresponds to the peak of neuron proliferation in the tive. the cortical plate. and synaptogenesis. provide cues that assist in the gen- cortical neuronogenesis occurring at about embryonic day appropriate migration patterns of neurons.) (See plate 15. CTX. subplate. Subplate neurons are transient cells that serve as temporary and differentiation occur prenatally in the cerebral cortex. thalamocortical projections.

. ously. 2004. and ultimately is reduced by almost 40 percent the rostro-ventral end of the lateral ventricle and can produce through a normal process of retraction and remodeling new neurons and glia in the mature forebrain. pharmacology. neurotrophins. (Caviness et al. have important roles in rotransmitters. tyrosine synthesizing neurons occur during this migratory process kinases. also can modulate tude more rapidly. which can be recognized as neurons migrate. These signals can act locally. and Recent studies have demonstrated that not all neurons of Rakic. it appears that most of the GABA interneurons of synapse number (Burrone. neuronal migration. including the activity. Eagleson. Recent studies indicate that regu- the cerebral cortex arise from the dorsal telencephalon. termed the subven. As noted previ. Downstream cortex. including cadherins. Neurotransmitters themselves can influence regulating synaptogenesis (Boulanger and Shatz. the ephrins. 2002) by the cerebral cortex are generated in the ganglionic eminence controlling the expression of intracellular signaling mole- of the ventral telencephalon and migrate tangentially to cules and transcription factors.time of origin of neurons residing in specific layers of the dritic development of projection neurons. Following the genesis. Levitt. other molecules. 2000). 2002.. In vitro studies have shown that neu- and months. The early postnatally and through adolescence. Levitt. 2006. which subtypes of receptor proteins are activated (see next phorins. These interneurons comprise 12–18 percent tofore were considered irrelevant to neuronal function and of all neurons in the cerebral cortex and exhibit many phe. Diffusible and membrane proteins serve as negative or positive regulators. and small GTPase signaling totic. the amino prior to neurons reaching their final resting position. Eph receptors. and areas that initially facilitate the correct targeting of axons functions. These This process appears to be independent of specific activity axons grow into the intermediate zone. acids glutamate and GABA have complex effects on cell Complex molecular signaling is responsible for the regula. influence gene transcription (Flavell et al. including major histocompatibility complex class I formation of axons and dendrites and the synthesis of neu. monoamines can tion of axonal growth. semaphorins. activity among the key regulators (McAllister. and which can be modulated by physiological notypic properties of neurons as they migrate. Moreover. Whereas axon targeting occurs rapidly. Dopamine (DA) has been implicated in a variety from the dorsal thalamus prenatally. and netrins are responsible both for chemoattraction and Developmental neuropharmacology of brain monoamines chemorepulsion. and increase the complexity of dendritic branching. and afferent-driven physiological (Behar et al. development. reaching target areas in some instances cell migration and dendritic growth. For example.and axon-specific proteins expressed proteins also have profound influences on axonal and den- during migration. beyond neurons of the superficial cortical layers and most of puberty. super. Bourgeois. 2003). 1997. receptors and complement proteins. O’Byrne.. small fraction of adult synapses are present by birth. some of which here- Powell. 2006). members of the Ig superfamily. In the Neuronal polarity reflects the asymmetry of information visual system. such as Mef2. rotransmitters. and Murthy. with dendrite. sema. 1999. In the cerebral cortex. Ephrins. These progenitor cells maintain a mammalian species. of functions in the mature CNS. and it is therefore possible that unique Bjartmar et al. In contrast. in primates synapse number peaks the macroglial cells (astrocytes and oligodendrocytes). Dendrites grow slowly over many weeks dritic development. the forerunner of in early developing circuits.. it is necessary to tion factors control the specification of different functional understand their normal ontogeny. transcrip. 1997. quantitative production of neurons destined for layers 6–4. a new. stanwood and levitt: effects of monoamines 85 . 2006). whereas axons grow several orders of magni. 1999). Similarly. including motor control.. Shalizi et Nadarajah and Parnavelas. survival and neurite growth. with effectors of axon guidance are thus distributed in unique the trailing process of migrating cells generally forming the patterns to produce a basic blueprint of long projections. plateaus for SVZ is maintained in adults in a restricted region along several years.. polarity is seen first when a neuron becomes postmi. with neurotransmitters. Goldman-Rakic. which resides between the subplate processes appear to be essential for mediating synapto- and the germinal matrix during development. or at a dis- tance to direct extension of axons along specific pathways to Dopamine (DA) In order to place the developmental roles reach their proper targets. section). which in turn reach all areas of the cerebral cortex (Anderson et al. small GTPases. For example. lation of neuronal excitability can have dramatic effects on Rather. brane ligands. activity-dependent cortical white matter. In all tricular zone (SVZ). the process of synapse formation and position away from the luminal surface and produce the pruning occurs over a relatively long time period. the receptor tyrosine kinase Ephs and their mem. analysis of synaptogenesis in the cortex indicates that only a ficial zone of progenitor cells appears. The control of dendritic growth is regulatory interactions between amino-acid-transmitter– complex. in the absence of synapses. axon. depending upon that comprise different families. Migrating cells exhibit polarized features. of monoamines in a proper context. neurotrophins are transported in a retrograde processing and the molecular and structural differences in manner by developing thalamic neurons from the cortex the accumulation of proteins and organelles. before extensive den. and al. 2004).

In the monkey. and changes in the availability ventrally located subcortical regions such as the nucleus of necessary cofactors for tyrosine hydroxylation. monoamines implicated. and amygdala. Cardinal. because the DA to contribute to several major neurological and psychi. neurons usually are able to match accumbens is thought to be a site of interface between limbic the rate of DA synthesis to the rate of DA utilization. (seconds) modulation of biochemical events in the target cell. can be metabolized in the nerve terminal by monoamine Transcripts for the D1. In humans. (Sibley and Monsma. and Robbins. The meso- ter. and rate of DA utilization within relatively narrow limits. thereby and motor systems and is a critical substrate for the develop- avoiding either the buildup or the depletion of the transmit. midbrain DA neurons appear in types (D1. emotional. which lies medially to the SN including end-product inhibition. D1 and D2 receptor proteins are measurable 86 fundamentals of developmental neurobiology . Axons addiction. and cardiovascular cortex. example. ADHD. Limbic cortical regions. receive the densest dopaminergic tors that are characterized by an extracellular N-terminus. 2004). DA synthesis. consistent with a morphogenic role nucleotide binding proteins (G proteins). 1998. and Weinberger. alter dopaminergic activity in nigrostriatal and meso- cal effects in neurons by way of its interactions with specific accumbens neurons. striatum. For and attentional processes (Goldman-Rakic. The striatum is the major output component of the The catecholamine DA is synthesized from the amino basal ganglia. DA depression. 1972). Because of accumbens. DA receptors are of DA. a process that may contribute to receptor proteins. ment and regulation of goal-directed behaviors. DA receptors belong to a cortex a few days later. nonneuronal catechol-o-methyl transferase (COMT) regulation. Rakic. several processes regulate DA release. DA neurons of the SN/VTA are classified into two subfamilies according to pharmacological produced by E30 of a 165-day gestation period (Levitt and profiles and sequence homology: the D1-like receptor sub. innervation. TH. Such influences of mesocortical DA neurotransmission has been associated represent negative feedback loops and act to maintain the with disease states including schizophrenia. and followed the primary pathology in Parkinson’s disease. DA can act back on the terminal from which it 2003. Furthermore. or and nondopaminergic functions. The mesolimbic DA system innervates structure of TH molecules. Parkinson’s disease. This input is thus already present in the intracellular C-terminus. Like These regions have been implicated in cognitive. attention-deficit hyperactivity disorder (ADHD). and is present by neuronal inputs. D2. act directly on DA systems and can compacta form the nigrostriatal tract. Abnormalities in brain DA systems are thought is primarily responsible for inactivation. including of DA-containing cells in the substantia nigra (SN) pars psychostimulants. Elston. a group of nuclei involved in motor and cogni- acid tyrosine through the actions of tyrosine hydroxylase tive functions. The mechanisms responsible for the proper guidance of The neurotransmitter actions of released DA and other dopaminergic afferents to the cortex and the morphogenic monoamines are typically terminated by transport back into properties of these afferents on cortical neurons are not presynaptic terminals by plasma transporter proteins that well understood. 1992). 2006). cortex even while more superficial cortical layers (II–IV) and coupling to specific effector functions through guanine are beginning to form. Dalley. atric disorders including schizophrenia. seven transmembrane domains. but netrins and ephrins have been form high-affinity uptake sites. These effects include relatively rapid pathophysiology. such as large superfamily of neurotransmitter and hormone recep. the rate-limiting enzyme in the process. D5) and the D2-like receptor subtypes (D2. polysynaptic circuits through release can also be potentiated or attenuated by both local glutamatergic pathways produce anatomical substrates by and distal actions of other neurotransmitters. as well as more gradual (minutes-hours) E14 in the rabbit. D4) the second month of gestation (Olson and Seiger. the ACC and mPFC. The mesolim- by aromatic amino acid decarboxylase. Degeneration of nigrostriatal DA neurons is (TH). DA release occurs cortical system provides dopaminergic afferents to the medial in response to an influx of calcium into the nerve terminal. which is triggered by the arrival of an action potential. prefrontal (mPFC) and anterior cingulate (ACC) cortices. and D3 receptors can be oxidase (MAO) or further sequestered into storage vesicles detected in the striatum and cortex by E14 in the rat. which provides the produce long-lasting alterations in endogenous dopaminergic dopaminergic innervation of the caudate and putamen. ventral tegmental area (VTA). Axons of dopaminergic cells reach the alterations in gene expression. and endocrine. The nucleus these regulatory processes. olfactory tubercle. 1982). Many exogenously administered drugs. is first resulting in changes in the responsiveness of the cell to other apparent at E12–13 in the rat midbrain. D3. Harrison. The rate-limiting enzyme in DA synthesis. The rate at which bic and mesocortical DA systems largely arise from the DA is synthesized is controlled by several mechanisms. and drug There are several major dopaminergic pathways. As is the case for all neurotransmitters. transporter is not present in these synapses (Tunbridge. which mesocortical DA dysregulation can secondarily Dopamine induces a wide range of cellular and biochemi.cognition. changes in the number or in the midbrain. In by vesicular transporters for later reuse. In human prefrontal addition. and disruption was released to inhibit subsequent release. Once taken up. emotional.

1972). and dependent processes also alter postnatal development of Levitt. The indoleamine 5-HT is in all species examined. the former being directly responsible for the is controlled by several regulatory mechanisms. tors that are activated. especially during the periods of synaptic matu. in our current understanding of where and when distinct 5-HT receptor subtypes are expressed during prenatal brain Serotonin (5-HT) The indoleamine 5-HT is found in development. It is formed by the hydroxylation and circuit formation has been demonstrated in mice where the decarboxylation of tryptophan by the actions of tryptophan gene encoding MAO-A has been disrupted (Cases et al. basal fore- in the midline raphe nuclei in the brain stem. and by the fifth week in humans (Olson and Seiger. Important roles for 5-HT have been implicated in a In vitro studies have supported a role for DA as both a wide variety of behaviors and conditions including anxiety. in a dose-dependent manner. DA receptors functionally These are grouped into seven families (5-HT1–5-HT7). month of gestation in the monkey (Levitt and Rakic. couple to G proteins very soon after their appearance. Cases. Persico. genesis itself within the neuroepithelial precursors of the Serotonergic axons reach their forebrain targets prenatally striatum and cerebral cortex. Luo. 2003. 2001. Finally. Later in prenatal development. Furthermore. receptor activation modifies specific aspects of dendritic sion of the D2 receptor in the developing striatum can cause development in differentiating neurons. changes in the availability of topographic vibrissae representation in the somatosensory tryptophan hydroxylase. the cell bodies for serotonergic neurons reside terns of 5-HT receptor expression in the cortex. 2003). Recent data also suggest that transient overexpres. Loss of MAO-A results in increases in 5-HT respectively. and as a function of the neuronal cell The indoleamine 5-HT is one of the earliest developing type being modulated. Di Pino. havior. whereas D2 receptor activation and Maroteaux. 2006). and drug abuse. and the nervous system. by way of influences on cell in the rodent (E16–17). DA receptors are present very early removed from the synapse by the actions of a high affinity in prenatal development. these Serotonergic neurons are first evident by E12 in the rat effects are reversed. and most widely distributed neurotransmitter systems in the selective D1 receptor activation decreases neurite outgrowth mammalian brain (Whitaker-Azmitia.. In cortical neurons.. influence of 5-HT occurs at specific sensitive periods. DA. 1974). stanwood and levitt: effects of monoamines 87 . 2003. DA receptors appear in binding affinities and physiological functions. DA Moreover. with D1 receptor activation serving to midbrain (Lauder and Bloom. 1982). MAO. other monoamines. most 5-HT receptors are G-protein– In the human fetus. hydroxylase and aromatic amino acid decarboxylase. For tion. but terminal arborization and peak cycle length (Ohtani et al. 1998). In striatal neurons. 1996. removal of 5-HT during very early fetal develop- the effects of prenatal cocaine exposure suggest that modifi. schizophrenia. 2006). Similarly to the catecholamines. 5-HT synthesis and NE levels.. expression patterns in mice indicate highly regulated pat- In the CNS. This pattern of cytoarchitectonic organization. and Lauder.prenatally. 5-HT-releasing of prenatal development induces permanent effects on circuit fibers influence Cajal-Retzius cells within the marginal zone formation and function (discussed in a later section of this of the cerebral cortex. The neurons may also be modulated by dopaminergic stimula. DA signaling also appears to be involved in prenatal neuro. Similar to the target regions of DA input by the first quarter of gestation. aggression. and dorsal thalamus (Bonnin et al. 5-HT chapter). by the end of the first promote neuronal differentiation and process outgrowth.. Gaspar. 5-HT serves as a precursor for melatonin production in the A particularly striking example of a role for 5-HT in pineal gland. 2006). 2005). Recent studies from our laboratory on the cardiovascular tissue. Neurite outgrowth lifelong changes in the activity of D1 receptor systems in the by dorsal thalamic neurons is modulated in a hierarchical prefrontal cortex (Kellendonk et al. consistent with a role for DA in 5-HT transporter. as postnatal development to reach adult levels of expression more than 15 different 5-HT receptors have been cloned. D1-like and D2-like receptor binding coupled receptors. The actions of appetite. role on its own neurons. and the activation of autoreceptors. brain. Zhang et al. blood cells. for example. a notable exception is the ligand-gated sites have been detected at gestational week six. including failure of the development of barrellike structures related to end-product inhibition. ment in rats can cause a permanent reduction in the number cation of DA D1 receptor signaling during a sensitive period of cortical neurons in the adult brain. 5-HT plays a negative feedback brain circuits. In the monkey. Unfortunately. Also. followed by intracellular metabolism by regulating neuronal differentiation and circuit formation.. sexual be- DA on outgrowth are modified by the complement of recep. increases outgrowth. alternative mRNA splicing and mRNA editing also is likely to have early biological activity in the primate create at least 20 additional 5-HT receptors with different brain. migraine. ion channel 5-HT3 receptor. cortex. for example. The 5-HT levels occur during the second and third postnatal phenotypic differentiation of inhibitory GABAergic inter. promoter and an inhibitor of neurite growth. Therefore. there are large gaps ration and refinement. however. between P14 and P21 in rodents. In addition. during synaptogenesis and circuit refinement. weeks. fashion by different 5-HT receptors (Persico. Studies from our laboratory and others investigating example. and they increase throughout prenatal and early Receptor proteins for 5-HT are diverse and numerous.

Although barrels are absent in the somatosen. The proteins for more sustained periods. approximately E13 in the rat. anxiety-related behavior. E30 in the sory cortex in the MAO-A mutant line. 1995). Thadani. 2004. and Zhou. using a drug to inhibit 5-HT synthesis during the criti. NE neurons in the pons (locus the remarkable sensitivity of somatosensory pattern forma. Olney weeks of age is sufficient to produce adult mice with increased et al. transmitted through several synapses in the tions have actions on the noradrenergic system. the ventrobasal thalamic projections to somato.. organization. In addition. the α2a NE receptor (as well as other mono- week. This conditional knockout strategy was used to show reader to other sources for discussions of other psychophar- that. the best characterized effect of NE has been in that alterations in monoamine levels during development studies examining the role of neuromodulators in critical- can lead to aberrant neuronal projection patterns and target period plasticity in sensory systems (Manunta and Edeline. anxiety. 2002. arousal. very little brain stem and thalamus. such as (Gross et al. results in normal the generation. neurons. which are segregated HT also leads to a loss of barrel formation. and maturation of cerebral corti- barrel development (Salichon et al. 1972). Mutation of the 5-HT1A receptor in mice drugs of abuse and psychotherapeutics.1). Because be rescued by expression of the receptor in specific regions of space limitations. mulate 5-HT during the critical period in the first postnatal Furthermore. in the somatosensory cortex? During normal devel. exposure to selective 5-HT reuptake inhibitors (SSRIs) during thalamocortical synaptic formation may have delete.and postnatal development. These cells are sensory cortex express transiently the presynaptic 5-HT the first neurons to be born in the cortex and are instrumen- transporter. our discussion will concentrate specifi- of the forebrain using a conditional transactivation genetic cally on the effects of in utero cocaine. Barrel formation in five major NE tracts originate that innervate the whole the MAO-A null mice can be restored with early interven. 2005). The modulation of cortical barrel formation by 5-HT amine receptors) is expressed by migrating neurons in the is shown further in the study in which genetic deletion of intermediate zone in close association with radial glia (Lidow presynaptic 5-HT1B receptors. the vesicular monoamine transporter. Cortical barrel for. and learning and memory. 1999). 5-HT plays a role in the establishment of Given the modulatory influence of monoamines on specific adult anxiety behavior through a mechanism in which activ. repression of receptor expression until three 2000. 2002). migration. aspects of neural development.. 1998. transport proteins and blocks the reuptake of the neurotrans- mitters. but directed studies are needed in this area. with conversion of DA to NE occurring through cal period for barrel formation. The primary pharmacological sites of action of cocaine sion during the early postnatal period. and NE. stages in the CNS.unique to rodent somatosensory cortex. An example: Alterations in brain development and rious consequences. is ineffective. 5-HT. There of MAO-A activity in wild type mice or total absence of 5. 2001). Forebrain 5-HT1A receptor expres. So why do non-monoaminergic research has been conducted on the developmental roles of afferents arising from regions with seemingly normal barrel NE during pre. cal cells. brain. Recent studies in rodents have suggested function due to prenatal cocaine exposure that this may be the case (Xu. coeruleus) and brain stem first appear at relatively early tion to 5-HT. Collectively.. 1982). These data also have led to the hypothesis that 2004). in the cerebral cortex (Naqui et al. in the context of excessive 5. Pharmacological inhibition the action of the enzyme dopamine β-hydroxylase. Trask and Kosofsky. particularly in the locus coeruleus. during the first postnatal week of life. and Wang.. One develop- formation produce abnormal barrel formation at the next mental function that has been described for NE during synapse. 2004). DA serves as a metabolic intermediate within NE tion. Carlezon and Konradi. This defect can effects on the development of the cerebral cortex. but not in the adult. whereas repression of receptor expression in the adult macological insults (Slotkin. humans (Olson and Seiger. Cocaine binds to these responses. Sari. embryogenesis is on the development of Cajal-Retzius cells opment. tal in neuronal migration and laminar formation (figure 6. 2004. and accu. Andersen. particularly those located 88 fundamentals of developmental neurobiology . mation is dependent upon activity arising from peripheral Despite the fact that many types of psychotropic medica- whisker barrels. resulting in excessive cell bodies of NE neurons are concentrated in the brain activation of these receptors. Post- these studies have provided the strongest evidence to date natally. thalamic and brain monkey (Levitt and Rakic. demonstrating into two families (α and β). normally forms stem. thus prolonging their time in the extracellular space. and by 5–6 weeks in stem barrellike patterns are still evident. From this structure. it is understandable that pre- ity need only be disrupted during the early postnatal period natal exposure to drugs that affect these systems. and other psychostimulants in the brain are the high-affinity is thus necessary for the expression of normal anxiety transporters for DA. and we direct the system. are at least ten identified NE receptors. Thus NE may be involved in regulating HT produced by MAO-A disruption. can have pronounced causes increases in anxiety-related behavior. Norepinephrine (ne) Norepinephrine is involved in This action permits the monoamine to bind to its receptor attention.

is unexposed infants. and yet others indicate no effects. increased risk of ADHD also has been documented in the 2005). gestational age at birth. and behavioral abnormalities that involve Pavlovian et al. and with the same period of species (see Stanwood and Levitt. intravenous rabbit model that cocaine use during pregnancy. there are measur. D2 and muscarinic cholinergic receptor coupling to Gi/Go Disturbances reminiscent of children diagnosed with proteins is normal. knockout mouse exhibits similar structural alterations in cor- tence. produces a host of neuroadaptations in the brain toneal injections of high doses of cocaine (20–80 mg/kg). 2003). These signaling during development. Prospective longitudinal studies of defects include aberrant growth of dendrites of cortical pro- cocaine-exposed infants and school-age children (Mayes jection and interneurons. However. and permanent effects on behav- typically occur following very prolonged and high levels of ioral functioning and on the structure and function of corti- cocaine intake by the mother. 16). 2001). We have viewed the D1 receptor signal- ADHD are consistently found in children exposed to cocaine ing defect as a manifestation of a cellular strategy. and may be tical development to rabbits in which prenatal cocaine worsening as these children continue to age. The effects are dren exposed to relatively low doses of cocaine in the womb. and caregiver characteristics. and perhaps the point comes has been assessed in 218 cocaine-exposed and 197 of origin for the structural and behavioral disturbances.2 and plate confounded and most compelling reports. Singer et al.. Strikingly. produced either by exposure for the majority of pregnancy These disturbances are due primarily to alterations in atten. and Day. and Stanwood. The anatomical and monoamine systems. tates the assessment of specific effects on the organization of The variable outcomes are at least in part the result of cocaine’s targets in the CNS. and can potently modulate monoaminergic logical effects on biological targets in the brain and the systems during prenatal development if the drug is used periphery of both the mother and fetus. important covariates such as the timing and amount of A low-dose (2–4 mg/kg). age of assessment. of the user that are associated with addiction (Hyman and However. 2004). Selective deficits in aspects of cognition and/or attention For example. likely stemming from differences in dosing. distractibility. exhibit profound sensitization to the behavioral stanwood and levitt: effects of monoamines 89 . perhaps more interestingly. and at the same dose and duration. pronounced teratological effects at high doses. rabbits treated with cocaine show near complete loss of an There are numerous inconsistencies in the basic science amphetamine-induced stereotyped behavior (head bobbing) literature regarding the biological effects of prenatal cocaine when tested as young adults (Stanwood and Levitt. dose-dependent. that closely mimics the pharmacokinetic response in human formations. 2000.2).. receiving cocaine of administration. which is tantly. language development. Cocaine is a drug of abuse in adolescents issue). Arendt et al. We have sug- Clinical reports of the impact of prenatal cocaine expo. for review of this withdrawal. 2004). the mothers of these offspring. exposure to other drugs. exposure. spective cohort where the relationship between prenatal 2005).. weight at This effect appears to be specific for D1-Gs coupling. 1997.. Singer and colleagues have assessed a pro. or. Stanwood and Levitt.7% versus 7. B. its G protein (Jones et al. and period during the human equivalent of the second trimester are likely caused by improper functioning of limbic cortices (Stanwood. and Levitt. 2002. from that in adults. time of exposure. during a short sensitive tion. 2003). task persis. Possibly the most remarkable demonstration of the cocaine exposure and developmental and cognitive out. Lewis et al. others observe specific deficits in cognitive and cocaine abusers. Singer cuitry. impact of prenatal cocaine exposure. cocaine has complicated and diverse pharmaco- Malenka. The rate of developmental delay was the striking reduction in coupling of the DA D1 receptor to nearly doubled (13.extrasynaptically. 2001. 2004. gested that a low-dose model. distinct prenatally (Leech et al. Impor. and stress responsiveness. 2002. Mayes. Washington. 2001). M. Zhen et al. 2004) have produced the least learning and stereotypic motor behavior (figure 6. this still ongoing study has controlled for prenatal initiated prenatally and sustained into adulthood (figure 6. 2004. as some suggest gross physical mal. Levitt. ces receiving a rich DA innervation (Levitt et al. 1999. the D1 receptor changes include deficits in recognition memory. offspring of women who smoke or consume alcohol heavily The neuroadaptive changes that occur in response to during their pregnancy. using a route of administration sure have been diverse. Many models have utilized subcutaneous or intraperi- and adults.. and the quality resulted in highly reproducible and selective brain defects of pre. Parlaman. 2004. 2001). route In contrast. the biogenic amine systems.1%.. Lewis et al. able deficits in cognition and emotional regulation in chil.. respectively).and postnatal care (Singer et al. polydrug use.. Conroy. also have been noted (Thompson.. and can exhibit during pregnancy. because birth. The offspring of during infancy and early childhood.. There are Severe physical abnormalities in cocaine-exposed infants specific. 1995. Harvey. provides a reproducible system that facili- emotional development.. for adapting to disrupted balance of DA 2004. and Levitt. Interestingly. suggesting disruption of local cir- et al. Richardson. Mayes. reduces D1-Gs coupling (Stanwood. was thus initiated by a group of investigators. Reports also have suggested that repeated exposure to cocaine vary with the maturational prenatal cocaine exposure delays language development state during which the exposure occurs. 1996. and regulation of arousal.

Figure 6.2 Schematic representation of cellular effects of in utero these neurons. D1 dopamine receptor coupling to Gs protein (blue)
cocaine exposure in the rabbit. Rabbits exposed to low doses of is reduced, whereas coupling of the D2 receptor to Gi (orange) is
cocaine intravenously exhibit alterations in the structure and func- unaffected. These changes likely influence the balance of excitatory
tion of neurons in the anterior cingulate cortex. The apical den- and inhibitory influences in the cingulate cortex and produce the
drites of pyramidal neurons (red) exhibit an undulating trajectory. aberrant behavioral phenotypes exhibited by these rabbits, includ-
The number of interneurons in which immunoreactivity for GABA ing psychostimulant responsiveness and attentional deficits (see text
is detectable (black) is increased. There also is an increase in parv- for more detail). (Adapted from Levitt et al., 1997). (See plate
albumin (green) immunostaining in the dendrites of a subset of 16.)

effects of amphetamine (Stanwood and Levitt, 2003). Our Environmental or pharmacological challenges, which would
most recent data suggest a similar double dissociation in the engage both receptors, however, would be influenced sub-
reinforcing effects of cocaine following previous in utero or stantially, with the outcome likely to produce atypical DA
adult exposure to the drug (B. Thompson, G. Stanwood, and modulation of circuits. Furthermore, the long-lasting
P. Levitt, unpublished observations). decrease in stimulant-induced behavior in the rabbit model
Two groups have utilized intravenous administration of suggests that brain pharmacology is permanently altered
cocaine in rats (Mactutus, Herman, and Booze, 1994; Mac- and “typical” responses to drugs of abuse or psychothera-
tutus, 1999; Morrow, Elsworth, and Roth, 2002, 2003). peutics cannot be assumed to occur in cocaine-exposed chil-
Although the studies have emphasized the analysis of distinct dren. The data further suggest that some children exposed
biological measurements and markers, direct parallels prenatally to cocaine will respond poorly to mild psycho-
between models are beginning to be established. Further- stimulants such as methylphenidate, a disturbing prediction
more, models of higher dose cocaine administration in given the high incidence of ADHD in prenatal cocaine-
rodents (Kosofsky, 1998; Rocha, Mead, and Kosofsky, 2002; exposed children. An alternative strategy might include
Melnick and Dow-Edwards, 2003) and nonhuman primates treatment aimed at restoring the “balance” of D1 and D2
(Lidow, 1998; Chelonis, Gillam, and Paule, 2003) have receptor signaling, which could be more efficacious (see next
revealed additional disruptions of CNS development by section).
cocaine, including potential effects on neuronal migration, Further interactions between DA and the other mono-
differentiation, and cell survival. amines are likely to play a role. Cocaine also blocks the
We propose that the loss of dopamine D1 receptor signal- reuptake of NE and 5-HT, and, as described earlier, these
ing may represent a conserved feature of prenatal cocaine neuromodulators also influence excitatory and inhibitory
exposure and quite possibly the primary cellular mechanism activity within the brain. Although no evidence for changes
used to compensate for excessive DA release and receptor in 5-HT or NE innervation or activity has been identified in
stimulation during neuronal differentiation. Given the pri- the rabbit model, deficits in serotonergic functioning cer-
marily extrasynaptic location of the D1 receptor, as com- tainly have been described in higher dose models of prenatal
pared to the intact primarily synaptically located D2 receptor, cocaine exposure.
and the activation of the D1 receptor by phasic, but not Intriguingly, the ACC and mPFC, the cortical regions in
tonic, DA release, we predict that the basal functioning which we have observed in utero cocaine-induced changes
of DA-modulated circuits would be minimally disrupted. in our rabbit model, contribute to the neural control of

90 fundamentals of developmental neurobiology

attention and are sites of brain dysfunction in ADHD. Chil- from animal models suggest that the efficacy of reinforcers
dren exposed in utero to cocaine perform poorly on tasks is reduced following prenatal cocaine exposure.
that depend on the proper functioning of the mPFC and
ACC, showing deficits similar to those of children diagnosed Balance of receptor signaling
with ADHD. Reduced signaling through the DA D1 recep-
tor appears to underlie the structural and functional deficits The amount of receptor stimulation by each of the mono-
observed in prenatal cocaine-exposed rabbits, and thus it is amines, as well as the molecular identity of those receptors,
intriguing to speculate that similar processes may be occur- determines the intracellular response to the extracellular
ring in cocaine-exposed children. The development of a cue. These molecules, however, have relatively slow modu-
therapeutic strategy to restore proper D1 receptor coupling latory actions, in contrast to fast-acting neurotransmitters
in these children might therefore be efficacious in the treat- such as glutamate and GABA. It has been hypothesized,
ment of attentional disturbances. therefore, that an even more important determinant of
Reduced D1 receptor coupling could have other severe ultimate functional response than the absolute level of
consequences throughout their lifetimes for children exposed stimulation is the balance of receptor subtype activation
prenatally to cocaine. D1 receptor activation is an important (figure 6.3 and plate 17).
substrate for reward pathways in the brain. Although not This concept was initially proposed nearly 20 years ago
yet studied in the human population directly, one predic- to explain some of the actions of DA D1 and D2 receptor
tion is that drug-exposed children would likely experience activation, but few studies have been conducted to test
defects in endogenous reward systems that could lead to the this hypothesis. Recently, two phenomena have returned
occurrence of anhedonia and/or depression. In fact, reports attention to the idea. First, detailed analysis of the

Figure 6.3 D1- and D2-like DA receptors produce distinct, and levels of receptor (above a certain minimum), but rather a balance
sometimes opposite, neuromodulatory effects on cell signaling, between opposing activities. Thus, in considering strategies for
electrophysiological responses, and behavior. They are often coex- restoring normal DA responsiveness, blockade of D2 receptors may
pressed within specific functional brain circuits, and sometimes have beneficial effects on the net outflow of DA-dependent neural
even by the same neurons. A reduction in D1 receptor signaling circuits. (Adapted from Stanwood and Levitt, 2004.) (See plate
could shift the balance of activity to D2 receptor subtypes. Normal 17.)
physiological responsiveness may not necessarily depend on the

stanwood and levitt: effects of monoamines 91

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outcomes of cocaine-exposed infants. JAMA 287:1952–1960. rabbit frontal cortex. J. Neurosci. 21:9160–9167.

94 fundamentals of developmental neurobiology

B. STRUCTURAL
FOUNDATIONS
OF SENSATION,
PERCEPTION,
AND COGNITION

7 Mechanisms of Auditory
Reorganization during Development:
From Sounds to Words
RICHARD N. ASLIN, MEGHAN A. CLAYARDS, AND NEIL P. BARDHAN

Several weeks before the human newborn is first exposed to underlying neural mechanisms in human infants and adults.
visual stimulation, auditory inputs are capable of stimulating Next we review how one class of auditory signals produced
hair cells on the basilar membrane, generating neural signals by the human vocal tract—speech sounds—are perceived
that travel from the auditory nerve to brain-stem, thalamic, by infants and how their underlying discriminative capacities
and cortical areas of the central nervous system, triggering influence the formation and maintenance of speech-sound
behavioral responses, and establishing rudimentary repre- categories in both infancy and adulthood. Finally, we review
sentations that can affect behavioral preferences several days how speech sounds are mapped onto words by describing
or weeks later. Newborns exhibit the ability to orient toward how infants begin to associate sounds with meanings and
sounds, to discriminate between some acoustic differences, develop a lexical categorization system that rapidly expands
and to show preferences for certain classes of auditory in size and is robust to considerable dialectal variation and
stimuli, only some of which could have been induced by other nonphonemic speaker-dependent acoustic variability.
prenatal experience. We conclude with some speculations about how a cognitive
Given this state of the auditory system at birth, the chal- neuroscience approach could reveal the underlying brain
lenge facing the developing infant is to determine which of mechanisms that make this progression from sounds to
the myriad of acoustic cues present in the proximal auditory words possible.
environment carries information relevant to solving particu-
lar ecologically relevant tasks. For example, sound localiza- Fundamental auditory capacities in infancy
tion requires the extraction of particular spectral and
temporal cues, the most important of which involve interau- The goal of studying basic auditory capacities in infancy is
ral differences. In contrast, speech perception involves the not only to document the normative course of auditory
extraction of different spectral and temporal cues, most of development and its underlying neural mechanisms, but also
which do not depend on binaural information. In addition to determine whether higher levels of auditory processing
to this problem of learning to extract the “right” acoustic are constrained by lower level immaturities. For example,
cues, the infant is also faced with tremendous variability the speech perception literature (see chapter 8 by Friederici
along the acoustic dimensions that are relevant for solving a in this volume) has highlighted the sophisticated discrimina-
particular task. For example, spectral cues are relatively tive skills of very young infants. However, it is unclear
unimportant for sound localization along the horizontal axis whether and how these discriminative capacities are used in
but play a crucial role along the vertical axis. Similarly, a natural language context to form speech categories and
variations in pitch and duration are less important than organize these categories in auditory memory for use in a
spectral cues for the perception of consonants and vowels, lexical (referential) context. Thus basic data on auditory
but these pitch and duration cues play a crucial role in tone detection and discrimination place a lower bound on when
languages and in identifying a particular talker or determin- higher level auditory processing can begin and how this
ing the talker’s emotional state. higher level processing compares to the exquisite sensitivity
We begin this chapter with a brief summary of the devel- of adults to linguistically relevant stimuli.
opment of basic auditory capacities in infancy, which, as
we will see, play a relatively minor role in constraining most The Onset of Hearing Evidence from the intact fetus
auditory tasks that involve suprathreshold auditory stimuli. and from infants born prematurely suggests that auditory
We then turn to underlying changes in auditory anatomy stimuli can elicit changes in heart rate (Lecanuet, Granier-
and physiology gleaned from invasive studies of nonhuman Deferre, and Busnel, 1988), eyeblinks (Birnholz and
infants, as well as behavioral evidence for plasticity in these Benacerraf, 1983), gross motor responses (Kisilevsky, Muir,

97

and Low, 1992), and auditory brain-stem responses (ABRs; Newborns raised in nearly all languages also prefer to
Hecox and Burkard, 1982) as early as the 28th week of listen to a pattern of maternal speech called “motherese,” or
gestation (when ABRs can first be recorded). Behavioral infant-directed (ID) speech, over the same sentences spoken
evidence using two techniques—conjugate reinforcement of by the mother in an adult-directed (AD) register (Cooper
sucking responses and preferential listening while fixating a and Aslin, 1990). Infant-directed speech is characterized by
visual stimulus—have shown that newborns exhibit auditory a slow speaking rate, a small number of words per utterance,
preferences (Cooper, 1997). Auditory preferences in and large pitch excursions (Fernald, 1985). In contrast to the
newborns reveal two important facts about development. early evidence for maternal voice and prosodic preferences,
First, any evidence of listening preferences confirms the the preference for ID speech is not induced by prenatal
newborn’s ability to discriminate among two or more classes experience. In the absence of prenatal exposure to ID speech
of sounds (of course, the absence of a preference is (Cooper and Aslin, 1990) or ID singing in hearing newborns
uninformative about discriminative capacities). Second, of deaf parents (Masataka, 1999), newborns show clear pref-
listening preferences in newborns could be due to the effects erences for these sounds over AD sounds, and newborns
of auditory experience (and learning) in the womb, analogous prefer hyperarticulated ID speech (despite never being heard
to the effects of auditory experience in prehatchling birds in utero) over normally articulated ID speech (Cooper and
(Gottlieb, 1976). Cooper, 1999). Thus there are some acoustic characteristics
The plausibility of auditory experience as a significant of sounds that are intrinsically preferred by newborns in the
influence on the human fetus was bolstered by demonstra- absence of any inducing experience.
tions that premature infants have a functional auditory Newborns also appear to spontaneously form categories
system and by hydrophone recordings showing that both for speech sounds along the linguistically relevant dimension
internal (maternal) and external sounds of high intensity and of lexical form class: function words versus content words.
low frequency are detectable in the amniotic fluid surround- Function words are generally shorter in duration and
ing the fetus’s ears (Querleu et al., 1988). DeCasper and unstressed compared to the longer and stressed content
Fifer (1980) reported that newborns suck differentially when words. Shi and associates (1999) showed that newborns who
given the opportunity to listen to their own mother’s voice were habituated to a list of function words or a list of content
over the voice of an unfamiliar mother. Thus not only are words failed to discriminate a shift to a novel list of words
maternal sounds available to a functioning auditory system from the same category, but succeeded in discriminating a
in utero, but also these sounds are apparently encoded shift to a list from the opposite category. Thus, when multi-
during some portion of the prenatal period and retained ple acoustic cues are available to differentiate two lexical
across a 2–3 day perinatal period to affect the newborn’s categories, even newborns can readily do so. However, as
listening preferences. When given a choice between a low- we will see in a later section, there are limits to category
pass-filtered version of their mother’s voice (similar to the formation in infants and a paucity of methods for assessing
spectral content available in utero) and an unfiltered version how sophisticated these speech categories are as compared
of their mother’s voice, newborns prefer the low-pass-filtered to adults.
version (Fifer and Moon, 1985), suggesting that they have An important point in the domain of speech is that mater-
learned the proximal characteristics of the most intense and nal input to young infants, although hyperarticulated to
frequent intrauterine sounds. enhance some auditory cues (e.g., vowel differences; see
In addition to a specific preference for the mother’s voice, Kuhl et al., 1997; Liu, Kuhl, and Tsao, 2003), cannot be
newborns exhibit a general preference for highly familiar exaggerated too much, or the exemplars will extend into a
auditory materials. DeCasper and Spence (1986) showed different perceptual category. Thus there are limits to how
that newborns prefer to listen longer to a familiar story that “simplified” the acoustic properties of maternal speech can
had been read aloud repeatedly by the mother during the be when it is presented to infants.
final weeks of pregnancy than to a novel story. The stories
were chosen to have different rhythmic structures, and the Absolute Thresholds The foregoing evidence confirms
newborns’ preferences were exhibited despite the presenta- that sounds of sufficient intensity are perceived not only by
tion of the test stories by an unfamiliar female voice. Simi- newborns but also prenatally. Thus, as long as sounds are
larly, Mehler and associates (1988) and Moon and associates above the infant’s hearing threshold, acoustic information
(1993) have shown that newborns prefer their native lan- along highly salient auditory dimensions is both detected
guage to a foreign language with different rhythmic proper- and discriminated. However, if auditory sensitivity is poorer
ties. Taken together, these results suggest that newborns in infants than in adults, then many sounds that are
have extracted a number of prosodic (rhythmic and intona- easily detected by adults will not be available to infants for
tional) characteristics of auditory input during the last few further processing. The available evidence from studies
days or weeks of prenatal development. using complex sounds like speech suggests that auditory

98 fundamentals of developmental neurobiology

thresholds do not impose severe constraints on higher level quency is exceeded by nearly all relevant speech and non-
processing. speech stimuli in the infant’s environment.
Three techniques have been used to assess sound thresh- Other studies using a masking technique to assess infants’
olds in human infants: the conditioned head-turning pro- thresholds for detecting a signal (either an octave-band noise
cedure (CHP; Moore et al., 1975), the observer-based or a pure tone) in the presence of either a narrow or broad-
procedure (OBP; Olsho, Koch, Halpin, and Carter, 1987), band masking noise (Bull, Schneider, and Trehub, 1981;
and the auditory brain-stem response (ABR; Hecox, 1975). Nozza and Wilson, 1984; Olsho, 1985; Schneider, Mor-
It is beyond the scope of this review to discuss these meth- rongiello, and Trehub, 1990, 1989; Spetner and Olsho,
odologies in detail, but the interested reader is referred to 1990) have shown that thresholds are elevated by the same
the works we have cited. The latter two techniques have relative amount in infants and adults, suggesting that fre-
documented significant improvements in absolute thresholds quency resolution is adultlike by 6 months of age. Perhaps
between birth and 6 months of age, and the conditioned more relevant to everyday listening, Bargones and Werner
head-turning technique has documented further improve- (1994) have shown that infants do not always appear to
ments between 6 months and 2 years of age. The ABR in selectively attend to the frequency range within which signals
newborns is 10–15 dB less sensitive than in adults (Hecox, are presented. How infants choose the specific acoustic cues
1975), and the OBP in 2-week-olds (Werner and Gillenwa- to which their processing is directed will be discussed in a
ter, 1990) is up to 50 dB less sensitive. By 3 months of age, later section on cue weighting.
OBP thresholds are 15–30 dB poorer than in adults (Olsho Duration discrimination is also important for supraseg-
et al., 1988). The CHP has also provided estimates of abso- mental or prosodic aspects of speech (and phonemic dis-
lute thresholds in 6- to 18-month-olds for pure-tone and crimination in languages that make duration distinctions),
octave-band noise stimuli (Berg and Smith, 1983; Nozza and and temporal acuity is important for the processing of bin-
Wilson, 1984; Schneider, Trehub, and Bull, 1979, 1980; aural cues to sound localization. Morrongiello and Trehub
Sinnott, Pisoni, and Aslin, 1983; Trehub, Schneider, and (1987) used the CHP to assess duration discrimination and
Endman, 1980). Although estimates vary across studies, by reported that 6-month-olds’ thresholds were 25 milliseconds
6 months of age, absolute thresholds are approximately 10– (ms) whereas adults’ were 10 ms. Werner and associates
20 dB poorer than in adults, and these estimates do not differ (1992) used OBP to assess gap detection in 3- and 6-month-
from those obtained using OBP (Olsho et al., 1988). In olds and, by altering the low-frequency cutoff of the noise,
summary, while there are significant postnatal improve- to determine which frequencies were used by infants in this
ments in absolute thresholds, many signals in the natural gap-detection task. Trehub and associates (1995) used the
environment are accessible to young infants (and to the fetus) CHP to assess two-tone gap-detection thresholds in 6- and
because they are well above threshold. 12-month-olds. These two studies show that gap-detection
thresholds decline from 4–5 times longer in 3-month-olds
Intensity, Frequency, and Duration Discrimination than adults to only a twofold difference by 12 months of age.
Given a sound above absolute threshold, one can ask whether However, several studies (Irwin et al., 1985; Wightman et
the infant auditory system can make fine discriminations al., 1989) have shown that gap detection thresholds continue
of intensity, frequency, and duration—the key acoustic to improve until at least 5 years and perhaps up to 10 years
parameters that are used to analyze auditory signals. Using of age. Duration discrimination also continues to improve
the CHP, thresholds to detect an intensity increment improve well into early childhood (Elfenbein, Small, and Davis, 1993;
from 6 dB to 4 dB between 6 and 12 months of age (Schneider, Jensen and Neff, 1993) and may play a role in the discrimi-
Bull, and Trehub, 1988; Sinnott and Aslin, 1985). Although nation of stop consonants in medial syllable position where
these infant thresholds are 2–3 times worse than adults’, closure duration is a primary cue.
most of the critical information carried in speech and A final aspect of duration discrimination is the processing
nonspeech environmental sounds contains intensity differ- of spectrotemporal cues. Aslin (1989) showed using the CHP
ences that are easily detected by infants. that 6- to 9-month-olds’ thresholds for discriminating a
The CHP has also provided evidence that 6-month-old rising or falling tone from a steady tone were quite good
infants can discriminate an increment or decrement in fre- (similar to the 2% thresholds for frequency increments or
quency of approximately 2 percent for midfrequency tones decrements). However, when these tone sweeps were rapid
(Olsho, 1984; Olsho et al., 1982; Sinnott and Aslin, 1985). (50 ms), thresholds increased by a factor of two, and when
The OBP has confirmed this 2 percent threshold in 6-month- infants had to discriminate one rising (or falling) tone from
olds and shown that 3-month-olds have a slightly poorer another rising (or falling) tone, their thresholds increased
threshold of 3 percent (Olsho, Koch, and Halpin, 1987). by an additional factor of 3–4. Thus, in the context of
Again, it should be noted that while adult thresholds are broadband spectral information whose components are
slightly less than 1 percent, a 2–3 percent difference in fre- undergoing rapid changes over time, as in the time-varying

aslin, clayards, and bardhan: mechanisms of auditory reorganization 99

formants of speech, infants are quite poor at discriminating Auditory Localization in Nonhumans A classic example
these spectrotemporal cues. This poor performance may not of specialization in the auditory domain is localization. Most
prevent infants from discriminating the major acoustic/pho- mammals that have a well-developed visual system combine
netic cues that are used to make phonemic distinctions in information from both their visual and auditory systems to
natural languages, but it may reduce the robustness of speech localize a sound source. Visual stimuli are essentially two-
discrimination under the less than ideal listening conditions dimensional projections of the external world onto a sensory
outside the laboratory. In addition, many of the subtle time- surface (the retina), with very high acuity along the line
varying cues in fluent speech may be inaccessible to the of central sight for some species (e.g., predatory mammals
infant until spectrotemporal sensitivity and working memory and birds). Auditory stimuli do not have this spatiotopic
have matured. representation at the sensory periphery (the cochlea), but
rather compute sound location from intensity (sound level)
Summary Fundamental aspects of auditory development and time of arrival differences at the two ears. In binaural
undergo substantial improvements in the first few postnatal animals, a sound originating from anywhere other than the
months. The processing of intensity and frequency infor- midline will strike one ear before the other because the ears
mation appears to reach values similar to those of adults by are separated on the head, producing an interaural time
6 months of age. However, temporal processing appears to difference (ITD), which is the main cue for azimuthal
have a more protracted development continuing at least into localization (right-left along the horizontal plane). In
the preschool years, and spectrotemporal processing shows addition, because the head sits between the ears of many
similar immaturities. How these basic capacities affect the binaural creatures, one ear lies in the sound shadow of the
processing of more complex sounds like speech remains head, reducing the intensity of the sound at that ear and
unclear. resulting in an interaural level difference (ILD). These
differences, in combination with monaural influences on
Neural specializations and reorganization sound quality (spectral cues) produced by the shape of the
external ears (pinnae) and head, provide the information
The foregoing summary of basic acoustic sensitivities and used in sound localization. Perturbing either the ITD, ILD,
preferences in newborns suggests that a quite sophisticated or spectral cues (see Parsons et al., 1999) can disrupt the
auditory system, albeit less mature than in adults, is function- ability to localize a sound source.
ing at birth. However, it is unclear whether newborns are The visual and auditory systems form a useful combina-
analyzing auditory stimuli with the same neural subsystems tion of contrasting characteristics: the auditory system detects
used by the adult brain. The classic view of how the neo- sound sources regardless of the orientation of the ears, and
cortex is organized in the adult brain is one of functional the visual system provides detailed information about a
specialization; that is, separate and discrete regions are stimulus and its surrounding environment in the visual field.
devoted to different sensory modalities and to the analysis A major concern is how these two perceptual systems are
of specialized features of sensory inputs. To some extent this integrated so that information from one is able to inform the
classic view is correct, with separate pathways from the other for stimulus localization. Visual and auditory informa-
sensory periphery to modality-specific regions of primary tion come together for the purpose of stimulus localization
cortex. However, the interaction among cortical areas is in the optic tectum in vertebrates and the superior colliculus
both extensive and far-reaching, suggesting that simple in mammals. The tectum contains topographic maps of both
models of neural specialization are at best incomplete and visual and auditory space, as well as bimodal neurons that
perhaps misleading, particularly models that fail to consider respond to both visual and auditory stimuli (Knudsen and
the multitude of direct and indirect inputs to any given Brainard, 1995). Thus the tectum provides a locus for cross-
cortical area. modal integration of auditory and visual information con-
A key developmental question in this debate about neural cerning the location of stimuli in the external world.
specialization is one of origins. Where do modality-specific An example of auditory localization that has clear paral-
and neural processing specializations come from? The two lels with humans comes from research on barn owls. In a
extremes of this question, of course, comprise the nature- series of perturbation studies, Knudsen and colleagues
nurture debate, in which neural specializations are either an altered the correspondence between visual and auditory
intrinsic property that arose from evolutionary processes localization cues in barn owls, either by placing prisms in
or an experience-dependent property that emerged during front of the eyes (Knudsen, 1988) or by monaural occlusion
ontogeny. Neither of these extremes is likely to be correct, with an earplug (Knudsen, Esterly, and Knudsen, 1984;
and the debate has shifted to understanding whether neural Knudsen, Knudsen, and Esterly, 1984). Wearing displacing
specializations can be modified by interventions during prisms or plugging one of the animal’s ears produces signifi-
development and perhaps even in adulthood. cant alterations in the tectal alignment of receptive fields for

100 fundamentals of developmental neurobiology

locations in space using auditory (ITD and ILD) and visual that visual information serves to improve localization
cues. If the prism or plug is in place during early develop- accuracy.
ment, then a remapping occurs and spatial localization is However, poor control of the motor system controlling
recalibrated. However, altered experience during adulthood head orientation could mask superior sensitivity to the
does not lead to a successful remapping. Thus there is a sensory cues for auditory localization. Studies of infants’
sensitive period for the alignment of auditory and visual ability to discriminate a change in the spatial location of
spatial cues in the tectum that directly mediates spatial local- a sound source (the minimum audible angle, or MAA)
ization responses. If the prism or plug is removed prior to reveal a substantial postnatal improvement in the spatial
the end of the sensitive period, then a return to “normal” is resolution of the auditory system. Studies using both the
achieved. However, if the prism or plug is removed after the OBP and conditioned head turning have shown that the
end of the sensitive period, then realignment is not observed MAA in the horizontal plane improves from nearly 30
and a permanent mismatch results. degrees in 2-month-olds to 9 degrees in 11-month-olds
Perhaps most importantly, Knudsen (1998) found that (Ashmead et al., 1991; Morrongiello, 1988; Morrongiello,
owls that had adapted to prisms during the sensitive period Fenwick, and Chance, 1990). Further improvements to adult
and subsequently readapted to normal vision before the levels (1–2 degrees) occur by 5 years of age (Litovsky, 1991).
close of the sensitive period were able as adults to show The MAA in the vertical plane, which is much greater in
subsequent shifts in the tuning of tectal neurons after the adults than in the horizontal plane because binaural cues
reintroduction of the original prismatic displacement. are absent along the midline, is approximately the same
Similar evidence was not found in control animals that had as the horizontal MAA in 6-month-olds. However, like
never experienced prismatic displacement. These results adults, the MAA in infants relies on the high-frequency
suggest that there is a trace of the former adaptive experi- spectral information that comes from the shape of the pinnae
ence that remains in the nervous system long after a different (Morrongiello and Rocca, 1987b; Morrongiello, 1987).
set of adaptive parameters has been adopted, and that the Importantly, improvements in the horizontal MAA in 4- to
neural pathways that were shaped originally by experience 7-month-olds are not the result of improvements in detect-
during the sensitive period can be resurrected during ing interaural timing differences (Ashmead et al., 1991),
adulthood. because the ability to resolve temporal cues is a factor of
two better than the temporal cues that are present in infant
Auditory Localization in Human Infants Auditory MAAs. Rather it appears that the MAA improves because
localization in human infants has been studied almost of a tighter sensorimotor mapping, perhaps because in early
exclusively by noting the presence of overt head-turning infancy, motor control of the head is so poor that the
responses to discrete sound sources (see review by Clifton, associated temporal cues cannot be learned with great
1992). Despite early anecdotal evidence of auditory reliability.
localization in a newborn (Wertheimer, 1961), Muir and Auditory localization in humans is susceptible to the
Field (1979) were the first to report definitive evidence that effects of early deprivation, though detailed occlusion exper-
newborns, under special circumstances, could reliably orient iments like those conducted with barn owls cannot be per-
their head toward a sound. Critical factors included sup- formed with human infants. However, Morrongiello (1989)
porting the newborn’s head to compensate for poor neck was able to test infants who had unilateral ear infections,
muscle strength and using broadband (preferably high-pass) both during the infection and after it had been successfully
stimuli of at least 1 second in duration (Clarkson, Clifton, treated. As expected, the accuracy of auditory localization
and Morrongiello, 1985, 1989; Morrongiello and Clifton, was systematically biased while the infant had a hearing loss
1984). in one ear. There was no long-term recalibration of auditory
These localization responses in the newborn are only localization, presumably because these episodes of unilateral
crudely spatial; that is, the sound source was located 90 hearing loss were quite brief.
degrees to the right or left of the head along the interaural
axis, and the criterion response was any head turn in the Recalibration of Auditory Localization in Human
direction of the stimulus. However, the presence of bidirec- Adults Although the studies of barn owls support a
tional head turns in newborns, and even in premature infants sensitive period for the calibration (and recalibration) of
at 32 weeks of gestation (Muir, 1985), suggests that this crude spatial localization using visual and auditory cues, there are
localization response is not learned from visual feedback. no experimental studies to determine whether a similar
The subsequent postnatal improvement in the accuracy of sensitive period is present in human infants. However, two
head turns (Muir, 1985; Muir, Clifton, and Clarkson, 1989) recent studies have addressed the question of auditory-visual
and their greater accuracy in the light (4 degrees) than in the recalibration in normal adults (Alais and Burr, 2004;
dark (16 degrees) (Morrongiello and Rocca, 1987a) suggests Battaglia, Jacobs, and Aslin, 2003). Both these studies

aslin, clayards, and bardhan: mechanisms of auditory reorganization 101

compared the ability of adults to localize a bimodal stimulus respond selectively to a frequency-shifted tone several days
consisting of a visual object and a briefly presented auditory after training. Thus the cortical representation of the tone is
noise. Under normal conditions, the spatial location of a dependent not on its absolute frequency but on the location
visual object and the sound it generates are coincident in along the BM from which it originated.
space. However, when these two sensory components are The shift in the frequency map between BM and cortex
spatially dissociated, subjects judge the combined stimulus occurs very early in postnatal development and is unlikely
to be located in the direction of its visual component—a to play an important role in humans because their auditory
phenomenon called visual capture. The accepted explanation periphery is quite mature at birth. However, other studies
of visual capture is based on the higher spatial resolution have shown that the frequency map in auditory cortex is
of the visual system as compared to the auditory system, susceptible to the effects of altered inputs. Robertson and
which renders judgments of spatial location more reliable, Irvine (1989) showed that the tonotopic map in the primary
since they are, on average, based primarily on visual auditory cortex (A1) of adult guinea pigs undergoes reorga-
information. nization in response to lesions to restricted areas of the
Alais and Burr (2004) and Battaglia and associates (2003) cochlea. In particular, the area of cortex that represents the
asked whether this visual dominance was fixed or whether lesioned region of the cochlea was negatively affected. Imme-
it was susceptible, even in adults, to recalibration. They diately after the cochlea was lesioned, there was an increase
could not enhance the spatial resolution of the auditory in the minimum intensity needed to trigger firing in the
system, so they degraded the visual stimulus so that its spatial cortical cells in that area. After several weeks, the area was
location was rendered less reliable. Then they presented the found to have cells with normal thresholds that responded
combined visual-auditory stimulus to adults in a cue-conflict to frequencies adjacent to those represented in the lesioned
situation—the visual stimulus and the auditory stimulus area of the cochlea. This reorganization is similar to that
were not located in the same position in space. The question found in the somatosensory cortex following amputation
of interest was whether the degree of visual capture was (Merzenich et al., 1984; Calford and Tweedale, 1988).
reduced. Both studies reported a significant reduction in the Recanzone and associates (1993) investigated changes in
magnitude of visual capture after less than an hour of experi- the organization of the tonotopic map in primary auditory
ence with a visual stimulus whose location in space was made cortex of adult owl monkeys after extensive frequency-
less reliable. Although some of the quantitative aspects of the discrimination training. Monkeys were trained on an audi-
data from these two studies differed, the important point in tory frequency discrimination task for several weeks and
the present context is that the weighting of auditory and demonstrated an improvement in their performance with
visual cues for object location in space is still plastic and can training. Compared to untrained controls and passively
be recalibrated in adulthood, at least over short time stimulated monkeys engaged in a tactile discrimination task,
periods. electrophysiological recordings in primary auditory cortex
of trained monkeys revealed that the number of recording
Cortical Plasticity in Nonhumans The foregoing review sites as well as the cortical area representing the frequencies
of auditory localization provided substantial evidence for used in training were larger than for frequencies not used
plasticity in both infants and adults, even though there may for training. This increase in cortical area of representation
well be a sensitive period for recalibration in infancy. was significantly correlated with behavioral improvement.
However, auditory localization is largely mediated by However, it is unclear whether these changes in cortical
midbrain and thalamic neural areas. Because the dis- organization reflect changes at the cortical level, the subcor-
crimination and identification of more complex sounds, such tical level, or both. Nevertheless, it seems that some aspects
as speech, are mediated by cortical areas, it is important to of the auditory system remain plastic into adulthood and
examine their developmental properties and their ability to that changes in behavior based on auditory experience may
undergo reorganization. A key question in this regard is reflect changes at the neural level rather than simple response
whether the mapping of frequency from the auditory biases.
periphery to the cortex is invariant during development. The Early acoustic environments play a major role in the orga-
basilar membrane (BM) and the outer hair cells undergo a nization of auditory cortex. Zhang and associates (2001)
normal developmental process of stiffening and elongation found in rat pups that repeated exposure to a pure tone led
that results in a shift of the best frequency that is represented to a greater representation of frequencies near that tone,
at a given locus along the BM. As a result, a pure tone of a as well as a compensatory lack of sharpening in A1-neuron
given frequency will be represented at a different location sensitivity at other frequencies. Exposure to a train of pulsed
along the BM as the animal matures. Hyson and Rudy noise (Zhang, Bao, and Merzenich, 2002) yielded similarly
(1987) showed that rats conditioned to a pure tone respond broad tuning curves at all frequencies. Noise may also effec-
selectively to that tone immediately after training, but they tively delay the sensitive period for A1 sharpening. Chang

102 fundamentals of developmental neurobiology

and Merzenich (2003) exposed rat pups to continuous white and better than subjects with residual vision. In the monaural
noise in the time period during which the neurons would condition, the totally blind subjects fell into two different
normally sharpen their tuning curves in response to relevant categories: those biased to judge a stimulus presented to the
frequencies in the environment. When frequency-specific occluded ear as originating from the side of the unoccluded
input followed noise exposure, sharpening occurred in adult ear (a bias shared by normal subjects and subjects with
rats as in naive younger rats. Thus the sensitive period can residual vision) and those not. Biased blind subjects
be extended by broadband early exposure. performed similar to normals, but showed increased
Another contributor to auditory plasticity is the presence variability for stimuli presented to the occluded ear.
of differential reward. Rutkowski and Weinberger (2005) However, unlike sighted subjects and those with residual
showed that a conditioned tone stimulus (CS) paired with peripheral vision, biased blind subjects reported qualitative
a water reward led to an expansion in representation of differences in sounds presented to the occluded ear as
the CS tone within primary auditory cortex of adult rats. compared to those presented to the unoccluded ear.
Control animals who received the tone but not paired Unbiased blind subjects performed better with stimuli
with reward showed no increase in the A1 representation. presented to the occluded ear than both normal subjects
Not only did the CS tone itself elicit changes in cortical and subjects with residual peripheral vision. The fact that
mapping, but there was also an increase in representation unbiased blind subjects outperformed sighted subjects in
for frequencies emitted by the reward delivery equipment. this condition, and that biased blind subjects reported
The measurable area of auditory cortex did not differ differences in sound quality even though they did not
between trained rats and controls; only the distribution of localize to the correct side, suggests that people blind from
representations differed. Similarly, Polley and associates birth are able to use monaural cues better than these other
(2006) found that the task-dependent properties of the two groups in analyzing their auditory environment, perhaps
stimulus determine the changes that occur in the cortical because of neural changes similar to those Korte and
representation. In their study two groups of adult rats Rauschecker (1993) found in binocularly deprived cats.
were exposed to identical stimuli and were trained to attend Röder and associates (1999) combined behavioral and
to either the intensity or the frequency of the sounds. The electrophysiological methods to investigate auditory spatial
rats in the frequency condition experienced an expansion tuning in blind and sighted humans and found better audi-
of neuronal representation for the frequency range of inter- tory localization in blind subjects, but only in peripheral
est. Similarly, those in the intensity condition had enhanced (lateral) auditory space. Normally sighted adults, after a
representation for the particular intensities presented in period of recalibration to artificially altered external ears
training. Moreover, the degree of neural retuning was well (pinnae), can also adjust their reliance on those spectral cues
predicted by each animal’s magnitude of perceptual learn- that are now most reliable for sound localization (Hofman,
ing performance. Van Riswick, and Van Opstal, 1998).
In summary, there is ample evidence from research with Perhaps the most direct measure of auditory cortical plas-
nonhumans that the auditory cortex has considerable plas- ticity in humans comes from the use of cochlear implants to
ticity, and that some plasticity is present even in adult cortex restore hearing in the deaf. Although this topic is beyond the
despite greater plasticity in infancy. We turn now to related scope of the present chapter, and the literature on the out-
findings from humans. comes of hearing loss are covered in chapter 26 of this
volume by Mitchell, a number of key points about the impact
Cortical Plasticity in Humans A number of recent of cochlear implants are clear. First, the success of cochlear
studies using noninvasive neuroimaging have confirmed implants is much higher in children and adults who have
the presence of cortical plasticity in humans. These studies already acquired their native language and are then faced
have approached the question of cortical plasticity by with a hearing loss. This result occurs because the implant
examining subjects who have experienced a variety of introduces two types of changes in the mapping of external
sensory deprivations, some beginning at birth and others sound frequencies onto the hair cells that send their signals
acquired later in life, or by exposing normal adults to a to the brain. These changes are caused by the inability of
specific auditory training regimen. Lessard and associates the multielectrode wire that is inserted into the cochlea to
(1998) reported evidence of auditory compensation in be positioned all the way to the tip (low-frequency end) of
humans similar to that found in binocularly deprived cats the basilar membrane. As a result, external sound frequen-
(Korte and Rauschecker, 1993; Rauschecker, 1995). They cies below approximately 1000 Hz are unmapped, and all
compared the performance of subjects with normal vision, higher frequencies stimulate regions of the basilar mem-
residual peripheral vision, or total blindness in an auditory brane that would ordinarily be triggered by lower frequency
localization task. In the binaural condition, totally blind sounds. As a result, the low-frequency sounds that carry
subjects were able to localize at least as well as normals, crucial information for speech are missing, and the frequen-

aslin, clayards, and bardhan: mechanisms of auditory reorganization 103

cies that the brain does receive are frequency shifted. Thus scale in rats and primates (changes in frequency sensitivity
a postlingual listener fitted with a cochlear implant can in A1). It is not currently possible to study small-scale cortical
attempt to match the frequency-shifted input to stored rep- plasticity at a neuroanatomical level in humans because of
resentations of lexical items. In contrast, the prelingual lis- the invasive procedures required. However, we can study
tener fitted with an implant has no remapping task, but must changes in human behavioral sensitivity to relevant stimuli
make sense of stimuli that are missing crucial pieces of low- in the environment. Changes in phonetic organization
frequency speech information. throughout the lifetime provide an excellent venue to study
Most adults and postlingual children are able, after weeks small-scale changes in sensitivity because (1) the stimuli are
or months of listening experience, to adapt to the frequency- highly behaviorally relevant, (2) the variety of languages
shifted sounds and to understand speech. But some implant provides us with a natural way to contrast the role of the
users never adapt. The situation is made much more com- environment with the role of maturation, and (3) the process-
plicated for prelingual children because they have never ing of speech stimuli requires the listener to make fine-
acquired their native language and so have no lexical repre- grained distinctions, thereby allowing us to observe very
sentations to which they can compare the distorted speech small-scale changes.
sounds. Although some prelingual deaf children learn to
perceive speech, these children are relatively rare (see Pisoni, Phonetic reorganization
2005).
More relevant to the present discussion about cortical Universal Inventories (Human and Nonhuman) The
plasticity is how normal hearing adults adapt to speech that voluminous literature on phonetic discrimination and
is frequency shifted in a manner that mimics what an identification in infants and adults is beyond the scope of
implant user would experience. Dorman and associates this chapter, but it is covered by several excellent recent
(1997) reported considerable difficulty in adapting to fre- reviews (Jusczyk, 1997; Kuhl, 2004; Saffran, Werker, and
quency-shifted speech, and Fitzgerald and associates (2006) Werner, 2006; Werker and Yeung, 2005), as well as chapter
showed that the sudden introduction of the frequency shift 8 by Friederici in this volume. We wish to make only two
results in a longer period of adaptation than a gradual intro- major points by way of introduction to the topic of phonetic
duction. This latter result suggests that cortical mechanisms reorganization. First, infants in all language environments,
for adaptation to frequency-shifted speech can better handle as well as several species of nonhuman animals exposed
small and progressive frequency shifts (much like prism to English, show discontinuities in discriminability along
adaptation in the visual-motor domain). What remains many phonetic continua, including continua that are not
unclear is which regions of cortex are involved in this adap- used contrastively in their language input. This fact has
tation. There could be a remapping in primary auditory been interpreted as evidence for an innate system of
cortex, where detailed maps have been revealed by fMRI categorization—categorical perception (CP). However, none
in both adult humans (Talavage et al., 2004) and monkeys of these findings from infants include the requisite labeling
(Petkov et al., 2006), or to changes in higher-level auditory data that would show a close correspondence between peaks
areas as revealed in a pitch-memory task after five days of in discriminability and labeling boundaries that defines CP.
training (Gaab, Gaser, and Schlaug, 2006). We will return Moreover, when both discrimination and labeling data are
to this question of levels in the section on adaptation to available from nonhumans, they suggest that CP is not
speech dialects. unique to humans, and therefore not unique to a linguistic
Taken together, these studies of blind and deaf adults, as analysis of the speech stimuli (because animals do not have
well as simulated frequency shifts in normal adults, suggest a phonetic system).
that both auditory and visual cortex can adjust to altered Second, an innate system of categorization could not
sensory input either by utilizing regions of cortex that would match every native language and, therefore, must be adjusted
normally process inputs from a sensory periphery that is now to conform to the details of the native-language phonetic
silent or by remapping the sensory or lexical representations. categories. This adjustment process requires exposure to the
Similar examples have been reported for the activation of distributional properties of linguistic input carried by the
visual cortex during tactile discrimination tasks by blind words to which the infant is exposed. The earliest evidence
subjects (Sadato et al., 1996) and for the filling-in of primary of such adjustments is present by 6 months of age for vowel
visual cortex by patients with a congenital absence of three perception (Kuhl et al., 1992; Polka and Werker, 1994), fol-
of the four classes of retinal photoreceptors (Baseler et al., lowed by language-specific consonant perception at 10–12
2002). months of age (Werker and Tees, 1984). Thus early phonetic
In summary, we have reviewed evidence of behaviorally reorganization is traditionally characterized as a shift from
relevant adult cortical plasticity both on a large scale in the language-universal sensitivities shared by all infants, and
humans (recruitment for a new modality) and on a small at least some animals, to language-specific sensitivities.

104 fundamentals of developmental neurobiology

Distributional Modifications We now turn to the example, vowel length plays a greater role in the /i/ versus
question of what can account for the changes in auditory /I/ distinction in Scottish English than it does in British
sensitivity that are observed in the first year of life and the English (Escudera and Boersma, 2003), and the F3 dimen-
language-specific sensitivities that are observed in adulthood. sion is more relevant for English approximates such as /r/
These changes have been described as a warping of the and /l/ than for Japanese (Lotto, Sato, and Diehl, 2004).
perceptual space by experience with a particular language When a language-specific cue-weighting strategy is then
environment (Kuhl, 1994; Iverson and Kuhl, 2000). The applied to speech from a new language that does not
result is that listeners become more sensitive to particular utilize the same dimensions, as in the case of native Japa-
dimensions of the speech stream (acoustic cues) and less nese speakers listening to English /l/ and /r/, listeners
sensitive to others. For example, a comparison of the may have great difficulty in making accurate judgments.
distributions of acoustic cues from many tokens (instances of Their cue-weighting strategy has led them to put the most
words) in English and Japanese reveals that in English, the weight on a dimension that is not informative (F2 in this
F3 dimension is relevant for identifying the approximates /l/ case) and to pay relatively less attention to the dimension
and /r/, while in Japanese the F2 dimension is the more that is informative (F3 in this case).
relevant (Lotto, Sato, and Diehl, 2004). Iverson and Kuhl
(1996) found that speakers of English, German, and Japanese Distributional Sensitivity The foregoing cue-weighting
showed different sensitivities in an F2–F3 space for account depends on sensitivity to the distributional frequency
distinguishing English /r/ and /l/. The Japanese speakers of tokens, a source of information that has long been
exhibited expanded sensitivity in the F2 dimension and known to be informative. Lisker and Abramson (1964) noted
reduced sensitivity in the F3 dimension, while English and that the major cue distinguishing stop consonants along
German speakers exhibited the opposite pattern of perceptual the voicing dimension was voice onset time (VOT). They
warping. There is still debate about whether the perceptual found that the frequency distributions of VOT across any
warping happens at the level of auditory processing or at given language tended to group into 1–3 roughly normal
higher levels that influence behavior but not perception. distributions. It is also known that there is a close relationship
Evidence that adults can show sensitivity to nonnative between the distributional frequency of tokens and phonetic
contrasts under certain testing conditions that reduce sensitivities. For any given language, the locations along the
memory load (e.g., Tees and Werker, 1984) suggests it is not VOT continuum where very few tokens occur also correspond
a matter of auditory processing. to category boundaries in that language. It is precisely in
There may be several mechanisms that could cause these regions of low token probability that we find increased
perceptual warping through exposure. In general they discrimination sensitivity and labeling boundaries (Lisker
should direct the attention of the listener toward dimen- and Abramson, 1964).
sions that are informative and away from dimensions that The sensitivity of infants to distributional frequency was
are not. This allows the listener to optimize his or her presumed to account for how innate phonetic categories
use of the acoustic information in identifying the target were adjusted to a specific native language. The empirical
utterance of the speaker. One way of formalizing this demonstration by Saffran and associates (1996) that 8-
optimization is to apply Bayes’ theorem: listeners should month-olds can perform distributional learning on the
base their judgments on dimensions (cues) to the extent sequential properties of speech streams set the stage for a
that they are reliable, and this reliability will depend on direct test of distributional learning of phonetic categories.
the variability of those cues in the environment (for a Maye and associates (2002) familiarized 6- and 8-month-olds
general overview of this Bayesian approach, see Ernst and to a range of values along a /d/–/t/ continuum that were
Bulthoff, 2004). It has been shown in the visual-motor either distributed unimodally: with no region of low token
domain that the relative reliabilities of different cues influ- probability, or bimodally: with a region of low token proba-
ence how heavily they are weighted by adults (Atkins, bility in the middle of the range of values. After exposing
Fiser, and Jacobs, 2001; Ernst and Banks, 2002). A similar infants to passive listening to these distributions, the research-
differential weighting of cues has been shown in the per- ers found that infants who had been exposed to the bimodal
ception of novel nonspeech sounds (Lotto and Holt, 2006; distribution discriminated the phonetic contrast, whereas
see Smits, Sereno, and Jongman, 2006, for a different infants exposed to the unimodal distribution did not. Since
categorization theory). Such an account predicts that in all infants heard the same tokens during training, it can only
learning a native language, the task of the listener is to be the frequency of occurrence of particular tokens that
track the variability of multiple dimensions and develop formed a distribution along the phonetic continuum that led
a cue-weighting strategy that relies most heavily on the one group of infants to show evidence of discrimination.
dimensions that are the least noisy. Since cue-weighting Maye and associates (2008) extended these findings to a
strategies are language specific, they must be learned. For more difficult phonetic contrast. These results provide

aslin, clayards, and bardhan: mechanisms of auditory reorganization 105

empirical evidence for the theory of distributional learning Despite the evidence that infants are sensitive to the
suggested by Lisker and Abramson (1964). Furthermore, a distributional frequency of tokens, it has not been shown
recent study by Werker and associates (2007) found that experimentally that infants use distributional frequency to
Japanese- and English-speaking mothers addressing their learn to weight a particular acoustic dimension more heavily
12-month-old infants produced just the kind of language- than another in order to make a phonetic judgment. Little
specific distributional patterns used in the studies by Maye is known about how infants combine multiple acoustic
and associates. cues or whether they show the same patterns of differential
It is important to emphasize a key assumption of a cue-weightings as adults. More is known about young
distributional theory of phonetic category learning or adjust- children. Like adults, young children often weight some
ment: Infants must be sensitive to small (within-category) acoustic cues more heavily than others, but their cue-
acoustic differences. If they were only sensitive to the cat- weighting strategies are not always the same as adults and
egory labels themselves, as presumed by a strong theory will change throughout childhood (Krause, 1982; Nittrouer
of CP, then there would be no distributional information and Studdert-Kennedy, 1987; Mayo and Turk, 2004; Mor-
available to the learning mechanism except for the fre- rongiello et al., 1984; Wadrip-Fruin and Peach, 1984).
quency of each category. While this assumption of a dis- The cause of this developmental shift in cue weighting is
tributional theory seems to fly in the face of empirical unknown. One theory proposes that children process speech
evidence that infants’ discriminative capacities for within- more globally and thus place more weight on cues such
category differences are poor, much as they are in adults, as formant transitions that occur over larger segments of
recent evidence from both adults and infants provides strong the speech stream and less weight on cues such as release
support for within-category sensitivity. McMurray and bursts that could be considered more local phenomena
associates (2002) used an eye-tracking measure to confirm (Nittrouer et al., 2000). However, a study by Mayo and
earlier research using rating scales and reaction times and Turk (2004) found that children’s strategies (like adults)
showed that adults are sensitive to within-category differ- differ according to the particular phonetic context of the
ences along a /b/–/p/ continuum. Moreover, the likelihood segment (e.g., /ta/–/da/ versus /ti/–/di/) and do not
of falsely labeling a given token along the continuum was always favor formant transitions over other cues. Instead
monotonically related to the distance from the category they may start out placing more weight than adults on
boundary; that is, sensitivity was gradient within the phonetic strong (i.e., intrinsically salient) cues and less weight on
category. Thus adults are sensitive to where along the pho- weak cues, achieving adultlike strategies over time. Further
netic dimension a given token resides. McMurray and Aslin investigation is necessary to determine whether distributional
(2005) found similar evidence for gradiency in the listening frequencies may be part of the developmental process.
preferences of 8-month-olds exposed to words whose initial
/b/ or /p/ consonant was in the center of the phonetic Distributional Sensitivity in a Second Language
category (i.e., prototypical) versus near the category bound- The dramatic changes seen in early infancy are by far the
ary. Further evidence of sensitivity to within-category dif- strongest cases of auditory reorganization by exposure to a
ferences comes from a set of ERP studies by Rivera-Gaxiola specific language environment. Moreover, infants raised in a
and colleagues showing early or preattentive sensitivity bilingual environment are able to develop and maintain
(mismatch negativity, late positive deflections, or N1/P2 two different underlying phonological systems (Bosch and
components) to within-category differences as well as non- Sebastian-Galles, 2003). In contrast, research on second-
native contrasts in adults (Rivera-Gaxiola, Johnson et al., language (L2) acquisition in adults shows that although some
2000; Rivera-Gaxiola, Csibra et al., 2000) and infants at modification of sensitivities is possible, it fails to result in
7 and 11 months (Rivera-Gaxiola et al., 2005) using an native-language proficiency and is very difficult to achieve. It
oddball paradigm. The result with 11-month-old infants is a well-established observation in second-language learning
is particularly surprising because this is an age when behav- that some contrasts are hard to learn by adults whereas others
ioral sensitivity to nonnative contrasts is reduced and are relatively easy (see Jusczyk, 1997, for a review) and that
because previous work (Cheour et al., 1998) had not found the phonological similarity of L1 and L2 is a major predictor
evidence of nonnative contrast detection. These empirical of success on L2. A well-known example is the difficulty that
results on gradient sensitivity provide the requisite evidence speakers of Japanese have in learning to distinguish between
that a distributional theory of phonetic category learning English /r/ and /l/. Speakers of German (which does not
and adjustment is plausible. These properties of gradient have a sound like English /r/) find this contrast relatively
sensitivity and the role of distributional input in forming easy. Similarly, speakers of English have little difficulty
and adjusting phonetic categories have recently been cap- distinguishing between different Zulu clicks (Best et al., 1988)
tured in computational models by McMurray and associates but find it relatively difficult to do the same task with Hindi
(in press) and Vallabha and colleagues (2007). dental and alveolar stops (Werker et al., 1981).

106 fundamentals of developmental neurobiology

A variety of models have been proposed to account for stimuli were cross-spliced so that one of the cues signaled
this complex pattern of results (Best et al., 1988; Flege, one place of articulation and the other cue signaled a differ-
Schirru, and MacKay, 2003; Kuhl, 2004; Werker and ent place of articulation. During training, listeners were
Curtin, 2005), but all these models propose that the phonetic given feedback on the “correct” place of articulation. After
categories of the native language are established early in training, they found an increase in responses consistent with
development and constrain the ability of older children and the trained cue across all stimuli. A similar study replicated
adults to acquire native phonetic proficiency in L2. this finding using an /i/–/I/ vowel contrast and real words
Crucially, it is thought to be the particular acoustic dimen- and found that individual variability in training success was
sions involved in the native and nonnative contrasts that correlated with sensitivity to the weaker dimension before
determine the amount of L1 interference on L2 (Iverson and training (Clayards, Tanenhaus, and Aslin, 2006). These
Kuhl, 1995). Although it is difficult to distinguish some studies demonstrate that listeners can change their cue
foreign contrasts, it is possible to improve on this ability weightings with training, but they manipulated the relation-
through training. Tees and Werker (1984) found that English ship between cues and labels, rather than the distribution
listeners could learn to discriminate the difficult Hindi dental of tokens. Maye and Gerken (2000) did study distributional
alveolar stop contrast with training. Similarly, several studies learning of phonetic categories in adults and found that
with native Japanese speakers learning English /l/–/r/, exposure to a bimodal distribution allowed for discrimina-
show that intensive training can improve discrimination tion while exposure to a unimodal distribution did not, just
(Strange and Dittmann, 1984), or labeling performance as in infants. Similarly, Clarke and Luce (2005) found that
(Lively, Logan, and Pisoni, 1993), but learning only transfers exposure to a shifted distribution of VOT values in sentence
to acoustically different stimuli when training involves mul- context changed listeners’ categorization boundaries.
tiple tokens of many speakers (Logan, Lively, and Pisoni, Although no study has directly tested the role of distribu-
1991). This training regime (called high variability phonetic tional learning in adjusting cue-weighting strategies (rather
training or HVPT) is thought to work because subjects get than category boundaries), Escudera and Boersma (2003)
a range of natural variability that allows them to determine have shown that the distribution of cues available to listeners
the relevant dimensions. McCandliss and associates (2002) in the dialect-learning study (Escudera and Boersma, 2004)
showed that by enhancing an acoustic cue to the /r/–/l/ could predict the optimal cue-weighting strategies that native
distinction in a training study of native speakers of Japanese, listeners use.
and then gradually fading out this enhanced cue (coined In summary, early universal auditory sensitivities are
perceptual fading), there was substantial enhancement of altered by language-specific phonetic reorganization in
discrimination performance, even when subjects were given infancy. This reorganization is characterized by a warping
no feedback during training. Thus enhanced distributional of the perceptual space to produce increased sensitivity to
cues may serve a useful role in drawing attention to other- some dimensions and reduced sensitivity to others. The
wise difficult-to-discriminate speech contrasts. A recent study likely cause of this cue-reweighting process is exposure to
directly comparing these two training regimes found equal the distributional frequencies of tokens along those dimen-
improvements in labeling performance for both HVPT and sions in the ambient language. In this way, children gradu-
perceptual fading groups (Iverson, Hazan, and Bannister, ally develop an adultlike cue-weighting strategy tailored to
2005). Thus it is unclear whether high variability in the their linguistic environment (though developing auditory
irrelevant dimension or increased attention to the meaningful capabilities may also play a role in the developmental pro-
variability in the relevant dimension is the more important gression). In adulthood, when faced with a new language
factor in learning new contrasts. for which the strategy is unsuitable, there is often initial
These studies do not explicitly test whether subjects are difficulty in distinguishing contrasts. With enough exposure
learning to attend more to one dimension over another. to the new distributions, however, new cue-weighting strate-
There is evidence, however, that subjects can learn to change gies can develop that at least partially accommodate the
their attentional weights. A series of studies by Escudera and new language.
colleagues has found that when learning a second language,
listeners will adopt a range of cue-weighting strategies at Reference and learning the lexicon
first and may eventually arrive at a strategy that is more
appropriate for the linguistic context (Brasileiro and Escu- Given that infants by the end of the first year have estab-
dero, 2005; Escudero and Boersma, 2004). Further evidence lished their native-language phonetic categories, how do
comes from cue-weight-training studies. Francis and associ- they deploy those categories in the service of learning
ates (2000) trained listeners to use either the burst cue or the words? It may seem straightforward to think of the pho-
formant transition cue when distinguishing between /ba/, netic categories as an acoustic alphabet whose elements
/da/, and /ga/ or /bi/, /di/, and /gi/ syllables. Training are simply strung together into a unique sequence (e.g.,

aslin, clayards, and bardhan: mechanisms of auditory reorganization 107

the auditory word form ball) and then mapped onto a be confused with a familiar word inhibits the lexical learning
real-world referent (a spherical object). Two problems process. And Graf Estes and associates (2007) have shown
confront the infant listener in solving this seemingly simple that novel auditory word forms that have recently been seg-
task. First, speech discrimination has been assessed in iso- mented from fluent speech using distributional information
lated word (or syllable) contexts rather than the fluent can be mapped onto referents in a word-learning task. Thus
multiword speech characteristic of natural linguistic input. there is growing evidence that infants have all the acoustic/
Thus there are working memory constraints that influence phonetic skills needed to map word forms onto referents,
whether the infant’s discriminative capacities are utilized provided that the word forms are familiar to auditory
effectively in recognizing maternal utterances. Second, there memory and not easily confused with similar words already
is substantial acoustic variability in how talkers (mothers in the lexicon.
and other adults) produce speech, including gender, speak-
ing rate, prosody, and subtle stress patterns used for Dialects and Multiple Representations One inter-
emphasis or to convey emotional states. Do infants readily pretation of the foregoing review of word learning is that
solve these two problems? candidate auditory word forms map transparently onto
Evidence from Jusczyk and Aslin (1995) suggests that the referents, provided that the word forms and the referents are
first problem is solved by 8 months of age. Infants can extract both familiar perceptual objects. However, such a model
auditory word forms from fluent speech and recognize these presumes that word forms have little acoustic variability,
words when presented in isolation. Moreover, infants do an assumption that we know to be incorrect. Adult listeners
not falsely recognize subtle acoustic variants of the words, are able to cope with widely varying acoustic information
thereby showing robust evidence for specificity in their audi- and normalize the signal to map it onto their phonological
tory memory of those words. However, the second problem representations in the lexicon in order to access meaning.
has proven more challenging for infants. Stager and Werker These nonphonemic acoustic parameters, although not used
(1997) showed that 14-month-olds who easily discriminate for decoding the speech signal itself, can provide so-called
a phonetic distinction in a nonreferential context (i.e., when indexical cues to the speaker’s gender, identity, and accent.
only listening to the phonetic contrast) fail to map these same How does the infant determine which acoustic cues are
word forms onto two different visual objects. Initially it was phonemically relevant and which cues are indexical?
thought that the referential context itself caused infants to Moreover, do indexical cues interfere with the extraction of
relax their criterion for what counts as a meaningful pho- phonemic cues?
netic difference. But more recent evidence suggests that 14- The indexical cue that has received the most attention
month-olds are, indeed, sensitive to the relevant phonetic in both adult and infant speech perception is talker vari-
information, but they fail to associate it with the visual ability. The voice quality of a specific talker is defined by
referents. subtle variations in pitch, harmonic structure, rhythm, and
Swingley and Aslin (2000, 2002) showed in an eye- vowel color. These are the kinds of indexical cues that play
tracking paradigm that 14–20-month-olds detect mispro- little or no role in decoding the phonemes from the speech
nunciations of known words when they are presented with signal. However, Allen and Miller (2004) showed that lis-
visual referents of those words. And Fennell (2006) showed teners can learn a particular talker’s distribution of voice
that this word-referent mapping problem can be alleviated onset times and use that to identify the talker, provided
by rendering the visual objects familiar. That is, evidence that there is sufficient experience with a talker and a task
now suggests that the mapping problem is most acute that demands tracking VOT as a cue. This ability trans-
when both the word forms and the visual referents are ferred to novel words they had not heard the speaker
unfamiliar. By making the word forms and/or the visual produce. McLennan and Luce (2005) discovered that index-
referents familiar, even in isolation, the associative mecha- ical information (talker identity and speaking rate) was used
nism that links sounds to objects can rapidly perform the late in processing, after early stages of phonetic processing.
mapping task. Thus it is not reference per se that is the Creel and associates (2008) found that talker identity was
bottleneck, but rather the facility with which associations processed earlier, but only for highly overlearned words
can be formed between sounds and objects—unfamiliar and not for newly learned words. And Houston and Jusczyk
sounds and objects are not easily encoded, and resources (2000, 2003) found that infants have long-term memory
devoted to this encoding are not available to form associa- for the indexical properties of word lists and are negatively
tive linkages. affected by talker variability in a word-segmentation task.
Swingley and Aslin (2007) added support to this view of Thus indexical factors play a role in speech processing both
word learning by showing that new words for novel objects early in development and in adulthood. Presumably, as in
are only acquired rapidly if the words come from sparse the case of cue weighting in phoneme identification, indexi-
regions of the infant’s lexicon. That is, a new word that could cal cues are up- or down-weighted depending on their reli-

108 fundamentals of developmental neurobiology

This finding suggests an early studies suggest that listeners are remarkably efficient in bias toward natural speech that could be based on an innate adapting to unfamiliar speech. to infants and children in the future. perceive it as a “witch” becomes “wetch”). to the top-down knowledge that adults of the vowel shift rather than simply accepting any unusual bring to any speech perception task. in part. this ability surely exists. versions of nonwords (Remez. hearing an exemplar of sine-wave speech. However. Unfortunately. and this paradigm may be applicable lexical candidates. A more pervasive exemplars of natural speech. This was true of repeated or when subjects are given instructions that the items that they had heard in the exposure phase as well as stimuli are degraded speech. had to match the sentence-final word. 2005. or a simple preference for children. of their perceptual vowel space to accommodate Although adults are also able to recognize sine-wave speech the speaker’s productions to arrive at the intended meaning. 1998). or noise-band speech is that they are being asked to make Talker-specific effects in speech perception are. Native speakers of Chinese and to an infant. to which nonprototypical speech can be compared. Another technique involves retaining of language processing (from phonetics to pragmatics) using the changing spectral information from the formants of either spoken or written materials because even the simplest natural speech but replacing these formants with a pure stimulus (phoneme or letter) is associated with each of these tone that follows the frequency contour of the center levels in natural language materials (Price. most listeners will suddenly other dialect items that they had not heard. as well as the question of whether phonetic Spanish spoke English sentences to which English listeners qualities differ fundamentally from indexical qualities. This question will not be answered here. when the same exemplar is they had before experiencing the dialect. Again. been used in an attempt to gain a foothold on this seemingly aslin. to date there species-specific preference. 2003). by defini. McCandliss. upon first English dialect wherein front vowels were lowered (e. Fellowes. replacing it with a parallel series of amplitude-modulated in part because no definitive studies have yet been published noise bands (Shannon et al. 1995). 1981).g.. Clarke These studies of adults with a robust phonological and and Garrett (2004) studied adult listeners’ adaptation to lexical system raise the question of what qualifies as phonetic foreign-accented speech. despite the fact is undoubtedly the outcome of a cascade of processing steps that nearly all the spectral cues of speech have been that are triggered by a simple stimulus. and Dehaene. Importantly. is unknown. Within a minute of Vouloumanos and Werker (2004) found that infants as exposure. Again. Bardhan and associates (2006) found the same results associates (2005) have shown for noise-band speech that when the spoken items were heard in isolation but paired improvement in identification is driven by activation of with visual images. Griffiths. Brain correlates of auditory plasticity and learning Sine-Wave and Noise-Band Speech An extreme form of dialect adaptation involves natural speech that has been One of the most seductive. In related work. and Nagel. For example. After exposure. questions in cognitive degraded in various ways. Adults are able to and in part because the topic of brain and language is so perform at nearly asymptotic levels in an identification multifaceted. Thierry. The ability of one implant. provided that there are at least guage it is impossible to isolate only one of the many levels four noise bands. this repetition effect is undoubt- subjects learned only the specific direction and magnitude edly due. These speech over sine-wave speech. Davis and vowel. hear them as speech. One technique involves neuroscience is what brain regions are responsible for lan- eliminating all the fine spectral detail in speech and guage processing. or rotation. many adults. and the mechanism by which adaptation occurs broadband stimuli over narrowband stimuli.ability in providing information about a specific property An important fact about adults’ perception of sine-wave of speech. Maye and associates (in press) exposed listeners to a 20. but plausible. in mature users of a natural lan- task with these stimuli. subjects were set of varying tones and clicks that lack any language-like more likely to classify items within the dialect as words than or phonetic quality. judgments of lexical identity from stimuli that are not good tion. at least in adults.. and bardhan: mechanisms of auditory reorganization 109 . speech stimuli at high levels of accuracy.. clayards. in part. because of their overlearned minute passage of an artificial. But as in the case of post- indexical variable is the regional dialect to which the infant lingually deafened adults who are fitted with a cochlear (or adult) is exposed (Labov. Cohen. American phonological system. a learned preference from early are no studies of dialect adaptation in infants or young exposure to maternal speech. Importantly. and frequency of each formant (Remez et al. adults are able to reliably identify these so-called sine-wave Thus activation of a particular brain area. 2007). Four paradigms have removed. yet vexing. these adults have a robust representation of the American English listener to understand another from a phonological system of their native language and a lexicon different dialect implies that a listener can impose a shift. listeners were as accurate at identifying the target young as 2 months of age preferred to listen to natural word as those who listened to unaccented speech. In fact. linked to particular vocal tracts.

Novelty responses were also observed showed that adults have greater activation in several por. Kim and associates (1997) gathered processing system may inhibit purely acoustic processing. in the right frontal cortex and hippocampus. but for most listeners they begin as non. although many other brain processing. but late bilinguals showing two separate but par- with a visual stimulus. Two recent studies have used this paradigm to study states—and asking the subject to report changes from one speech perception (Joanisse. tially overlapping regions of activation. tokens followed by a novel fourth token (BBBA). Zevin and McCandliss (2005) reported fMRI binocular rivalry. with specific response. none of the subjects by between. fMRI data from both early and late bilinguals. demonstrating the McGurk effect. and a left hemisphere bias for the nonprototypical speech. The Kim and asso- Liebenthal and associates (2003) found categorical percep. marginal gyrus responded to phonemic changes. epochs.. 2007. Benson and associ- monolinguals to native and nonnative speech. activations in a broad array of temporal cortex to these speech and transition (typically rapidly) to intelligible but four-stimulus epochs. Joanisse and associates (2007) extended no areas responding more to sine-wave speech. The second is to elicit but only when subjects perceived them phonetically. They Brain responses in bilinguals have been used to determine suggest that while phonemic and nonphonemic auditory whether language fluency is predictive of differential pat- stimuli may be processed simultaneously. 2005). Zevin. This paradigm has great potential for use with posterior superior temporal sulcus (pSTS) was indeed sen. the phonemic terns of activation. Thus the evidence fraught with difficulties because it depends on the ability of from adults points fairly clearly to the left STS as the the subject to control attention and exclude other levels of locus of phonetic processing. Zevin and McCandliss. Moreover. ciates report suggested a sensitive period for the formation 110 fundamentals of developmental neurobiology . incom. Vouloumanos and associates (2001) novel BBBA epochs. Henson. four identical speech tokens (AAAA) or three identical 2006). response to sine-wave speech in left pSTS in informed But activations in frontal cortex differed. L2 speech did not differ in temporal cortex between the tönen and associates (2004) not only found a greater BOLD two groups. and Martin. Meng.. Activations to L1 and are aware of the speechlike quality of the stimuli. tion to a particular level of processing. native capacities. Brain responses correlated with that per. Greater activation was elicited same brain regions. infants and young children because it does not require the sitive to mode of perception (speech versus nonspeech) listener to perform a task and appears to tap basic discrimi- while listening to sine-wave speech and that the supra. with both languages activating common areas.than by within-category contrasts in the BBBA interpreted the sine-wave tokens phonetically.intractable problem. short-term habituation design in which subjects heard either patible) attentional states (see Tong. the typical paradigm of using two regions are activated above baseline to speech and non- different classes of stimuli (e. with early bilin- subjects (i. Under fruitful type of stimulus for controlling the level of processing the assumption of neural adaptation in brain regions is one that is perceptually bistable.g. vowels. left STS was differentially activated by the Directing attention to a particular level of processing is sine-wave speech and normal vowels. These stimuli do not from scalp electrodes (Dehaene-Lambertz. with fluency This inhibition presumably can happen only after subjects in L2 greater in the early group. Unfortunately. The first is to direct the subject’s atten. state to the other. lar rivalry—a spontaneous fluctuation of two perceptual 2006). tion for phonetic continua created with sine-wave speech. This design The sine-wave speech stimuli discussed earlier serve a was based on the mismatch negativity response gathered similar role in the auditory domain. speech and music) can never speech stimuli. and Uppenkamp and associates (2006) levels of language processing. This paradigm has been involved in stimulus processing. Finally. Both these studies used a ceptual shift are taken as evidence of separate (in fact. Naatanen oscillate between two perceptual states. and Blake. The third is to examine left medial and anterior STS activation to this phonetic brain responses in bilinguals to L1 and L2 speech or in difference in the speech mode. repetition effects have been used to great effect in the visual modality by eliciting binocu.e. but also found that these guals showing an overlapping region of activation to L1 subjects were able to integrate the phonetic information and L2. with the former tions of the left temporal lobe and right frontal lobe in most likely a general novelty response and not a speech- response to natural speech than to sine-wave speech. in speech mode).. A more are the hallmark of the infant habituation paradigm. as in the case of et al. Möt. Again. and McCandliss. and these activations were located in the left tem- Dehaene-Lambertz and associates (2005) found that the poral cortex. adapted for use in fMRI (Grill-Spector. eliminate the possibility that differential brain responses are Repetition effects (decrements and recovery to novelty) due to the physical differences between the classes. And the ates (2006) contrasted sine-wave speech with sine-wave fourth is to study infants who have not yet attained higher nonspeech stimuli. 1997). 1997. Each of these paradigms has contrasted normal vowels with spectrally matched non- advantages and disadvantages. This finding this paradigm to study between-category and within- suggests that these stimuli are both being processed by the category phonetic contrasts. with repetition effects to passive exposure.

These results suggest that near-optimal bimodal integration. aslin. Thus. and D... 2004. D. Listener sensitivity to indi- different levels of speech and language processing can be vidual talker differences in voice-onset-time. 05071) and the McDonnell and Packard Foundations to Dehaene-Lambertz and associates (2002) reported greater RNA. N. and chapter 8 by Friederici in this tinue to expand in adulthood but limit nativelike acquisition volume). Am. Allen. The ventriloquist effect results from from primary auditory cortex. D. R. D. 2002. A. Two other studies have reported that native speech straints on learning or the ability to rapidly adjust the contrasts elicit greater fMRI activations than nonnative weights attached to these cues based on their functional contrasts (Callan et al. clayards. Mueller.5T scanner. but of course tensor imaging that estimates the organizational complexity studies of language development must be limited to humans. We have attempted adopted into French homes and acquired L2 without the to outline the major events that enable the auditory system maintenance of L1. It is not clear if traces of L1 were to access sounds. to language materials and to answer fundamental questions Atkins. and that these patterns of activation are similar to those Ashmead. contrasts during training (Golestani et al. and R. 2006) are par. 1989. 41:449–461.. Odom. visual and haptic percepts.. we speculate that as infants of the brain. Soc. Furthermore. Child Dev. E. emanating Alais. We outlined a Bayesian model of cue weighting in when one phonological system dominates the other. and near-infrared spectroscopy rated as the phonological system matures in infancy and the (NIRS) responses have been measured from normal infants lexicon expands rapidly in childhood. of white matter tracts (see Dubois et al. many more studies will be required to human infants.. Two fMRI studies (Dehaene-Lambertz et al. 2004. which entails solving acknowledgments Preparation of this chapter was made problems of scanner noise (and hearing safety). ERP. S. Fiser. and by NIH training grant (DC-000035) to the Uni- activation to forward then to backward speech in left tem. L. T. Vision Res. Acoust.. Whalen. there are structural aspects perception. Curr. Finally. fMRI. offer about where in the brain activity is present as speech stimuli the prospect of accounting for individual differences in are being processed. J. 2004. to its reliability.. 86:582–590.of subcomponents of frontal brain regions for processing Summary and conclusions speech in different languages. J. Davis. Soc. map out the functional activity of brain areas that respond Aslin. and bardhan: mechanisms of auditory reorganization 111 . Hertz-Pannier. rendering them invisible as a spatially separate cue weighting in the tasks of sound localization and speech region of activation. J. localization and sensitivity to interaural time differences in 2006).. ing the role of experience in auditory learning. beginning prenatally. 2006. and J. nisms of adaptive plasticity that enable the lexicon to con- and Dubois. utility. of a second phonological system will prove crucial in address- Dehaene-Lambertz. Hertz-Pannier et al. Jacobs. such as diffusion anisms have been studied invasively in animals. 2001. brain which the relative importance of a given cue is proportional activations may swamp the smaller nonnative (or L2) acti. by grants from NIH (HD-37082 and DC- artifacts. However. Sound observed in adults (Dehaene-Lambertz.. poral areas and right frontal areas. that predict the facility with which they map sounds onto meanings using a similar Bayesian adults improve their discrimination of nonnative speech cue-weighting scheme. However. J. and R. 14:257–262. Biol. in part. The challenge for the future is to under- language proficiency. Dehaene et al. J. Dehaene-Lambertz. This process of selecting a subset of the available of maintaining L1 simply used the same area of frontal acoustic cues implies either the operation of innate con- cortex.. and select those present but below detection thresholds (as in the case of acoustic components that are useful for solving a particular barn owl sound localization). versity of Rochester that supported NB. 2003). 1991. Hertz-Pannier. the mecha- (see recent review by Dehaene-Lambertz. Acoust. Miller.. stand how these neural systems develop and become elabo- Finally. Jacquemot et al. Pallier and associ- ates (2003) found no such segregation of L1 and L2 in Our coverage of auditory development and early language adults who had acquired Korean as L1 and then were learning has admittedly been selective.. Am. Burr. are available to support auditory development. Finally.. These mech- These and other structural measures. movement possible. and chapter Recent neuroimaging techniques have provided insights 17 in this volume by Wozniak. 2006). and data analysis in uncooperative subjects. volumetric properties. 62:1211–1226. or whether L2 in the absence task. both in terms of white matter density and acquire the referential properties of their native language. 2006. and Lim). Experience- about how these areas are interconnected and change with dependent visual cue integration based on consistencies between experience. Discrimination of frequency transitions by human infants. extracted from the same recording session in young infants 115:3171–3183. 2007) and infants We also reviewed a number of neural mechanisms that progress through the vocabulary spurt (Pujol et al. and associates (2006) presented short sen- tences and recorded activations that unfolded over time REFERENCES in both an anterior and a posterior direction. ticularly impressive because they obtained data from normal 3-month-old infants in a 1. Empirical evidence supports this model of vations.

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8 Brain Correlates of Language Processing during the First Years of Life ANGELA D. input can be achieved by different tools. or whether they are quali- around them. Keen I will not review the behavioral studies supporting the to extract rules from auditory input. while others. support for the continuity hypothesis that assumes that ogy. 2005). Baldwin just change quantitatively with development (Gleitman and and Moses.. lexical. Measuring brain activity in early development languages differ in the extent to which the different lexical categories are marked by morphology or position in the The goal of measuring the brain’s reaction to particular sentence. Pinker. Wanner and Gleitman. 1984. the infant around the different theories (e. when preceded by an auxiliary the likelihood is high that the word refers to an action. this is not an easy task discontinuity hypothesis claiming that processes underlying to accomplish. For example. 2004). FRIEDERICI Introduction marking.) It has been shown that infants are sensitive to functional categories starting at 6 months of age (e. quantitative differences such as and gaze to innerlinguistic cues provided by functional changes in latency and duration of processes would provide categories such as function words and inflectional morphol. Werker beyond the mere probability of occurrence of particular and Yeung. age of 7 to 8 months demonstrates the ability to abstract 1984.g.. when preceded by a determiner. and Weissenborn. 2000. Since the relations between words and the objects and Qualitative differences would indicate support for the actions they refer to are arbitrary. Höhle et al. used measures in infants and young children are event- have relatively free word order but more morphological related brain potentials (ERPs) as registered with electro- 117 . Gleitman and Gleitman. Weissenborn et al. studies have demonstrated that the learn. and syntactic pro- learn that certain segments of the speech stream carry cesses between 4 months and 4 years of life are similar meaning that refers to objects and actions in the world precursors to those of adults. Infants are helped in this task by a number language performance differ between children and adults of cues ranging from extralinguistic ones such as pointing (Felix. such as German. syntactic rules in the mother tongue is already partly laid. infants must supporting prosodic. the likelihood to investigate the brain bases of language processing in early is high that the word refers to an object. 2003. the different methods used example. (For example. some languages.g. It Therefore. 2000. With this ability. cognitive literature relevant to the topic of how the infant 2000). 1992). questions in this context is whether the brain mechanisms Parallel to the task of syntactic rule extraction. “a ball. Jusczyk. processes are principally the same during development and ing of object names is eased by social cues (e. 2001.” but development will be briefly reviewed. cal and positional regularities of items in speech input. (For that is relevant to these theories. 1982. semantic. functional cat.. egories help in determining whether a particular name Before reviewing the available neurophysiological literature belongs to an object (ball) or an action (rolling). the goal of the present chapter is to provide has been argued. however.”) In addition. such as English. One of the important innate and domain-specific principles of linguistic structures. 1982. 1994). but instead will focus on the neuro- items in a sequence (for a review see Gomez and Gerken. The most frequently have a strict word order... Also. Tomasello. “is rolling. the foundation for acquisition of extracts his or her target language from auditory input. tatively different.g. Pinker. Höhle Children first experience language by calculating phonologi. 2003). Wanner. In contrast. that the acquisition of syntax can information concerning the brain basis underlying early only be successful if statistical learning is constrained by semantic and syntactic processes.

but its spatial resolution is higher than that the right temporoparietal cortex as the region supporting of OT. This feature is important.. It allows us to examine the cortical hemodynamic analyses of awake infants revealed an additional activation response in infants. leaving formant and hemodynamic responses. including Heschl’s gyrus extend- to reflect a slowing down of a particular cognitive process ing to the superior temporal sulcus and the temporal pole. the pitch cortex. but each Sentential prosody can be defined as the overall intonational intonational phrase boundary is a syntactic boundary. has a characteristic scalp distribution. Results from the One crucial aspect of sentential prosody is that it marks respective measures. The left-hemisphere activation ranged from anisms they reflect. fore. The resulting changes in oxygenated hemo. and observed bilateral activation in the temporoparietal and globin. Schroeter sodic information in German-speaking adults (Meyer et al. Thus no right-hemispheric dominance in the processing of sentential measurement tool has really been available for the study of prosody seen in adults is established in babies as young as infants and children that combines optimal temporal and 3 months. attention for the normal speech condition in awake infants. “Peter knows # Mary the brain bases of language development in its early stages. found clear right-hemispheric resolution depends upon the number of channels measured activation in the temporal cortex for the processing of pro- (Obrig and Villringer. Using the same paradigm in Japanese. the right hemisphere is responsi- in light attenuation at different wavelengths greatly depend ble for suprasegmental prosodic processing (for a review see on the concentration changes in oxygenated and deoxygen. This method’s temporal resolution is low as it reflects contour) of sentences was removed. Event-related potentials reflect the that mark intonational phrases. and each peak. In adults. Forward and backward speech processes associated with them. which was interpreted to reflect higher the cerebral cortex resulting from increased regional cere. A direct is measured in fMRI. a par- 118 fundamentals of developmental neurobiology . elicited stronger activation in the left-temporal lobe com- sions of the ERP can indicate changes in the cognitive mech. they applied near-infrared optical topography imaging (fMRI). Friederici and Alter. changes can be interpreted the superior temporal gyrus. the blood-oxygen-level-dependent (BOLD) contrast frontal cortex for both normal and flattened speech.encephalography (EEG). lobe. (reflected in the latency). This method relies on the spectroscopic for forward speech compared to backward speech in the determination of changes in hemoglobin concentrations in right frontal cortex.g. Its spatial spectral information intact.. In an experiment using fMRI. This method’s temporal resolution is comparison between normal and flattened speech revealed similar to OT. a reduction in the processing but no significant activation was found in the right temporal demands or efficiency (amplitude) of a positivity or negativ. 2004). A study comparing normal ated hemoglobin ([oxy-Hb] and [deoxy-Hb]) in the cerebral speech and speech in which the intonation (e. 2004). because intonational phrase boundaries Processing sentential prosody signal syntactic phrase boundaries. spatial resolution as well as feasibility. This finding suggests that the infants only when they are asleep in the scanner. For example.. Each time-locked average tion.g. Changes ing in right-handed adults. auditory input.. Changes within the dimen. Left-hemispheric asymmetry between forward and ity. An infant’s first exposure to brain’s activity in response to a particular stimulus event language is based on the processing of phonological informa- with a high temporal resolution. due to neural signaling is functional magnetic resonance In their study. as well as the latency and scalp distribution speech in 3-month-old sleeping and awake infants who were of different components.” the # indicates the prosodic break). 2004). One of the crucial abilities in this first step in language waveform typically shows several positive or negative peaks acquisition is the differentiation of speech from nonspeech at particular latencies after stimulus onset. Every syntactic phrase boundary is not necessarily marked by prosody. which are relatively slow. once infants are able to detect intonational phrase damental frequency in the acoustic input. allows us to dissociate cognitive exposed to French language. 2004. et al. pared to silence. cuneus. they are equipped with the information needed linguistically relevant pauses inserted in the speech input to structure incoming speech into phrases. Dehaene- or component. Separate 1997). or a change in the cortical tissue supporting a particular backward speech was found for the angular gyrus and pre- process (topography). loves her work. however. of fast transitions in auditory input such as speech. There- pattern of a sentence including the fall and rise of the fun. but also including boundaries.. These data suggest that infants as young as 3 months A second method is near-infrared spectroscopy (NIRS). Until now. 2003. It assesses the spectroscopic characteristics While the left hemisphere is dominant for speech process- of the cerebral cortex through the scalp and skull. Homae and Another method used to measure the metabolic demand associates (2006) investigated 3-month-old sleeping infants. this measurement has been applied to pitch information processing. of age show a left-hemispheric dominance for the processing also called optical imaging (OI) (Villringer and Chance. evoked by normal (forward) speech and reversed (backward) tive to baseline). add up to provide insight into intonational phrase boundaries (e. bral blood flow. The Lambertz and associates (2002) measured the brain activity polarity (negative/positive inflection of the waveform rela. Okamoto et al.

this shift is referred to segment disyllabic words with stress on the first syllable from as closure positive shift (CPS) (Steinhauer. The CPS has also been observed for at the age of 7. of ERPs suggest that infants are indeed sensitive to the pre- ognize words when they hear the target language. and speech input but not those with stress on the second syllable Friederici. (b) Grand-average ERP for phrases and the intervening IPh boundary in sentence type A 8-month-old infants at electrode P4 for sentence type A (solid line) ([Kevin verspricht Mama zu schlafen] IPh1 [und ganz lange lieb and sentence type B (line) (Modified with permission from zu sein] IPh2 / [Kevin promises Mom to sleep] [and to be a good Friederici. It has 8. hummed sentences and can. Toward identifying the lexical form as behavioral paradigms require the attention of infants during testing. and the language acquisition: From syllables to sentences. Trends Cogn. has been observed in adults could be observed for intona. and Newsome. multisyllabic words. This ability was also reported for 9-month-olds learning purely prosodic processes (Pannekamp et al.ticular ERP component has been found to correlate with contrast. Cutler. the positive shift. In such a paradigm different rules according to how stress is assigned within a string of identical stimuli or standard stimuli are presented. Behavioral studies guage—that is. however. (a) Grand-average ERP for [und ganz lange lieb zu sein] IPh3 / [Kevin promises] IPh1 [to kiss adults at electrode PZ. English.1 The closure positive shift (CPS) as an index of process. 2005. is a stress-based and a deviant stimulus is introduced at rare occasions. be taken to reflect 1999). is a syllable-based language that tends to lengthen intonational phrase boundary processing in spoken lan. neurophysiological studies using the method ble phonotactic structure enable infants to successfully rec. The ability to segment words ERP study with 8-month-old infants. French. and Redanz. Houston. three intonational phrases and two intervening IPh boundaries in 9:481–488. However. sentence type B ([Kevin verspricht] IPh1 [Mama zu küssen] IPh2 ing intonational phrase boundaries. infants first have to segment acquired this knowledge but attentional lapses make words from the auditory stream. The language and has a bias toward a stress-initial pattern for brain reacts to the deviant auditory stimulus with a mis- two-syllable words (Cutler and Carter.) friederici: brain correlates of language processing during the first years of life 119 . Future studies will have to show whether this mechanism been shown behaviorally that infants learning English in is in place at an even earlier developmental stage. in match response that in adults is characterized by a more Figure 8. 1999). D. it appears that knowledge about the stress phrase boundary processing is clearly established by the age pattern of possible words in a language must be available at of 8 months (Pannekamp. therefore. 1987). the so-called oddball para- Stress Patterns of Words Different languages have digm or mismatch paradigm was used.. In these studies. the word’s last syllable (Nazzi et al. Neurophysiological markers of early boy for a while]) represented as solid line (with one CPS). This finding learning infants (Jusczyk. 2006) (figure about 7 months in order to be used for segmentation. and IPh3 bars indicate the length of the two intonational as dotted line (with CPS1 and CPS2). and Friederici. Alter. A.1). Vertical line indicates sentence onset. As the intonational phrase have demonstrated that infants learning English are able to boundary signals the end of a phrase. it may well be that infants have already To achieve lexical knowledge. Both knowledge about a this fact undetectable. and Newsome. 2000). a CPS similar to what with stress on the second syllable in various contexts. word’s stress pattern and information about a word’s possi. Houston... ferred stress pattern of their target language as early as 4 to 5 months of age. In contrast. Weber. particular acquire this knowledge between the ages of 6 and 9 months (Jusczyk. 1993). was only observed by the age of 10.5 months (Jusczyk. 2005). indicates that the brain mechanism supporting intonational Therefore.. 2006).5 months in English- tional phrase boundaries in spoken language. In an Dutch (Houston et al. Sci. 1999). Mom] IPh2 [and to be a good boy for a while] IPh3) represented IPh2. IPh1. like German.

In an ERP study with infants learning Dutch.. This finding suggests that a pattern that is a language-specific discrimination response by the age of 6 nontypical for a particular language is considered deviant months (for a review see Kuhl. mismatch paradigm to investigate the infants’ ability to dis.. However.. whereas infants learning French demonstrated a larger effect criminate different phonemes early during development for the language-nontypical trochaic pattern (stress on the indicate this general ability very early on and start to show first syllable).2). 2007). standard stimuli (Näätänen et al. Kooijman labic words with stress on the first syllable (baaba) and the and associates (2005) found that 10-month-olds recognized deviant stimuli had the stress on the second syllable (babaa). 2004).e. 2001) and that in infants they differed in the amplitude of the brain response: infants is sometimes expressed as a more positive going wave for the learning German showed a larger effect for the language- deviant stimulus (Weber et al. both within the experiment (i. paradigm was used in which the standard stimuli were disyl. Friedrich. established knowledge about the dominant stress pattern of criminate between different stress patterns. groups of 5-month-old German. and and with respect to an individual infant’s target language. in turn. (b) Grand-average ERPs for iambic stress pattern for the deviant stimulus condition (dotted line) as compared to (stress on the second syllable) as a deviant stimulus in a train of the standard condition (solid line).negative going wave for the deviant as compared to the between the two types of stress patterns (figure 8. Christophe. Studies that used the nontypical iambic pattern (stress on the second syllable).or This finding. The MMR is indicated by trochaic stress pattern (stress on the first syllable) as a deviant the arrow. two-syllable words with stress on the first syllable when these The data showed that both groups are able to discriminate were presented in continuous speech after they had heard the Figure 8. a rare stimulus in the set) In a recent ERP study (Friederici. 120 fundamentals of developmental neurobiology . presupposes that infants have already French-learning infants were tested for their ability to dis.2 The mismatch response (MMR) during processing (rarely occurring) stimulus in a train of stimuli with stress on the of a word’s stress pattern expressed as a more positive going wave second syllable. A mismatch their target language by the age of 5 months. 2004). (a) Grand-average ERPs for stimuli with stress on the first syllable.

the N400 amplitude is phonological and semantic knowledge interact at around 12 larger for pseudowords than for words. these data suggest that at the age of 19 hemispheric negativity (Mills. that is. no N400 effects were observed in 12-month-olds. The so-called preferential looking paradigm used in a picture-word priming paradigm. Friederici. In the study of semantic processes in infants that is a pseudoword that is phonotactically legal or illegal. object might not be sharply defined.3). At this age. our group has found an these studies revealed a preference for auditory input early frontocentral negativity between 100 and 400 ms in containing stimuli that are phonotactically legal (“str” at 12. 2005a). 2000. 1997). Kutas and Van Petten. phonotactically legal or not (for reviews. map sounds onto objects (or pictures of objects) at about 11 months of age. 1994). 1997). an N400 dissimilar words they knew. This early effect was is not a possible word ending in English or in Dutch. 2005a. The preceding behavioral and electro. 2005b). The available data thus indicate that ous words (see figure 8. and Neville.words in isolation. Semantic processes digm appropriate for both adults and children is one in which the participant is shown the picture of an object and The adult N400 component is taken to reflect the integration at the same time is presented with an auditory stimulus that of a lexical element into a semantic context (Kutas and Van is either a word matching the object’s name or not. Coffey-Corina. unknown words. these behavioral studies cannot an object. the interpreted as a familiarity effect reflecting the fulfillment of language in which in infants were tested by Friederici and a phonological (word) expectation after seeing the picture of Wessels. or one Petten. a negative-going month-olds showed an ERP difference between phonetically waveform peaking at around 400 ms. After training. months. both real words and phonotactically legal pseudo. and no shown that initial phonotactic knowledge is established by 9 correction for multiple comparisons was applied. There are some concerns about the combinations of phonemes in syllables or words and about statistical techniques used in this study. meaning infants either knew or did not know. that is. an N400 effect for the incongruous words and phonotactically legal pseu. This development has been indicated by a Phonotactic Knowledge and Lexical Form There are negativity around 200 ms reported for 11-month-olds in only a few ERP studies that have investigated infants’ response to listening to familiar versus unfamiliar words phonotactic knowledge. challenges the authors’ interpretation to some extent. This result was interpreted as a developmental change words are considered as possible word candidates. paradigm. This lexical status of a given stimulus is by means of the electro. whether they are months of age. infants seem to have some lexical resolve whether this phonotactic knowledge is considered to knowledge. 1993. infants between However. but this knowledge is not actually with a novel object or without an object. The ERP effects in 19-month-olds compared. we observed a developmental change ERP template pattern against which the ERPs for semantic between the ages of 12 and 19 months (Friedrich and knowledge and processes during early development are Friederici.. but the specific word form referring to a given be lexically relevant by infants. Behavioral studies have performed to cover every millisecond of recording. and Neville. see Kutas and Federmeier. so phonetically similar One way to test phonotactic knowledge and thereby the words are still considered as possible word candidates. In phonotactically illegal pseudowords have already been a more recent study. so this fact months (Friederici and Wessels. are quite similar to those of adults. infants’ ERPs showed a repetition effect indicated by a friederici: brain correlates of language processing during the first years of life 121 . but that toward a hemispheric specialization for word processing. the adult N400 has been used as an Using this paradigm. Word Level In a study on the processing of words whose dowords but not for phonotactically illegal pseudowords. 2005a). In adults. Coffey-Corina. that is. interpretation is supported by the finding that 12. Using 1994). 20-month-olds acquired novel words either paired tic knowledge at 9 months. 1994). the used in lexical processing until several months later. 13 and 17 months old showed a bilateral negativity for As the N400 is taken to reflect mechanisms of lexical. the effects of word experience (training) excluded from the native language lexicon (Friedrich and and vocabulary size (word production) were tested (Mills.and 14- physiological N400 component. but 20-month-olds showed a left- semantic integration. knowledge about the legal (Thierry et al. In this word-learning physiological data indicate the presence of initial phonotac. Moreover. A para. 2003). but not between words they effect is reflected in a larger amplitude for words that are knew and phonetically similar words (Friedrich and semantically incongruous to a given context than for congru.and 14-month-olds for auditory word targets that were word onset as in “street”) in the respective target language congruous with a picture compared to incongruous words compared to those that are illegal (“str” at word offset which (Friedrich and Friederici. However. An ANOVA was legal positions of syllables in words. 1993). Jusczyk and Luce. Recognition was reflected in a greater Phonological Familiarity of Words There is another negativity between 350 and 500 milliseconds (ms) over the left ERP effect suggesting that children are already trying to hemisphere for familiar words than for unfamiliar words. and young children. Friederici. 2005a).

. Bottom: Trends Cogn. it is not entirely clear whether the N200–500 either that children’s semantic processes are still more image reflects semantic processes only or whether phonological based (adults show a frontal distribution when pictures familiarity also plays a role.3). as well as the study with 3. (Silva-Pereyra. (Modified here showing a picture-word incongruity effect.) N400 effect (difference between congruent and incongruent words) 122 fundamentals of developmental neurobiology .3 The N400 as an index of lexical-semantic processes. Note the markers of early language acquisition: From syllables to sentences. than in adults. the children listened passively to sentence context than those that did (see figure 8.and 19-month-olds (Friedrich Neville. D. My uncle will blow the movie) while watching a puppet lasted longer. and Kuhl. 2005). A small vocabulary results in a low number of Sentence Level The processing of congruous and phonologically possible alternative word forms. 1992) and 6.and 4-year-olds.g. 2004). Figure 8. 1990) in addition to possible. Rivera-Gaxiola. given that semantic effects or that children may recruit frontal brain regions associated in adults are observed later in reference to the N400.to 15-year-olds (Holcomb. after hearing a word’s first phonemes been investigated in children younger than 4 years of age (see earlier section on phonological familiarity). 2005. West and Holcomb. Sci. allowing the incongruous words in sentential context has only recently brain to react earlier. which was sentences in children of all age groups. with permission from Friederici. however.. It is with attention in adults (Courchesne. and Kuhl. Top: Grand. 2005b. Coffey. different mircovolt scales for the different age groups. bilaterally distributed reported N400-like negativities for semantically anomalous negative-going wave between 400 and 1400 ms. The latency differ- 500 was found for novel paired words. context showed a centroparietal. that the early onset of this effect in infants those subserving semantic processing. and been demonstrated for 14. whereas an increased bilaterally distributed N200– frontal electrode sites than adults did. Previous A clear semantic-context N400 effect at the word level has studies with 5.reduced N200–500 amplitude to familiar and novel unpaired of the effect as children showed a stronger involvement of words. The more frontal distribution could mean However.to 13-year-olds (Hahne. The ERP to words in picture Friederici. The interpretation of this early instead of words are processed. 2002) effect as semantic is challenged. Compared to stimuli that were either semantically correct or anomalous adults. and and Friederici. There were also small topographic differences show (Silva-Pereyra. 2005). A. this N400-like effect reached significance later and (e. Rivera-Gaxiola. 2004). as compared to adults is due to infants’ relatively small vocabularies. This finding is taken ences suggest slower lexical-semantic processes in children to indicate that the N200–500 is linked to word meaning. In the study with 3- more negative for words that did not match the picture and 4-year-olds. Negativity is coded in dark gray. 9:481–488. Neurophysiological average ERP at electrode PZ for the different age groups. as a distributional map. Eckstein.

Syntactic processes One of the key questions in early syntax acquisition is whether infants rely on statistical cues of the input or whether Figure 8.4).g. The later negativities were taken to reflect sentence closure. Die Katze trinkt den Ball/The cat drinks the ball) or semantically correct (The cat drinks the milk). children possess lexical representations of verbs speci- fied with respect to their lexical restrictions and that brain mechanisms underlying semantic processes at the sentential level are established in an adultlike manner. the N400 effect was present between 300 and 800 ms. but extends longer. a frontally distributed negativity between 300 and 500 ms with a statistically significant difference between semantically anomalous and nonanomalous sentences was reported (Silva-Pereyra. a first negativity was observed between 400 and 500 ms followed by a sustained negativity between 600 and 1200 ms (figure 8. Using the same paradigm with slightly younger children at 30 months. an N400-like semantic effect at the sen- tence level has been reported for children at 19 and 24 months (Friedrich and Friederici. The presence of the N400 effect indicates that before the age of two. These data suggest that the semantic processes at the sentential level similar to those reflected by the adult N400 are present between the ages of 30 and 36 months. and a third negativity between 800 and 1000 ms. For 19-month-olds. The longer duration of the children’s N400 effect suggests that the integration of the object noun into the sentence context requires enhanced efforts. until 1200 ms. friederici: brain correlates of language processing during the first years of life 123 . the negativity was found to start as early as 300 ms and lasted until 1200 ms. et al. Grand-average ERPs of N400 effect across different age groups.Whereas 3-year-olds showed a first negativity between 300 and 500 ms... Right: Distributional map of the N400 effect (difference between correct and incorrect condition). The negativity in the time window relevant for the adult N400 was not given any specific interpretation but could be taken to reflect semantic processes. In 24- month-olds. 4-year-olds demonstrated a first negativity peaking at around 400 ms and a second negativity between 500 and 800 ms.4 The N400 as an index of lexical-semantic integration processes at the sentence level. More recently. were interpreted to reflect different semantic mechanisms. This study inves- tigated children learning German and used sentences that were either semantically incorrect (e. which were anteriorly distributed. 2005b). here showing a verb-object noun incongruity effect. it is apparent that the N400 effect in children starts at around the same time as the adult N400. For adult listeners. Klarman. These negativities. a second negativity between 500 and 800 ms. 2005). From these data.

et al. 2006) structure or the repair of a syntactically incorrect structure (figure 8. the ELAN and the P600. structure building reflected in the ELAN is established later Currently..g. and the other has been used to examine phrase Gaxiola. the ERPs revealed a late P600 trolled processes of syntactic revision that could either be a but no ELAN component or any other left-lateralized nega- syntactic reanalysis of a correct but falsely analyzed syntactic tivity preceding the P600 (Oberecker and Friederici. Rivera. of the children’s negativity suggests that this component can tactic processing in 2. Rivera- English. Der Löwe im brüllt/The lion see Gomez and Gerken.5 The ELAN-P600 pattern as an index of syntactic ent mircovolt scales between children and adults. Moreover. The morphosyntactic para. 2005). we late P600 for such syntactically incorrect sentences cannot answer the question about the innateness of syntax. in-the roars) in children at 32 months demonstrated a biphasic 1996). While the ELAN is months. using sentences containing a morphosyntactic viola. Sci. 2002). When applying the same phrase structure violation para- the P600 has been interpreted to reflect later. A. PZ) across the different age groups.5). Note the differ. Cogn. nisms for phrase structure building (ELAN) might be tion (My uncle will watching the movie). reported a P600-like established earlier during development than those for mor- positivity for 3. Aslin. ERP patterns resemble those of adults. the positivity observed between 600 and Conclusions 1000 ms did not reach significance (Silva-Pereyra. digm to younger 2-year-olds. and the LAN is seen in response to morphosyntactic errors. These groups be interpreted as a child precursor to the ELAN observed will be evaluated for whether and to what extent infants’ in adults for phrase structure violations. (Modified with processes. D. only a few ERP studies on syntactic processing than the late integration processes reflected in the P600. a recent ERP study investigating the processing system during early syntax acquisition (for recent reviews of phrase structure violations (e. more con. (Oberecker et al.to 4-year-old children.. For slightly younger 30-month- old children. although the processes are clearly slower in children seen as a fast response to violations of local syntactic rules than in adults. phosyntactic processes (LAN). Saffran. 9:481–488.the acquisition of syntax is guided by some innate rule However.5). ELAN stands for early left anterior negativity and P600 permission from Friederici. 2005) (figure 8.and 4-year-olds (Silva-Pereyra. started later and persisted longer Studies of sentence processing in adults have shown that than those observed in adults. P600 also seems to precede the development of morphosyn- digm has been used to study morphosyntactic violations in tactic processing reflected in the LAN (Silva-Pereyra. The during early language acquisition are available. Gaxiola. ERP pattern consisting of a left-hemispheric negativity Because ERP studies that focus on whether infants can around 500 ms and a bilaterally distributed centroparietal detect rule deviations are not available in the literature. The appearance of these violations of syntactic rules are associated with two ERP syntax-related components indicates that the neural mecha- components: a late. The left lateralization However.. are beginning to formulate a developmental neuroscience of Figure 8. there are ERP studies that have investigated syn. and Kuhl. One para. 2005). German and English studies suggest that the neural mecha- digm. and Kuhl. Klarman. and Newport. 2000. the data from the structure violations in German. centroparietal positivity (P600) and an nisms of syntactic parsing are present in principle at 32 earlier left anterior negativity (ELAN). Both components.. Trends electrodes (F7. 2005). Neurophysiological mar- for a late centroparietal positivity. Thus it appears that the automatic initial phrase (Friederici. No LAN effects were observed at any of the The literature reviewed in this chapter demonstrates that we ages tested.) 124 fundamentals of developmental neurobiology . 2005. Grand-average ERPs at selected kers of early language acquisition: From syllables to sentences.

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a scaled version of adult vision. information processed by the infant brain is of a different tomical or physiological data to observed behavior or from quality than that available in normal human adults. These theories are developmental examples this information addresses two age-old developmental ques- of what Teller (1984) referred to as linking propositions in tions: What structure is present innately in the visual system. neuroarchitectural transformations. more noise in the young visual system or that the signals are strate. that is. has focused on the major visual pathways. and genetic data from human and animal primary motor and sensory information mature earliest. brain-behavior relations. visual development research without going into the extensive whereas parietal and temporal association cortices that will literature on plasticity and deprivation in early visual devel- serve as substrates for spatial attention and basic language opment. large role in visual development. and gene expression. or con.g. vision in cal levels and has attempted to link observed data on visual the early postnatal human infant is not simply assumed to be function.. The regions that process cal. In the former case. Atkinson (1998) proposed that the magnocel. physiological activity. acuity. Johnson (1990) different rates. DANNEMILLER Empirical and theoretical work on the relations between and decision-making processes. mentioned observation that different structures and pro- lular pathway may lag slightly behind the parvocellular cesses in the infant brain develop at different times and with pathway early in postnatal development. This work has It is important to realize that in these theories. Lewis. We will review the anatomical. visual science. such 25 in this volume by Maurer. Different struc. formal propositions that link aspects and how did that structure arise in the absence of visual of visual anatomy and physiology with observed visual experience? The important role played by inhibition in capacities and behavior. data on the states of various neural that rely on specific brain structures for their processing or elements within the visual system are used to explain extraction will never be available to the infant because those observed behavioral data (e. In the latter case. color vision. this period is characterized by how mature visual processing differs both quantitatively and variable developmental timetables for processes such as qualitatively from visual processing early in postnatal life.g. structures are not yet capable of extracting that information. we also review important tioning of various subpopulations of feature-selective neurons studies on the roles of intrinsic activity in setting up the within the visual pathway (e. visual processing also provides an opportunity to understand At the neural level. neural maturation and perceptual capabilities during infancy 2004). biochemical. orientation or direction neural circuits that experience will later mold. The interested reader might wish to consult chapter skills mature later. We will look at the progress made at different and Banton and Bertenthal (1997) based their models on levels in understanding neural development and its relations data showing that different layers within primary visual with perception. and corti. subcortical. trast sensitivity). on the early postnatal development of the visual system as tures and functional pathways within the visual system an example of how one might think about these complex (and many other brain systems) develop at different rates.. but rather that the sensory and perceptual development typically make inferences either from the ana. physiologi- cortex develop at different rates. observed behavioral data While it is well known that postnatal experience plays a are used to make inferences about the presence and func. ILIESCU AND JAMES L. especially addressed development at the retinal. and Mondloch for a as prefrontal cortex responsible for integrative behavior discussion on visual system plasticity. Higher order association areas. The purpose of this chapter is to review the available data biochemical events. We will focus on the previously For example. soning behind this claim is that some types of information strate. mature last (Gogtay et al.. In some ways selectivity). It is not simply that there is to changes taking place within the underlying neural sub.9 Brain-Behavior Relationships in Early Visual Development BOGDAN F. those referring to development at the cortical level. 127 . Theories of brain-behavior relations in early visual generally weaker. The rea- observed behavior to the anatomical and physiological sub. whether behavioral or evoked electrical activity.

With postmortem anatomical measurements Fulton and Two factors make it possible to construct reasonably associates (1999) showed that the amount of rhodopsin—the rigorous. The Hansen and Fulton model is somewhat simpler. 1990. We months of age. to understand these have the virtue of simplicity. 1987. If the anatomi. Instead. more complex. 1993. perhaps capture of light by the photoreceptor mosaic. because they tell us what spatial information is avail. infant rod OS lengths are approximately 68 will turn next to the Hansen and Fulton (1999) model percent of the adult value. Information in the optical infants or to their lack of motivation for behaving like prac- image that is lost at this first stage of processing can never ticed psychophysical observers as explanations for why their be recovered. noted that no infant in their study who was 6 months of age 128 fundamentals of developmental neurobiology . rhodopsin content toreceptor absorptions are fairly well understood. adults. This is a purely physical/optical calculation like in the lengths of the rod outer segments (OS) in which the calculating the optical aperture of a telescope.Retinal development Absolute thresholds are significantly higher in young infants than in adults (see Brown. in the photorecep- cal data on which the models are based are accurate and tors themselves. 1993. it can only be equal level attentional or motivational processes. best or “ideal” visual performance. It appears and outer segments determine what proportion of the to reach its adult value sometime near 40 weeks of age. 1999) and development of absolute thresholds. and if the assumptions are valid. Hansen and Fulton. Candy. These increases in rhodopsin are likely to reflect the increases pigment. Crowell. Why The absorption of photons of light by the photoreceptors is is this statement true? It would be possible to answer this the first step in the visual cascade that eventually leads to question in many ways. Only after estimates have been derived representative.3 times longer than they are in 5-day-old infants. incident photons are likely to be absorbed by the photo. should one then proceed to models tell us importantly that vision can be quantitatively attribute any remaining infant/adult differences to higher no better than what has been calculated. if one is temporal contrast) that has been lost in the sampling and going to explain improvements in absolute threshold. processes should only be entertained as explanations for able to the remainder of the infant’s visual system for impor. Brown. layout. This figure would predict a differ- exist between the absolute thresholds of infants and adults ence of approximately one log unit. and Maier. and that it eye to the amount of information in the pattern of pho. One can use these data to calculate lengths at a peripheral retinal site in adults are approxi- estimates of information transmission to and including the mately 2. Absolute threshold is simply a absolute threshold at this parafoveal site was approximately measure of the minimum amount of light that can be 1. then these using these anatomical data.4 log units. At a more parafoveal retinal site. psychological models.06 log units higher than the adult threshold. at 11 detected reliably under a set of fixed viewing conditions. The only thing that subsequent stages in the thresholds are higher. for a review). portional to the length of the rod OS (assuming equal densi- Examples of the models that have been proposed at this ties). some observed behavior after simpler. 1994). this finding would predict a threshold increase for level are ones covering scotopic (night) vision (Brown. and it reaches example. Finally. the contributions of various structures in the and term infant eyes than it is in adult eyes. Hansen and Fulton (1999) ment of visual sensitivity. Hansen and Fulton photopic (day) vision (Banks and Bennett. point at which photons are actually absorbed by the Given that the amount of rhodopsin should be directly pro- photopigment. It pays.58 log units higher than they were in 1987. In other words. Wilson. These models to or worse than this. leading to the prediction that because it illustrates how anatomical measurements can be infant thresholds at this age should be only 0. anatomical data exist on the characteristics of these optical Hansen and Fulton (1999) noted that rod outer segment and retinal structures. Banks and (1999) reported that the thresholds for 10-week-old infants Crowell. therefore. and Maier. in adults are approximately 9 times as long as they are in because it is meant to explain only the large differences that 5-day-old human infants. The answer to this simple question seeing. Second. rhodopsin is held (Hendrickson. The 10-week-old in the detection of light. First. and Banks. increases rapidly during infancy. infants relative to adults of 0.16 log units used to make reasonably accurate predictions of the develop. were approximately 0. 1988. Dobson. At birth. rod OS lengths 1993). they cannot recreate information (spatio. the diameter and length of photoreceptor inner 50 percent of its adult value by 5 weeks postnatally. quantitative developmental models at the retinal photosensitive pigment in rods—is much lower in preterm level. the place to start is at the very beginning. 1988. For is approximately 35 percent of its adult value. In their study of the Dobson. One information transmission in the visual pathway? There is a could point to the weaker attentional capacities of young simple answer to this question. more peripheral tant tasks like object recognition and the perception of spatial explanations have been ruled out as being incomplete. Brown. Why is it important to focus on this first stage of illustrates one of the primary virtues of these models. higher than adult thresholds. these models choose to answer visual pathway can do is to operate on the information that this question by using known anatomical data to constrain leaves the retina. 1998.

60 cpd for adults). Of course. Crowell. and Banks Banks. These models start with the optics of the eye. and they most certainly are not (see discus- quite simply how increases in rod OS length and by infer. Dobson. Crowell. As was true of rods. 1998).1 retina. adult values are available from (1998).35)2 in favor of infants. Once the optical properties of the cornea. 1998). Prior to The morphologies of individual cones in the neonatal being absorbed by the photoreceptors.88 (0. Candy. Candy. of the adult’s eye. and media olds and how those differences narrow over the course of have been factored into the model. and Banks erties and their mature. 1986). and Banks (1998) estimated (1998) calculated an acuity limit of 15 cycles per degree (cpd) that the image of a small. The latter intensity effect is across a small region of the retina. 2005). Brown. lower mately 2/3 as large on the neonatal retina as on the adult packing densities also imply fewer photon absorptions given iliescu and dannemiller: brain-behavior relationships in early visual development 129 . Candy. Curcio of visual acuity and contrast sensitivity. Sampling the image very offset by the smaller pupil size of the infant’s eye. 1. Optical ture of the neonate’s cones means that slightly more photons systems generally attenuate contrast more at high spatial will be absorbed per infant cone given the same flux.or older had an absolute threshold that was more than 0.to 7-week-old effective apertures of these cones through which photons human infants (Wang and Candy. Banks and Bennett (1988) modeled this difference First. the outer seg- contribute to the optical quality of retinal images. and Banks. 1998). We will con. 1987.. must be funneled to be absorbed was estimated by Banks fer function represents the extent to which contrast is attenu. If photoreceptor packing densities were the same at log units above the median adult threshold. the of image quality caused by the optics in 5. and Bennett (1988) to differ by a factor of approximately ated as it passes through the optics of the eye (cornea. assuming equal densities. 1986).1 Based on the spacings of the photo- media transmittance in the neonate (Candy. and (2) the number of photons falling on a small patch determines to a large extent the highest spatial frequency of retina (photons/degree2) would be higher in the infant’s that can be reliably signaled from the photoreceptor catches eye if pupil sizes did not differ. and Banks (1998) and Banks and as a factor of approximately 16 : 1 for foveal cones. Hendrickson and Drucker.. Yuodelis and Hendrickson. very coarsely attenuates this high-spatial-frequency infor- except for small differences resulting from the slightly higher mation significantly. The optical trans. Data on the development of these prop- Maier (1987). models (Curcio et al. but it frequencies than at low spatial frequencies. Crowell. Candy. 1982. because this distribution differs significantly across the retina however. This fact has two consequences: (1) the The cones are also packed much less densely in the new- retinal image is spread over a smaller area in the infant’s born’s fovea. include the spatial distribution of the cone photoreceptors 1992. 1994. This packing density is important because it eye. and (packing densities). between young infants and adults in their absolute thresh. It is many of the conclusions offered by these alternative models known that in adults there is considerable individual vari- regarding front-end constraints on vision in early infancy are ability in some of the anatomical parameters used in these very similar. remaining factors are (1) the morphologies of individual The same strategy has been used by Banks and Bennett cone photoreceptors and (2) their spatial arrangements (1988). Brown (1993). Additionally. 1990). while sampling the image is probably not very different between infants and adults. then this difference in eye size alone ence in the amounts of photon-catching rhodopsin (Fulton would spread the image over fewer photoreceptors in the et al. Bennett (1988) both assume that the optical transfer function this length difference implies that the amount of photosensi- of the neonatal eye is similar to that of the adult eye. photons must of retina are markedly different from those of adults (Youdelis course pass through the optics of the eye. lens. because Banks and Crowell (1993) showed that be kept in mind (Candy. The slightly larger aper- and ocular media) as a function of spatial frequency. old human infant (Yuodelis and Hendrickson. Crowell. and it has strong implications for photon capture contrast vision during early infancy come from one 5-day- and spatial contrast transfer from the retina. More tive material for capturing incident photons is that much less recent evidence suggests that there is a modest degradation in the neonate. 1999) can be used to explain some of the differences neonate’s eye. for newborns (cf. Several factors and Hendrickson.. and Wilson (1988.48/0. the adult. Banks and Crowell (1993). that these anatomical data used to model spatial in adults. leading to a less detailed initial encoding. Hendrickson. Crowell. issue of the representativeness of this example must always leagues.. For the ments of the cones are much shorter in the neonate than in purposes of this chapter it is sufficient to note two things. so the centrate here on the models proposed by Banks and col. These data show these two ages. 1990. the most important postnatal development (see also Nusinowitz et al. Additionally. These models also et al. The second also means that higher spatial frequency information will be factor that is important for the purposes of this chapter is degraded more because of greater spatial averaging over the that the length of the infant’s eye is shorter than the length cone’s aperture. and receptor inner segment spacing. lens.. Crowell. Curcio. sion later in this section). 1993) to model the development several sources (Abramov et al. It should be noted. 1986). so that finely permits information about high spatial frequencies the actual number of incident photons per patch of retina (fine detail) to be transmitted well. distant object would be approxi.

theories trying to make a direct connec- Recent evidence from the study of the development of tion between the neural substrate and visual behavior tend retinal circuitry in other species suggests that it is not just the to be less quantitative than their retinal counterparts. beyond the retina. Stacy and Wong When all of these factors were taken into account. For an overall view of the visual pathway up to primary gene manipulation to two-photon microscopy helped in visual cortex please refer to figure 9. on approximately 350 photons would be absorbed by the adult and off pathways in the visual system are important for cone lattice for every one photon absorbed by the newborn’s encoding the visual signal into positive (increments) and cones. random process. 2001). photoreceptors. In the mouse this class of ganglion cells is a very dynamic evolution of the biochemical landscape corresponds to directionally selective ganglion cells in other during this period. Imagine trying to estimate retina might inform our understanding of early postnatal a mean with a set of observations that was 18 times as vari. It is hard to overstate the significance of this factor for Models of retinal function based on extant data do not newborn vision. orientation the visual system in the form of action potentials. reflecting the postnatal maturation of this aspect of of a normal neural architecture and connectivity. The immaturity of these sites. We will focus mainly on two themes in consider- retinal ganglion cell dendritic arbors are subject to signifi. The 350 : 1 ratio of absorbed photons for adults subcortical and cortical. ing development beyond the retina: (1) While there is incon- cant remodeling during development. postretinal sites in the visual pathways where significant ment in sensitivity that is proportional to the square root of information loss occurs. eventually making trovertible evidence for postnatal experience playing an contact with amacrine cells in very specific strata within the important role in shaping cortical development and instruct- inner plexiform layer. because the emission of light is an inherently acuities observed during early postnatal life. both the mean.g. In other words. In other words.g. Yoshida et al. although this is certainly not an exhaus- opment of this functional relationship between these two tive diagram of such pathways.. the excitatory and inhibitory neural species. on and off laminae in the inner plexiform layer as well. The cal theories generally make predictions about the presence ganglion cells of the retina collect signals from prior levels or absence of a certain perceptual capacity. The major subcortical 130 fundamentals of developmental neurobiology . Experimental techniques ranging from ways. Banks and suggest that amacrine–ganglion cell interactions are impor- Bennett (1988) estimated that if identical patches of light tant in determining the stratification of ganglion cells into were to be presented to newborn and adult central retina. In mice. brain–behavior relations. negative (decrements) contrast levels. could further limit visual function. It is clear that the normal devel. While human retinal ganglion cells do not exhibit mechanisms in particular that.2 is a schematic of several subcortical and corti- 1997. intensity discrimina- tion at an edge) that depends on pooling and averaging the A selective look at cortical development responses from these isomerizations will surely suffer sub- stantially by having such impoverished information on which Because of the greater complexity of the visual circuitry to base performance. Fewer photon absorptions mean much fully explain the poor contrast sensitivities and reduced noisier signals. these studies nonetheless show that account for important developmental phenomena during intrinsic chemical signals within the retina play a role in the this period are particularly malleable. Before discussing postnatal development of retinal circuitry in at least one these themes.a fixed nodal distance because more of the photons pass retinal cell types is essential for the appropriate computation through the retinal space not occupied by photoreceptors. Cholinergic amacrine cells probably ing specific functional capabilities at least in the visual cortex. Any visual task (e. directional selectivity. (2) There the retinal circuitry. able as another set. known or in the retina and pass this information to higher levels in thought to depend on cortical processing (e. in light of the latest data. working out the details of this circuit (He and Masland. we will review briefly the major visual path- mammalian species.. Corti- photoreceptors that undergo marked postnatal change. compared to infants means that the signal-to-noise ratio In the remainder of this chapter we will consider the evi- for infants would be at best 1/18 (square root behavior) as dence for how structures in the visual pathway beyond the strong in newborns as in adults.1. cal visual pathways. the prenatal period has a crucial influence on the formation 2003). the signal-to-noise ratio expressed possibility is that we lack a comprehensive understanding as the ratio of the mean to the standard deviation will of the retinal circuitry and its development beyond the increase with the square root of the mean. another possibility is that there are probably the availability of more photons ideally leads to an improve. Because the variance in the number of observed values for these measures are worse than would be photons emitted from a source or reflected from a surface is predicted from a visual system with the optical and retinal proportional to the mean number of photons emitted or characteristics included in these models. guide and shape this remodeling of ganglion cell dendritic there is also clear evidence that intrinsic neural activity in processes during postanatal development (Stacy and Wong. Although an obvious reflected (Poisson process). Figure 9.. of the direction of motion in mouse vision. sensitivity).

1992). 1999. These streams are evident in distinct classes superior colliculus (SC). as noted earlier. The magnocellular or parietal-directed stream is iliescu and dannemiller: brain-behavior relationships in early visual development 131 . several models discussion of these pathways as they exist in mature primates advance the hypothesis that the differential maturation of can be found in Rodiek (1998).1 Schematic representation of the visual pathway with inset reproduced from Grinvald et al.g. with kind permission emphasis on the functional organization of the dorsal lateral genic. are segregated in layers within terminate primarily in the superficial layers of the superior the LGN (four parvocellular and two magnocellular layers. LGN. upper insert). There are also parvocellular stream.) ulate nucleus (upper insert) and of the primary visual cortex. as they while the magnocellular stream projects to layer 4Cα. projects mainly to layer 4Cβ. This are relevant to the issues that we have raised.. parallel and quasi-independent streams of processing: par. 1988). 1987. and project to distinct layers with pathway runs from the retina to the lateral geniculate nucleus the recipient zone of layer 4C of primary visual cortex. cells in the primate retina. vocellular streams persists to some extent into other cortical Maunsell and Newsome. The major cortical figure 9. The division of this pathway into magnocellular and par- vocellular and magnocellular (Livingstone and Hubel.1. The (LGN) to area V1 of visual cortex (VC). A good general division is important because. The axons of retinal ganglion cells of ganglion cells in the retina. cortical layers explains corresponding differences in certain The retinocortical pathway is thought to consist of two aspects of visual performance. (Lower pathway involves direct projections from the retina to the Felleman. Van Essen. We will discuss selective aspects of these pathways. pulvinar) that are not shown here. of Springer Science and Business Media. colliculus (Kaas and Huerta.. SC. 1988. postulated to subserve mainly color numerous descending pathways from VC to subcortical and form vision and comprising 80 percent of all ganglion structures (e. Anderson.Figure 9. and areas.

by to the superior colliculus and to the LGN. parvocellular. P. There are also extensive permission. Notice the retinal projections both is not discussed in this chapter. The K (koniocellular) pathway magnocellular.) reciprocal connections between various extrastriate cortical areas 132 fundamentals of developmental neurobiology . (From Casagrande. 1994. and the pulvinar not shown here. frontal frontal ITp ITr VPP IT ITc MST FSTd DLr FSTv DLc DM MT MT CO Inter CO V2 (area 18) V1 (area 17) SC K M P LGN retina Figure 9.2 Various subcortical and cortical visual pathways: M.

They of the columns mapping the deprived and the nondeprived showed that closing one eye during a critical period in eyes. the is evidence for cross talk between these two streams. geniculate nucleus (LGN) and of the primary visual cortex the role of this activity in constructing some receptive field is the presence of a highly organized structure. there In the case of the ocular dominance (OD) columns. it looks as though the segregation postnatal life rendered that eye permanently incapable of of the OD column in layer 4 is driven mostly by molecular driving cortical cells (Wiesel and Hubel. and terminate at different ages (figure tal data suggest that the initial formation of the OD columns 9. tivity. pro. However. MT. exist showing that electrical activity is essential in maintain- ganization of the brain due to the lack of input from one ing these columns (Chapman. Wiesel. that of cortical areas and connections. (Nassi. This is a good example of neural two primary streams does not imply complete independence structure being formed by spontaneous activity rather than between the processing of information within these streams evoked activity. The development of these structures is a good the visual cortex.associated with areas V3. Electrophysiological data in neonatal kitten place to examine the roles that intrinsic (e. The result was that. normal cerebral circuitry are laid from the two eyes.g.. these processes start at different postnatal ages. 1965). The LGN properties has yet to be challenged. Wiesel.3A). maintenance in development as noted by Gottlieb (1976). More impor.. 1978). The same investigators (2000) also showed ity has a profound impact on the normal development of that changing the balance between retinal inputs through the visual system connectivity has its roots in the pioneering unilateral enucleation had no significant effect on the sizes deprivation studies of Hubel. The latest relevant research shows that although the is not influenced at all by the balance between the inputs foundations of a healthy. 2006). neighboring corticothalamic feedback was intact. These findings call to eye (Hubel. while the visual cortex Katz (1999) in particular makes a strong case for a causal presents ocular dominance columns—collections of neurons relation between spontaneous correlated activity from the driven more strongly by the input from one eye than from LGN and the early appearance of orientation selectivity in the other. Although the instruct- area innervated by that eye and by a significant increase ing influence of spontaneous electrical activity on the forma- in the cortical territory allocated to the geniculocortical tion of cortical columns is questionable. sequent results have shown that retinal activity is very tantly. 2002). with these preferences mostly concentrated defining the final form of cortical and subcortical visual around the cardinal axes (Fregnac and Imbert. 2003) following the Hebbian parietal areas. and posterior 2002. It has been suggested that this within. In other words. Chronic stimulation with synchronous electrical activ- eye correlated retinogeniculate activity and the uncorrelated ity (through a nerve cuff implanted postnatally on one of the activity between the two eyes will lead to the laminar seg. The parvocellular or temporal-directed postulate that coactive inputs are preferentially stabilized stream is associated with areas V4 and inferotemporal relative to temporally uncorrelated inputs (“cells that fire cortex. although the role of spontaneous activity from the was accompanied by a marked reduction in the cortical LGN cannot be completely excluded. evoked activity of neural circuits and showed the presence of OD columns in ferrets that were certain biochemical transformations that take place after enucleated at birth. in spatial cortical periodicity. and Callaway. and LeVay. Lyon. Weliky areas. and Chapman. Although thinking about the role of neural activity in zation of visual cortex? The mark of the adult lateral forming OD columns has undergone recent serious revision. Experimen- gress at different rates. these waves occur independently in the two eyes (in Significant binocular correlations were present only when contrast to evoked activity). mind the important distinction between induction and 1978). the other eye being enucleated) disrupted regation of the LGN (Huberman. optical nerves.g. and later Shatz. initial view was that visual stimulation was needed to form Many of the visual processes that are important in the these columns in the primary visual cortex. Stellwagen. 1977. The idea that neuronal activ. tantly. Based on these data. Even in area V1. convincing data axons serving the nondeprived eye—that is. iliescu and dannemiller: brain-behavior relationships in early visual development 133 . This effect cues. Impor. unlikely to be the cause of OD band formation. the spontaneous retinogeniculate drive. Shatz and Stryker. 2000). normal animals. The work of Weliky and is segregated into eye-specific layers. sub- mature brain only begin to appear postnatally. What factors are responsible for this postnatal reorgani. Huberman et al. and MST. genetic) factors cortex suggest that some neurons have a weak orientation and extrinsic factors (e. The work of Crowley and Katz (1999) down before birth. with a frequency similar to that of spontaneous retinal waves. Consider the fact that the retina of infant ferrets is and Katz (1999) showed that synchronous bursts of sponta- swept every minute by spatiotemporal waves of intrinsically neous activity occur in the LGN of ferrets before eye opening generated neural activity (Katz and Crowley. a massive reor. The OD structure in these animals birth ensure the formation of highly specialized and essential closely resembled. specific sensorial inputs) play in preference. It is important to keep in mind that this division into together wire together”). Weliky and Katz (1999) cells in one retina will fire at nearly the same time.. but also showed that disruption of these natural input patterns the firing of corresponding ganglion cells in the two retinas results in the degradation of early cortical orientation selec- will be uncorrelated.

that is. by axis) plotted against postnatal age (x-axis). that is. (Reprinted from Staley and Smith.) (B.Figure 9.3 (A) Time line illustrating many of the main events sufficient to cause GABAA reversal potential to be either below or during the development of the visual cortex and its connections above the resting membrane potential or the threshold for action with the thalamus in ferrets. concentrations.) 134 fundamentals of developmental neurobiology . 2002. acting as an inhibitory or excitatory 2001. messenger. C) Devel. a small change in the ion concentration is 1993. plotted with open symbols. time-lagged correlation between this the reversal potential. (Reprinted from Sur and Leamey. Synaptic density is permission from Macmillan Publishers Ltd. by permission. The curve is very steep at physiological anatomical measure and this functional measure. by permission from Macmillan Publishers Ltd. (Reprinted from Ben-Ari. There is a close.) (D) Cortical synaptic density (left than adult neurons. potential generation. (From Wilson. (B) The electrochemical equilibrium potential y-axis) and the percentage of infants displaying stereopsis (right y- for Cl− decreases with age. by permission oping neurons have a higher concentration of intracellular chloride from Macmillan Publishers Ltd. and stereopsis is plotted with closed tion relates the transmembrane chloride concentration gradient to symbols.) (C) The Nerst equa. 2001.

Furthermore. with inhibitory GABA but one example of the complexity confronting our under. epilepsy or a rearrangement of the excitatory-inhibitory balance to a Tourette’s syndrome). 2001). receptor channel) this shift changes the GABA-related stim- These uniform waves of spontaneous activity. Gamma-aminobutyric acid (GABA)... Pallas.3B). Trombley. to beetles. a concentration sufficient to change the action activity) plays a significant role in defining the shape and the of GABA from being inhibitory to excitatory (in adult organization of the future mature brain. von a universal developmental signal throughout nervous system Melchner. are polarizing signal (i. cortex. Intimately related to the intracellular property that appears to depend both on intrinsic and extrin. and Drosophila.. possibly making this higher Cl− concentration most direct evidence comes from the work of Sharma.although the macroscopic aspects of the orientation prefer.g. 2000). These potentials gen. iliescu and dannemiller: brain-behavior relationships in early visual development 135 . see figure 9.. of GABA. Chen. neurons even though the orientation map is less orderly. An addi- difference between immature and adult neurons: The con. and other areas) that GABA ence maps in the visual cortex apparently were not very produces depolarization and an increase in intracellular different than in the normal case. 2000). The signature ask whether these animal models of visual cortical develop- electrical activity of developing circuits is the presence of ment are also valid for the development of the human brain. 2005). We Additional evidence shows that the marked difference in have reviewed several of the intrinsic mechanisms that are GABA activity in infancy and adulthood is due to yet another important in the development of the visual system. 1995. 2005) showed that the mature expression erate large oscillations of intracellular calcium and lead to of the gene responsible for the formation of the GABA- an activity-dependent modulation of neural growth and the producing enzyme and the conversion of GABA receptors formation of synapses. von structures. it is reasonable to one finds at very early stages in development. In the mammalian neurons show orientation tuning comparable to that of V1 brain it has been shown in a variety of systems (spinal cord.. plays an network occurs slowly. present ulation from being a depolarizing signal to being a hyper- throughout the brain as a mark of developing networks. orientation selectivity was calcium levels in the immature but not in the adult brain. Owens et al. played by the balance between excitation and inhibition that Considering the focus of this chapter. and Sur. rerouting retinal projections into the auditory pathway GABA or its phylogenetic homologues have been described makes the neurons in what should be the primary auditory throughout the animal and vegetable kingdoms (from toma. These studies look neurons the intracellular chloride concentration is around at the development of cerebral circuitry and resultant func- 7 mM. Some of the Kocsis. then is an example of a visual (Ganguly et al. e. and Sur (Sharma. who showed in ferrets that well conserved developmental signal phylogenetically. 1996. ances can lead to pathologic conditions. (Murphy et al. is the main inhibitory neurotransmitter in the adult brain. when light stimuli were presented in the Van Den Pol. Black. process that involves both intrinsic and extrinsic factors. it is also interesting to note that it is probably tive role in the formation of orientation selectivity within GABA itself that promotes the developmental switch of neu- the neuronal population of V1 (Sengspiel. tional line of evidence offers striking support for the comple- centration of the Cl− ion is higher in immature neurons with mentary idea that sensory experience itself (evoked neuronal about 25 mM. hippocampus. hypothalamus. to nized into orientation modules (a mark of visual cortex). and Furthermore.3C). 2001). Stawinsky. 1995. Given this important developmental change in the action tional evidence shows that visual experience plays an instruc. Leinekugel et al. Cl− concentration (the main ion conducted by the GABA sic neural activity to achieve its mature form. retinal scotomas in adulthood produce. GABA exerts an excitatory effect and more immature state (Arckens et al. 1999). The cortex becomes orga- toes. Pizzorusso. 2000). 1999. lower at both the population and single-cell levels. as noted. Wegerhoff. Another example can be found in the role figure 9. 1996. Angelucci. Reichling et al. Addi. 1999).. Additionally.e. Lee and O’Dowd. 1992). particular injuries like brain lesions or responsible for optimal information processing (any imbal. and that normally process different modalities. portion of the visual field seen by the “auditory” cortex. Here. it amblyopia in humans (Berardi. generates significant trophic effects early in development The development of the brain function is a very dynamic (Owens et al. 2000.. Hensh. cortex respond to visual stimuli.. probably playing a very important role in the mature standing of the relations between brain and behavior during brain’s ability to adapt dynamically to evoked activity (see development. over several years—a fact that is important role in the generation of the excitatory GDPs consistent with the extended length of the critical period for (Ben-Ari. Gallego et al. Although. giant depolarizing potentials (GDPs) (for a comprehensive Recent evidence from postmortem samples of postnatal V1 review please refer to Ben-Ari. 1994. Comparative research shows that GABA is a very Melchner.. to a state compatible with driving plastic changes within a an inhibitory neurotransmitter in the adult brain. inhibitory). and ronal GABAergic responses from excitatory to inhibitory Bonhoeffer. and Maffei. and Sur. 2002) early in development.. there are data that tion in animals that have the afferents that carry information suggest that the same thing is true for the astrocytes of the about one sensory modality redirected to cerebral targets developing but not adult optic nerve (Sakatani. among other effects. 1996.

For example. it is best to However. Erickson it is difficult if not impossible at this point in our understand. months of age. processing. Additionally. Although the postnatal increase in tagmus (OKN). 1984. 1990).. What visual capacities might we expect Several other investigators have proposed models of early to be present when only subcortical structures are mediating visual development that involve cortical brain-behavior vision or when vision is mediated by pathways other than relationships (Atkinson. 1998) proposals that the parvocellular lesions or without primary visual cortices. 1992. this work provides a gence of certain aspects of visual attention and motion clear if somewhat artificial example of how the final organi. thereby leading on several visual capacities present in unilaterally decorticate to the earlier emergence of certain visual functions typically human infants. While it is tomical data showing differential maturation of the laminae undoubtedly true that intrinsic factors play a large role in in primary visual cortex to argue for the differential emer- setting up the initial circuitry in cortex. Atkinson. theme common to these models is that early visual devel. zation and function of a section of cortex depends critically Bronson (1974) first proposed that early in postnatal life on the incoming. although the substrate for this is surely set up in the visual system (see figure 9. tion of visual cortex. pathway may lead the magnocellular pathway in matura. color vision is typically opment may be characterized by differential rates of matu. We turn next to the enterprise of trying to construct models Atkinson (1984) echoed this proposal that much of the of behavioral development during infancy from what is observed visual behavior in the first month is controlled known about the anatomical and physiological development subcortically and added the additional postulate that the of the visual pathways beyond the retina. Figure 9.g.. much of the visual capacity of the neonate could be explained by supposing that the subcortical pathway from Cortically motivated developmental brain–behavior models retina to superior colliculus matured or was functional earlier than the cortical pathway from retina to visual cortex. Banton and the ones through primary visual cortex? Several reports exist Bertenthal. binocu- as reported by Huttenlocher and associates (1983. it is important when examining these models to be content with the apparent correlation between the brain determine just what vision is like with and without the opera- and behavioral measures. binocular rivalry. thalamus. et al. This report is important. midbrain–brain stem) were probably more functionally relation between stereopsis development and the increase in mature than various cortical areas (e. 1974. 1998. so it is synaptic density to a measure like stereoacuity.“rewired” animals responded as though they perceived the (1990) and Banton and Bertenthal (1997) have used ana- stimuli as being visual rather than auditory. leading to changes around two months in model. Of course. reflects the function of this structure.g. temporal prior to frontal.g. synaptic density over the first year of life.4 natural to suppose that the visual orienting in newborns. 1974. Aspects of visual behavior such as orienting ing of cortical circuitry to relate quantitatively a measure like probably depend heavily on the superior colliculus. One good example descending pathways from visual cortex to superior collicu- of such a model was proposed by Wilson (1993).g. 1997. Finally.. this and temporal). Wilson attempted to relate cortical synaptic density certain visual capacities (e.3D shows that there is a time-lagged but close cor. it is fields. All that one can do at alone may mediate much of the visual behavior observed in this point is to agree with Wilson (1993) that until adequate the neonatal period. 1998). 1987) to the development of Using resting positron emission tomography (PET). Stoerig and Cowey of subcortical function than of cortical function (e. and the disappearance of these asymmetries later in another matter to try to relate this increase quantitatively to the first half year of life imply that the superior colliculus some aspect of visual performance. see also lar convergence). thought to involve cortical processing within the parvocel- ration both within subpathways and between subpathways lular stream. a reflexive visual tracking of large moving dendritic complexity is evident even to the naked eye. shows Conel’s (1939. Different cortical areas might also mature correlation cannot be interpreted causally.2).. In this lus mature later. attentional switching. Huttenlocher and de Courten. (1992) and Barbur and associates (1998) reported color dis- Bronson. The most common initially within the color opponent ganglion cells of the example of this type of model involves earlier maturation retina.g.. cortex from a newborn human infant (left) and a six-month. Additionally. Johnson. early postnatal asymmetries in optokinetic nys- old human infant (right). 1951) renderings of sections of visual however sluggish. Johnson of striate visual cortex does not necessarily imply that all 136 fundamentals of developmental neurobiology . This theme is also evident crimination in individuals with significant primary cortical in Atkinson’s (1992.. Bronson. One that are relevant to this question (see Stoerig and Cowey. models of functions like stereopsis are available. Despite this cortical involvement. Figure 9. parietal. 1997.g. 1984). occipital. mainly because earlier than others (e. Braddick and associates (1992) have reported tion during early postnatal development. various functions most likely to be mediated cortically (e. stimulus-evoked afferent activity. various subcortical areas (e. Chugani and Phelps (1986) concluded that prior to three orientation selectivity. for a review). because the absence attributed to the parvocellular pathway. and stereopsis)..

1951 [right] by permission. 1939 [left] and Conel.) iliescu and dannemiller: brain-behavior relationships in early visual development 137 . (From Conel.Figure 9.4 Striate cortex from a newborn (left) and a 6-month-old (right) human infant.

. were said to be able to recognize familiar adults. true evidence cortical pathways. and Chugani. We will use Atkinson’s (1992. although Atkinson’s model (1992. by this model is primarily pattern vision (e. This possibility is significant. several of these children cortex. 1998) model as an example because even in the newborn infant OKN is binocularly of the theme of explaining early visual development by symmetric. This observation implies that contrary to earlier of striate cortex from deeper to more superficial layers ideas that cortical involvement need not be invoked to may explain various aspects of the development of motion explain symmetric binocular OKN. however. Additionally.g. Banton and Bertenthal (1997) also proposed that cal pathways. Finally. few weeks of life to discriminate the orientations of grating 1997. Johnson’s (1990) model is meant to explain were missing. 1988) and the temporal-frequency Byrne (1999) propose is that subcortical structures may be dependency shown by evoked responses to orientation “vertically” plastic and organize prenatally or reorganize to changes are evidence of the early maturation of the parvo- take over supposedly cortical functions in the absence of cellular pathway (Braddick et al. Holmes. orientation ates (1992). 1991). Cohen et al..visual function is then mediated subcortically. 1986) because this function target occipital cortex (see also Kalil and Behan. and in one cal evidence on the maturation of various areas in visual case fixate steadily. What Shewmon. and Byrne (1999) reported clinical modern visual neurophysiology with its major division of observations on multiple functions in four congenitally visual processing into parvocellular and magnocellular decorticate children. Chugani. Nonetheless. which is evident various visual capacities. however. Additionally. Atkinson (1992. posed that descending pathways from striate and extrastriate edly. Shewmon. and Yoshioka. moving objects such as faces. both striate and extrastriate cortex sensitivity). visually orient development as well as the anatomical and neurophysiologi- to objects moved into the peripheral visual field. pointing to differential maturation of subpathways. Somewhat unexpect. it is (but see also Levitt.. and Byrne (1999) proposed the province of the magnocellular (dorsal) stream. and Wandell. 1998) has pro. In the two cases reported in Braddick and associ. it is possible in postnatal development than the magnocellular pathway. binocularly symmetric OKN. well before 6–8 postnatal weeks. of direction-selective responding does not emerge until The remaining models of visual development have all after 6–8 weeks of age. All these children were assumed to be cortically the parvocellular (ventral) stream while others are the blind. It is these streams (the binding problem) so that the infant even- generally accepted that “horizontal” plasticity between dif. infer the state of various cortical areas.. ment may indeed be necessary. in the visual system as explanations for the emergence of Thus. 1996. that projections to extrastriate visual cortex could also be The behavioral evidence that is meant to be explained involved.. Holmes. 1987). this magnocellular char- posed that the parvocellular pathway is more mature early acteristic—directional selectivity—is not evident until near 138 fundamentals of developmental neurobiology . and patterns (Atkinson et al. which had cortex to superior colliculus mature at different rates. 1998) relies heavily on the idea such recognition probably occurred through other sensory that certain aspects of visual processing are the province of modalities. motion processing that is selective for capacities are. Lund. Excluding OKN. 1996). This representation is disrupted and its function is taken over or usurped by serves the purposes of object recognition and action. This One other recent report is relevant to the question of what model is a good example of using behavioral evidence to vision might be like in the absence of striate visual cortex. This model affords a good oppor- that some of these children could actively track. son argues that the ability of very young infants in the first 1999. and it is evident at slow velocities proposed differential maturation of specific subpathways before it is evident at faster ones (Wattam-Bell. unlike orientation discrimination. observations such as these are direction is supposed to be handled primarily by the valuable in giving some insight into what vision is like without magnocellular pathway. Johnson pro- subserved by the superior colliculus. been thought previously to be mediated by crossed subcorti. interesting idea that some of these visual capacities might development in this model consists of integration across represent “vertical” plasticity in subcortical structures. Holmes. Muller. Until is subserved primarily by parvocellular neurons in adults more systematic visual tests are done on such children. difficult to say precisely how good these remaining visual In contrast.2). Sadato et al. Morland. Atkin- remaining cortical tissue (Baseler. tually comes to have a complete representation of objects in ferent cortical areas may take place when tissue in one area the world and of their spatial positions. 1951) that the primary orient to a conspicuous target presented to the contralesional visual cortex matures from deeper (levels 5 and 6) to more visual field as would be expected if such a function were superficial layers (layers 1–3). albeit not tunity to review the behavioral evidence on early visual very smoothly. Additionally. 1996). Of particular relevance are their reports streams (see figure 9. was found to be asymmetric in both these differential postnatal maturation of the laminar structure infants. so subcortical pathways must have mediated primarily orienting and attentional behavior based on ana- the remaining visual capacities. As such it relies on Shewmon. such cortical involve. These infants could visually tomical data from Conel (1939. processing.

Lund. and Teller. Depth to support effective function before those receiving projec- processing is thought to be handled by the magnocellular tions for more superficial laminae.g. sibly even neonates and 4-week-olds (Adams. 1980. may be expected to respond to translatory motion. The same was also true of Type II inhibitory synapses The retinal ganglion cells that make up these two streams in layer 4C with those in the magnocellular recipient layer diverge early in embryonic development in the primate developing slightly ahead of those in the parvocellular layer visual system. large pyramidal neurons in layer 5 tended to mature when slices of future visual cortex and LGN are cocultured earlier than smaller neurons in other laminae. lar). The projections from relay neurons opment of excitatory synapses in the same laminae (Lund in LGN arrive at their targets in layer 4C in striate cortex and Harper.the end of the second month. area MT) might be expected (Birch.. Lund.. magnocellular neurons anatomical data to make inferences about the presence of a appear to be slightly ahead of parvocellular neurons. Boothe. visual cortical neurons occurs at the same rate in all laminae 1996. Once again. 1982. and the axons terminate in appropriate sublami.. 1997). As noted previously. 1991). again before any visual experience is attained 5 than in layer 3 in visual cortex prenatally and during early (Mates and Lund. 1997). 1984) and pos.. 1987). Atkinson (1998) concludes tenthal. Lund and processed primarily by the parvocellular pathway (although Holbach (1991) showed that the development of Type I see Barbur et al. maturation of the morphology of 1998. It is evident in vitro (Toyama et al. functions attributed dendritic spines that are associated with synaptic contacts mainly to the magnocellular stream (disparity. 8-week-olds (Hamer. 1987) can detect pattern in striate cortex. 1998). depth) appear reaches a peak in macaque monkeys approximately five to emerge slightly later than one attributed to the parvocel. physiological studies on humans or closely related species? 1991). 1986. Fox et al. weeks postnatally for neurons in lamina 4Cα (magnocellu- lular stream (color). particular function is that it is not clear exactly which characteristics should be used to infer effective function. As others have noted (e. Katz and Shatz. whereas a similar peak is not reached for neurons in What do we know about the differential emergence of lamina 4Cβ until eight weeks postnatally (see also LeVay. Shatz.g. and If one examines other markers of anatomical development Davis. we agree with Banton and Bertenthal (1997) its postnatal maturation. ate earlier than those in more superficial laminae. feature maps superficial layers until densities stabilize several months after (e. Packer.2 from this brief review that whether or not there is a notice- Anatomical data on the development of visual cortical able advance in the maturation of parvocellular versus areas from humans and closely related primates present a magnocellular neurons or by laminar layer depends on what mixed picture on whether or not one of the two processing aspect of cortical or neuronal morphology is being consid- streams is ahead of the other in terms of its state at birth and ered. differential gradients of maturation are differences based on color alone. or one could examine synaptic connectivity and Most of the models based on cortical development that we morphology for clues to when a particular region appears to have discussed argue that the order of emergence of certain be functional. One of the problems in using the that on many of these characteristics. In contrast. Becker and associates (1984) showed that prenatally. ocular dominance columns) birth (Leuba and Garey. and for Banton and Bertenthal’s (1997) proposal that newborns Teller.. For example. in humans. and color is thought to be either not as clear or are conflicting. Godecke and Bonhoeffer. the laminar structure of visual with perhaps some advantage based on the size of the cortex and its reciprocal connections with LGN even develop neuron. and Lund (1977) concluded that pathway prior to extrinsic. and Held. Hartmann. Maurer. orientation preferences. 1996. 1982. 1980). Subtleties of the differential maturation hypothesis One could examine myelination as a marker for effective function.. Alexander. these two processing streams from anatomical and neuro. it appears that LGN postnatal development—a trend consistent with the myelin- neurons may also project to layer 6 of striate cortex before ation from deeper to more superficial laminae. 1983).. 1976. 1991). visual functions in early postnatal development reflects the iliescu and dannemiller: brain-behavior relationships in early visual development 139 . Banton and Ber. Conel (1939) pointed out that axons in the that magnocellular function lags parvocellular function early deeper laminae (5 and 6) of striate cortex appear to myelin- in development. Thus Disparity sensitivity and binocular correlation detection extrastriate areas receiving projections from neurons in do not emerge until approximately 3–4 months postnatally striate laminae 5 and 6 (e. 1977). visual experience (Hubener. This reasoning is the basis pathway. However. and appropriate projections in the retinogeniculocortical Finally. in macaque monkeys. Wiesel. and Chung.g. intrinsic densities in human striate visual cortex also appear to follow activity during prenatal development probably plays a major the gradient noted earlier with deeper layers preceding more role in organizing the laminar characteristics. Initially. Maurer and Adams. and they project to the appropriate laminae (Lund and Harper. 1991). Indeed. Gwiazda. 1996). It is also interesting to note that in the developing LGN well before any visual experience these presumed inhibitory synapses in layer 4C lag the devel- (Meissirel et al. Neuronal birth (Rakic. and Hubel. dendritic branching was more advanced in layer nae within 4C. Holbach.

in the first year do the contrast sensitivities of the magnocel- and Lund. Maunsell. 1987. Lia. showing that both magnocellular and parvocellular influ. lular pathway may mediate detection of both luminance and This argument is similar to Johnson’s and Vecera’s (1996) chromatic spatiotemporal contrast. Thus the extent of cortical indicates less independence of these subpathways than may versus subcortical mediation for a given task early in devel- be indicated in some of the models discussed earlier. 1994. and Lia (1999) the subsystems may not show the degree of stimulus separa- have argued from psychophysical tests of chromatic and tion early in life that is characteristic of the mature visual luminance temporal-contrast sensitivity that the magnocel. for a similar magnocellular processing.differential maturation of subpathways in the visual system. A corollary to this point is that early channel and luminance contrast is signaled by a temporally in postnatal development there may be transient connec- band-pass magnocellular channel. Pimm- expected to fall to the parvocellular system. Nealey. direction of motion. from the parvocellular neurons that showed little improve- 2. then it would differ substantially from the case later of visual information processing into subsystems only occurs in development in which chromatic contrast sensitivity is postnatally with many of these subsystems operating initially signaled primarily by a temporally low-pass parvocellular after birth unsegregated. be surprising that the most sensitive pathway for mediat- 1. 1988. If the hypothesis of differential rates of matura- regarding explicitly developmental brain–behavior relations in tion of subpathways is taken seriously. If this assumption were “cortical parcellation” hypothesis in which the segregation true. so this result Smith. but Morton and Johnson (1991) have proposed that face somewhat neglected. In all between excitatory and inhibitory neurons in a given cortical these cases. For example. A particular visual function that is ascribed to one subsystem in ment in peak luminance-contrast sensitivity over 8 months. process visual information. patterns defined opment (Huntley et al. opment may differ substantially from that seen in mature furtner and Kiper (1996) showed that as early as cortical adults. a visual function typically attributed to one area). Lund. 1997. Hawken. Dobkins. the mature adult may not necessarily be mediated by that subsystem It may prove very difficult to attribute processing early in when it first emerges in development. neurons were multiply selective for form. ence on visual development. 1996. For example. 1994). is the emergence of cortical structure processing. Levitt. Gegen. 1999. system. 1991. temporal cortical pathway. 1994). motion. by color contrast alone or patterns defined by luminance 1994). level or subpathway within the mature visual system may We will conclude with several subtleties and implicit emerge first in development being mediated by a different assumptions that can arise when models are formulated subsystem. and argued that there is no functional segregation when they first emerge there may be considerable overlap in how they of these stimulus features at this level of the visual pathway. and Yoshioka. This situation contrasts strongly with evoked activity combine to determine the precise develop. Anderson. Lund and Yoshioka. spatial cal studies showing interneurons as early as cortical areas V1 contrast sensitivity functions of magnocellular and parvocel- and V2 that merge the parvocellular and magnocellular lular neurons overlap quite substantially at birth. Levitt. For example. may first emerge during the tions (e. There is even evidence from the other end of the life 140 fundamentals of developmental neurobiology . The degree of independence of the visual subpathways involved ing detection of some stimulus feature early in development in these models may not be as great as postulated. Blakemore. lular neurons improve substantially enough to separate them Yoshioka. Dobkins and Teller (1996) tions between cortical regions that disappear later in devel- concluded that for 3-month-old infants. ences to signal the directions of motion. thought to be the paradigm case for hood (see also Banton and Bertenthal. it is clear that intrinsic factors and extrinsic. and Morley (1997) showed that in the monkey LGN. Perhaps as important. These neurophysiological studies are supported by anatomi. Only later streams (Levitt. Rodman and Consuelos. and Worden.. contrast are both detected by mechanisms sensitive to the As noted earlier. but been paid over the years to the effects of postnatal experi. Even if subpathways are quasi-independent in mature adults. A great deal of attention has nance contrast are selective for direction of motion. area V2. Yoshioka. color. the case in adults in which mechanisms sensitive to lumi- ment of the visual pathways. then it should not vision. Schneider.. a function typically attributed to the ventral/ determined by intrinsic factors with very precise timing rela. Differences in effort or automaticity have been shown in ences can be detected in the responses of area-MT neurons. adults to be related to differential activation of cortical versus Color processing by a strict division of labor would be subcortical areas (Alexander et al.. Lund. suggestion). those mediating detection of color contrast are not. and 3.g. are capable of using color differ. A corollary to this point is that infants and adults almost and DePriest (1990) had reported similar results earlier certainly differ in the effort required to execute visual tasks. and Lund. development to one subsystem or another simply because and Teller (1997) and Dobkins. may not necessarily be the same pathway that mediates Dobkins and Albright (1994) showed that neurons in area detection of that feature later in childhood or in adult- MT of the macaque. triggering a sensitive period by the precise balance newborn period mediated by subcortical structures.

We will not discuss the phenomenon of aliasing that occurs in in the absence of input/output from primary visual cortex. Hendrickson. C.. Hainline.span that the two major processing streams may become less eye movements—a result that is not found in adults. Eye 6:129–135. D. glutamate and activity levels: The missing allow the magnocellular stream to process chromatic bound. Cooperative movements may produce enough spatiotemporal contrast to changes in GABA. Van Horn. G. Morland. shaping cortical function. I. D. Differential maturation of laminae within 2. process information in ways that are not characteristic of the Schapiro. Our modeling should respect the thal. Hum. For example. T. M. This possibility makes it very difficult to try to our lack of understanding of complex cortical circuitry and link the anatomical and neurophysiological data and the of how various visual functions arise from such circuits behavioral data. Science 217:265–267. F. or scanning eye Vandesande. 3:61– 1998). Furey. and Cheney (1987) for an example and a discussion of A similar suggestion was made by Baseler. Human visual development over the first 6 months of life: A review and a hypothesis. Maurer. Unlike distinct with age (Grady et al. but only in a 6-month-old human. Banton and Berten. and Blakemore (1998) suggested that a NOTES subcortical pathway from superior colliculus through the inferior pulvinar to area MT may mediate such capacities 1. M. Gordon. Horton and Hocking (1996) primary visual cortex early in postnatal development would reported the presence of clearly defined ocular dominance only be expected to impose an order on the emergence of columns in newborn macaque monkeys. Davis. Wandell (1999). Atkinson. Child Psychol. Y. nor is it necessarily like infant. 1997. Neurobiol. Early visual development: Differential function- when isoluminant chromatic stimuli are used to drive the ing of parvocellular and magnocellular pathways.. in postnatal development may signal chromatic contrast to Arckens. D.. 1990) which propose that gradients of matura. J. E. G. Pow. Grady. “Bottleneck” developmental theories (e. J. One note of caution is in order. undersampled systems. Adams. not eliminated. L. Benson. Nonetheless. LaBossiere. striate cortical areas and inhibitory interactions within and 5. (V1) visual cortex and its subsequent input to area MT. J. M.. S. U. a much greater extent than in the adult. an adult visual system that has been scaled down in terms and E. Qu. L. Wouters. Individual differences in adult visual system. Neurosci. J. cally associated with cortical area MT (direction discrimina- tion. and spatial aliasing in vision. J. 1986. Guo. between these areas. B. simply been deleted. Chino and associates (1997) makes it inherently more difficult to link brain and behavior demonstrated that binocular. disparity-sensitive neurons when the brain side of the link is visual cortex. It should also be informed by the consider- alternative pathways to extrastriate cortex that do not go through striate able cortical structure and connections present prior to the cortex. For example. Exp. Thus the magnocellular pathway early PET activation of object perception and attention systems predict face matching accuracy. L. Epelbaum and Teller (1995) showed that asymme. Eur. 74. It is entirely possible that prior to the 41:267–281. although Horton and visual capacities if these alternative routes from subcortex Hedley-Whyte (1984) did not observe these columns in new- borns. Guo. Johnson. The retina of the newborn human of spatial and temporal processing. and coherent acknowledgment This research was supported by grant motion in random dot displays) remain after loss of primary NICHD R01 HD32927 to JLD. Possible species differ- to extrastriate cortex were immature or if these extrastriate ences should always be kept in mind when generalizing from areas themselves were also immature. Dobson. point at which these subpathways are segregated and subse. Atkinson.. Alexander. Berman. Moeller. monkeys to humans. additional.. J. 1982. 1992). V. R. Benson. Orban. and M. L. Rapoport. Newborns’ discrimi- an adult visual system in which some subpathways have nation of chromatic from achromatic stimuli. 2000. 1984. quently integrated in a mature fashion they may interact and K. There may be significant temporal lags between the emergence in which the brain–behavior relationships can be modeled of a given function at the single-unit level and behavioral evidence for based on well-understood physical and optical principles. models based on photoreceptor morphology and geometry 4. Schweigart. J. tries in OKN in 2-month-olds are reversed. iliescu and dannemiller: brain-behavior relationships in early visual development 141 . 1999.. exist at or near birth in macaque area V1. that function. A. R. V.g. and G. 12:4222–4232. Eysel. NeuroReport 10:1965–1971. although it is much of the interesting development that occurs postnatally not for several weeks that stereopsis can be demonstrated in the visual system undoubtedly involves striate and extra- behaviorally. aries to the point at which discrimination is possible (Teller. A. 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and walking independently. one finds the involvement of some form of practice that an individual needs to learn about control of motor action almost invariably in every activity. 1982). and even sleeping entail these early actions may constitute the core of higher order movement. the early a human being. planning. implicit effects in the development of cognitive skills. 1995) cognitive and motor-emotional domains. 1991). (consequences of action). so the infant could see it (van de Meer. emergent cal movement. memory. Most textbooks include a small “Motor development is not just a question of gaining control section or a chapter outlining the stereotyped sequence of over the muscles. in order to keep the arm in view (van de Meer et al. The pro. but also generates perceptual information by from bodily actions in the real world. When the motor system of an individual fails.. walking. and how children (or even infants) anticipate crawling. we will present a theoretical approach movements are never just reflexes. Moreover. 1997). von Hofsten. equally important are questions such as expected gross and fine motor accomplishments of a child. that is. posals claim that cognition is embodied. gross motor milestones include rolling over. 1952) and dynamic sys- of development. these actions have been shown to the acquisition of skilled motor behavior. dancing. where newborns and infants modified their spontaneous arm speed. we wish consequences are critical to understanding the emergence of to accomplish five major objectives. means to learn about anticipation. when the location of the light Relevance of movement in the developing human being beam was moved. and sequencing. 1999. ity) and selection (stability) of motor actions coexist to allow gaze. Furthermore. An example substrates related to the development and control of posture of such flexibility can be found in studies by van de Meer and the different aspects of movement such as initiation. and motor consequences has of the fingers and the maintenance of good postural control. having implications for attention. First. cognitive development. we will summarize the neural Rochat and Hespos. In fact. motor behavior has received little attention in consequences of action. Thelen tion. therefore. why a particular movement is made. eating. lips. typing on a computer requires the action planning. Third.10 Motor Systems Development ROSA M. delays. Farroni et al. are planned. Fifth. memory. Second. we stress the skilled motor behavior. Haith. 147 . 1997. He proposes that actions are funda- importance of the motor systems in the wholeness of child mentally different from reflexes and that even newborns’ development. motor memory. not only during early way of the proprioceptive systems. Thelen and Bates. and it also constitutes a development but also throughout the entire life span (Thelen. The what is going to happen next” (266). we will be flexibly controlled and adaptive depending on the context expose and delineate the differences between postural and (Craig and Lee. writing. perception. Similarly. developmental psychology. how the movements For example. coordination. When considering the most common activities performed by Such newborn and infant actions are. motiva. Only a few of the well-accepted life becomes difficult and limited in many ways. so (1) the arm functionally controlled a weight outline the existing relationships between the motor. standing up. we will movements. and hand orienting. In fact.. 2003). recent dynamic systems pro- realize that every motor action not only generates the physi. the newborn stopped compensating for it. TIERNAN Typically. are flexible goal-directed actions. Hence. movement. and prospective control duction of speech involves the movement of the tongue. and 2000. 1994. and planning. motivation. abundant evi- that facilitates the understanding of motor development as dence supports the view that most newborn motor behaviors a complex and dynamic process where exploration (flexibil. Within this chapter. ing to which planning of movement and prediction of its cal development of the child. von Hofsten development of these motor milestones tends to be discussed proposes an action approach to motor development. accord- in isolation with little apparent relevance to the psychologi. As stated by von Hofsten (2004). motor behavior is at the core opment: Piagetian theory (Piaget. Fourth. From rooting to sucking. weight had no functional consequences. 2002. To end. If moving the tions in the motor domain. learning about motor and vocal cords. Would it psychological theories of human development stress the not make sense then to think that movement is an essential importance of movement as a core foundation to early devel- part of development? In fact. 1980. movement control. infants also moved their preferred arm locations so they could see their hands. ANGULO-BARROSO AND CHAD W. we will and (2) the hand was kept within the range of a light beam draw conclusions in an effort to guide therapeutic interven. tems approaches (DSA) (Thelen and Smith. planning. It is imperative to and Ulrich.

infants tenets of this approach is that new forms of behavior emerge not only control their actions and become more skilled. This definition means that human tor phase.e. or diverse and coex- Similarly. system (see figure 10. human cognition has its origins in the changing their levels of stability. one in more detail in a later section (“Interconnectedness . Heriza. Intrinsic factors (organis- sensorimotor activities of the infant. . human movement is schemata) that will be later used as a foundation for higher defined as the emergent behavior of a complex and adaptive cognitive functions. Thelen and Smith. For instance. A complex been able to disconnect (overcome) the bodily component. mic. an object once he/she has cooperate to accomplish a unifying goal: the task. Kelso. Abundant research evidence points toward a relevant terms as a series of states and phase shifts. Some subcomponents of the system must disrupt the currently stable movement pattern Dynamic systems approaches (DSA) have been commonly so that the system is free to change its state. esting consequences of their actions by means of repetition 1991. gains further cognitive skills has been recently challenged by Change in movement activity can be seen in dynamic DSA. responses (Goldfield. physiological. Turvey and (circular reactions). infants bang their hands or Fitzpatrick. the individual ultimately finds the most adaptive forms of tive developmental view of becoming progressively more motor patterns (i. which lasts from birth to about one year of age. Using repetition. This cogni.. Infants and children are the processes of exploration and selection so motor patterns emerge complex adaptive systems with particular intrinsic and extrinsic that are adaptive (flexible) to task demands. Through practice and action-perception coupling. Piaget called this period the sensorimo.Context . 1954). From dynamic principles. and context) abstract concept of.Psychological Instability Creation of variability Exploration Experience/Practice Action-perception coupling Selection Stability Adaptive Motor Patterns Figure 10. as we will see particular task constraints. 1993. 1994. dynamics. but in a nonprescribed fashion from the cooperative interaction they also form action-perception relationships (sensorimotor of multiple subsystems.”).Informational cues .Organismic . for example. The components used to explain the development and acquisition of motor of the system disrupting the current stability and thus Complex and Adaptive System Intrinsic Dynamics Extrinsic Dynamics . 1995.Surface of support . 1993. In other words. and psychological) as well as extrinsic Piaget’s assumption is that the child can only form the factors (informational cues.1). Ulrich. . to initiate a process of exploration and initial egocentric references is critically necessary for the selection.1 Schematic diagram of the process of motor develop. the system retains relative flexibility to disconnected from action and perception as the individual adapt to task demands). Piaget (1952) proposed that infants initially discover inter.Neurophysiological TASK . beings are open systems constantly exchanging energy and From this perspective. can predict that change is facilitated by the loss of stability. Therefore. and adaptive system creates variability. however. reflecting the interaction between motion and cognition not only in early probability that a pattern of movement will emerge under development but also throughout the life span. surface of support. With time. 148 fundamentals of developmental neurobiology . Kay. highly variable movement patterns might Theoretical approaches to motor development represent an exploration stage. 1997). Task-oriented activities drive development by means of ment from a dynamic systems approach. ignoring the information of the senses and his/her isting alternatives. One of the most important feet on a surface to make sounds. and Warren. emergence of formal operations (Piaget.

chose to present the development of reaching and walking ceptualization of motor development: (1) A child is viewed as examples of how motor skills emerge and change as continually shifting his or her movement pattern stability: through time. Angulo-Kinzler. however. From this perspective. one can say reaching skill come from advancements in postural trunk that children become skillful motor performers because they control (Spencer et al. and motor synergies (i. 1998. the range Posture. 2000).engendering change can only be known through careful have also examined the underlying processes of develop- empirical study. the muscle patterns change distinct contribution within motor development. 2001a. Thelen. As infants transition definitions of posture and movement so we can clarify their to their first successful reaches. the current dynamic state of effective action takes place. Zelazo. 1979. but rather by the interaction movements. Nevertheless. infants as young as 6–8 months are capable of precision A large body of literature exists describing the orderly grasping. motor action/movement. However.. von ing factors. nervous system. 1982). become more efficient and finely tuned to environmental The task in question dictates the relevance of the contribut. movement 6-month-old generally grasps an object with the entire hand. in situations later in development.. such study is diffi. (2) The Development of Reaching From 0 to about 4 The stability of these motor patterns depends on the degree months of age. ing posture itself. allow infants to practice and learn between the embedded components (i. In this chapter we There are critical implications of a dynamic system’s con. Thelen et al. and reaching and grasping are a gross measure of all types of movements independent of coordinated into one continuous movement. Fentress and McLeod. Still. the developmental trend is an increase in use of progression of postural control and movement acquisition the pincer grasp over time along with progressive elimina- observed in infants and children. and environment forces (Spencer and Thelen. 1990. (4) Finally. 1997. Thelen et al. through time.. Younger infants do not angulo-barroso and tiernan: motor systems development 149 . The ment such as reaching for an object. Initial improvements in the basis for future states. Hofsten. such as leg-mass-to-strength ratios. it is useful to agree about functional movement options) (Zaal et al. Bertenthal and Clifton. about their movements during this period when perception- body) and environment. there will be times when some motor behaviors are very stable and other times when new patterns will emerge. 1998). No one part of the child is privi. action could be the performance of any goal-directed move. For instance. movement. and adjustments in arm velocity and muscle coupling among the nervous system. experience or mental studies have focused on how these motor actions socioemotional conditions may have a greater influence. Many of these studies tion of ulnar and palmar grasps. infants show increased hand skill in several dimensions. could be defined as changes in the body configuration so a showing only primitive aspects of coordination between the goal-directed action is accomplished. In general. see Angulo-Kinzler. Schmidt and Fitzpatrick. action relationships are formed and selection of more leged in this regard. a motor action could be maintain. are important in early Jouen and Lepecq. 1995.e. As Thelen (1995) stated. These initial in one subsystem or part. 2000. 1993). task at hand. However... as we do when standing on an icy sidewalk Subsequent changes in the reaching abilities of infants while waiting for a bus on a winter day. (3) Change in hand motor control. Still other motor develop- However. 1999). and overall level of motor activity of patterns that infants explore is not infinite but rather is constrained by their initial preferences and other Movement scientists may have different views about the neurobiomechanical factors such as formation of linear definitions of posture. In fact. coupling of two or more joints to reduce activity today. Finally. demands (Adolph. 1981). body. infants explore a range of patterns and select those that take their arms close to the desired toy. at the same time that they are dynamically responsive to the During this phase of spontaneous pre-reaching movements. but motor behavior cannot be explained on the basis of change they are not successful at grasping an object. growth or physiological factors. By 9–10 months. 2001b. They are able to move their arms. mental changes in the aforementioned areas (for reviews cult because these agents may be nonobvious and changing of motor development. eye-hand coordination (von have the capacity to maintain flexibility in the degree of Hofsten. the child begins to use is useful to estimate overall motor activity because it gives us the forefinger in grasping. Although goals. 1986. infants demonstrate a level of poor arm and of coherence among the important parts. Infants learn to first move their the child is a function of previous states and also serves as arms to the vicinity of the object. 1993). infancy for the development of functional leg movements. the motor continue during the second half of the first year. reaching (Morasso. In this case. these reaches lack the smoothness in the hand of it) while facilitating motor action efficiency in other parts path and the bell-shaped velocity profile observed in adult of the body. that minimizes movement in some parts of the body (or all 2000). We define from a more predominant use of biceps and triceps to a posture as the maintenance of a specific body configuration preferred use of the deltoid muscle (Spencer and Thelen. 1996.. as scientists it palm and fingers.e.

activity of flexors and extensors) (Grillner. infants can correct hand trajectory stage. “integrated walking. however. While the general development sequence described by In other words. the last half of the first year is characterized McGraw is largely agreed upon. Thelen. young infants upright in warm water to decrease the load Next. Initiating this adaptation. Results showed that infants increased their step be observed. the years.. 1980b). Forssberg. planning. rudimentary elements of “independent stepping” can of their legs. It has been proposed brain and the assumption of localization of function were a that direct connections between neurons in the cortex and much too simplistic view of development. the decline in stepping after two months of age to cortical inhibitory processes. upright locomotion over the first two years of life. takes twice as during the second year of life. are rate when compared to the out-of-water condition. However. Similarly. works as higher brain centers develop. including spinalized dent. 1998). Such cats that have been shown to produce hind-limb move- transitions became the focal point of developmental research ments similar to those of their nonspinalized counterparts starting in the 1930s and 1940s with the work of Gessell and (Forssberg. 1982). control of movement. sequentially through seven phases to achieve adultlike erect by proponents of DSA who question the functional capa- locomotion and ascribed maturation within the nervous bilities of neural networks and argue that the nervous system system as a cause for these development acquisitions. Gessell motor neurons in the spinal cord by way of the corticospinal (1945) stated that it was more appropriate to describe such tracts are critical for the control of fine hand movements developmental processes as dynamic and nonlinear. whereby CPGs were the basis for prospective control. McGraw. can generate muscle-specific activations (i. The first should not be seen as a privileged component within the phase was known as “reflexive stepping. 1980a. Also at 9 months. McGraw Concomitant changes at the neuromotor systems level herself later acknowledged that histological changes in the also occur during the first year of life. The next period was movements and concluded that the observed activation pat- classified as the “static phase. 1975.” where coordination improves and grasp configurations as a function of object size. In the fourth phase. 1981. although not yet refined. 6-month-old infants do not change “heel-toe progression. while 9. many researchers believe that “central 1983). 1982). The sixth phase was referred to as pincer grasp. and explanation of walking. In particular. since reaching involves motivation. and increase in myelination and axon diameter of the walking because these neural networks within the spinal cord relevant corticospinal tracts (Eyre et al. In apparent decline in stepping behavior. Similarly. years. Fisher. Thelen and Fisher (1983) examined the first two months of life. These neurons and connections have a than stagelike and maturationally driven. alternating other neuromotor areas are also important in the develop. Finally. neural special role in precision grasping. McGraw (1945) suggested that infants progress Neural network accounts have been challenged. According to Thelen and Smith (1994). Third. Forssberg (1985) argued for a hierarchical attention.” During this time. rather (Kuypers.. Increasing hand skill parallels the decline in latencies pattern generators” (CPGs—a set of neurons in the spinal of motor evoked potentials (motor responses resulting from cord capable of a patterned neural activation which matches stimuli over the motor cortex). strike and end with pushing their toes off the ground. 1985). however. stepping is gain (Thelen et al.” which occurs during system. Research has shown that step frequency in difficulty discerning whether or not the stepping movements early infancy is related to infant arousal and rate of weight are reflexive or deliberate. that needed for gait) drive the development of adultlike ity. as they are active in a accounts of walking have still been popular throughout the pincer grasp but not in a palmar grasp (Muir and Lemon. the “transition phase” has been shown to be influenced by other than purely is marked by heightened variability in leg movements and a neural factors. there is an terns were far too complex to be explained by CPGs. which of the nervous system and the deterministic nature of these in turn allows the development of other forms that are more characterizations of walking has been largely debated over adaptive. infants more consistently initiate stance with a definite heel month-olds adjust their hand opening (amplitude) accord. locomotor development. The final ingly.” shows refined coordination and to a moving target even after they started their reaching smooth and automatic independent upright locomotion action. characterized by the integration of posture and forward while older infants use the inferior forefinger grasp or the propulsion of the legs.. both the extent of the role by the acquisition of a more stable form of reaching. ment of skillful reaching. much time as it does in adults (Berthier and Robin. anticipation. increase in conduction veloc. which she attributed addition.e. She described these movements as muscle activation patterns of infants during early stepping primitive and subcortically driven. For example. He contended that adultlike loco- motion resulted from the refinement of these neural net- The Development of Walking Infants undergo sub. These movements. 150 fundamentals of developmental neurobiology . 1991). for CPGs stems from animal research. and described as “deliberate”: infants take steps in an intentional Ridley-Johnson (1984) manipulated leg mass by placing manner resulting from more direct cortical participation.exhibit a consistent grasp pattern with the smallest objects. Much of the support stantial changes during their transition to adultlike indepen. In addition. Regardless.

2002a. (Data published by McKay and Angulo-Barroso in Infant Behavior and Development 29:153–168. 1986. Since many of these processes occur groups. anemia (Angulo-Kinzler et al. We used activity monitors the changes that have been described in the development of to objectively quantify the frequency of spontaneous motor reaching or walking. it is important to note that although the Recent advances in the memory capacity and sensitivity of nervous system is an important contributor to development. and complicated physiological measures such as heart rate As reviewed in the section on our theoretical approach to telemetry and energy expenditures (Sirard and Pate. they are perfectly compatible Traditionally. activity monitors were used in sleep research with neurodevelopmental theories that view the brain as a (for review see Sadeh and Acebo. Recently. such as body dimen- small lightweight devices simply attach like a wristwatch sions. Although dynamic ecologically valid.05. The other physical and contextual factors. 2001). the brain are activated. That is. in awake and alert infants with and without iron-deficiency 2005). 2002b).. and basal ganglia. 2002). motivation) 100 that cooperate with the nervous system during locomotor. A seemingly simple task for movement artifacts. p < . 50 related tasks. Furthermore. timing the different muscles locomotor activities such as crawling and walking in both involved. reprinted with permission. it is implied that many interconnected areas of also showed later onset of locomotion (McKay and Angulo. 350 Advocates of DSA acknowledge the critical role of nervous. time-consuming and intrusive direct observations. Months Day data cations for individuals with locomotor delays. Previous research has shown that many validity of activity-based research (Puyau et al. a neurobehavioral theory. 2001). indicated that infants with DS spent such as reaching for an object requires motivation. are rather complex and activity for 48 continuous hours.. 1982. The neural mechanisms that could explain (DS) from 3 to 6 months of age. contrib- to the limb or to the trunk of the participant and allow ute equally to motor behavior (Thelen and Fisher. Vereijken and Thelen. quantifying the frequency of motor activity was beset with a number of problems. Thelen.. .2 Group means and SD values of time spent in low- facilitated the onset of independent walking in infants with intensity activity in infants with Down syndrome (DS) and typical Down syndrome. little is known about the specific changes occur- work in our laboratory has examined the spontaneous leg ring at the brain level that accompany the acquisition of new motor activity of infants with and without Down syndrome motor behaviors. planning night (see figure 10. and so on . 200 150 neural factors (i. activity monitors have improved the reliability and ecological it is not the only one. body composition. researchers the opportunity to collect less intrusive. a possibility that has impli. development (TD) at 3 through 6 months of age. controlling involve many neuronal structures. motor development.e. Data analyses.. These results are important for illustrating visual cue of the object to be reached activates not only the relationship between the amount of motor activity and visual association areas but also areas related to motor plan- motor development as measured by the onset of important ning and preexecution such as the supplementary motor/ milestones. goal more time in low-intensity activity during the day and the identification. For instance. 1983. 300 DS (min) system maturation in locomotor development but argue 250 TD that such findings illustrate the importance of other. 1986. the aforementioned findings 0 suggest that locomotor development is not fixed and can be 3 4 5 6 influenced by early intervention. 1997). . 2006). cerebellum.. premotor areas. Ulrich and associates (2001) found that treadmill training Figure 10. for instance. infants who spent more time in low activity in parallel. setting the appropriate amount of force and activity showed a significant relationship with the onset of correct direction of movement. non. postural control. proportions. including questionable reliability of self-report Neural substrates of motor behavior measures. In addition. 2002) but more recently dynamic and complex system whose development complies these devices have been shown to be sensitive enough to with the similar dynamic principles proposed for motor detect differences between spontaneous motor activity levels development (Sporns and Edelman. Ulrich et al. visual processing. Stiles et al. postures. 2005). the level of low motor the response. all of which angulo-barroso and tiernan: motor systems development 151 . and inertial properties. activity related to the Barroso. Additional Currently. 1993.) What about Overall Level of Motor Activity: Does It Have Any Role in Development? In the past. and objective motor activity data for approaches to development make no explicit proposal of extended periods of time in children (Trost et al.treadmill training has been found to increase functional 500 Time in Low Intensity Activity stepping patterns in infants who initially showed little or no 450 400 * * * stepping (Thelen. strength..2).

the these graphics only begin to depict the complexity of the neurons that code for reaching direction involve not only neuromotor system. predominately in motor functioning. As stated by Stiles (2001): conduction velocity—it also helps provide nutritional and “the developing brain is a dynamic. but they do not necessarily do so at the same seems that the distinction between what defines a visual cue. of a dynamic and complex system.. by decreases in the threshold of motor evoked potentials ity) and selection (stability) in a child’s motor repertoire. iSP is thought to depend on transcallosal con- or among the different cortical areas. 2004). other brain Phelps. In (MEP) and decreases in the ipsilateral silent period (iSP). However. it implies that brain areas are multiply and densely with the latter defined as a transient interruption of ipsilat- connected and that the child’s experiences with motor skills eral voluntary muscle activation. adjacent or connected areas of the neuromotor system and their corresponding fields of these areas correspond to adjacent parts of the functions. Diamond. whereas those most active in the infancy phase and emotional development (Allin et al. The interconnectedness among these areas and body). Both structures develop relatively late in neuronal 152 fundamentals of developmental neurobiology . 1988) but also those in the parietal cortex. those in the primary motor cortex (Georgopoulos. and cerebellar vermis. and Mazziotta. 2005).. 2001. Table 10. Huttenlocher et al. reductions in frontal white matter have been found in oth- Throughout development.1 summarizes the most relevant in the motor and sensory cortices (i. In contrast.are involved in motor planning. However. Whether activity. function as well (Rademaker et al. However. These measures were have a structural and functional impact on the development recorded while children of different ages performed finger- of the brain itself (experience-dependent plasticity. once the while the rest of the cerebellum is devoted to motor control. time.3. 2004). male children who exhibit complex stereoty- activity of the different areas of the brain are not uniform. It ways improves. 1987). pies (Kates. responsive. it nal pathway improved its efficiency with time as evidenced also brings the advantage of permitting exploration (flexibil. motor memory. tem.. Similarly. 266). (Heinen et al. transcallosal pathways Huttenlocher and Dabholkar. both the cerebellum and basal ganglia are are more ready to ascribe specific function to particular somatotopically organized. the dependent experience is the guide for an already highly basal ganglia have two major interconnected loops: one for interconnected brain or the interconnections are formed as motor activity (cortico-putamen-thalamo-motor cortical the child learns is still under debate ( Johnson. it is Kleim. Therefore. Simi- continue through development. especially when comparing subcortical and cortical regions. Lanham. Please note that learning ( Jeannerod. the iSP is absent in children under 6. Interestingly. 1994). poral. Schwartz. and execution of the action is discussed in the work of Garvey and associates (2003) where becoming blurred as we learn more about the activation they examined the cortical correlates of neuromotor devel- patterns of the entire brain (Anderson et al. 2000. parietal. the most active areas often ascribed to motor behavior. and Singer. As children get older the efficiency of each of these path- and Schwartz. are already capable of motor planning. the neocerebellum is more dedicated to cognitive tasks. such as the brain. thalamus. 1990. peak nectivity and is mediated by inhibitory circuits in the motor density of synaptic connection occurs earlier in the visual cortex.e. activity-dependent plasticity. or more tapping movements. One important aspect nal and neurotransmitter activity modulation (Fields. Middleton and Strick. Interestingly. Jones. From this perspective. areas of seem to be involved in the production of finger movements. It is thought that MEP threshold precisely in our case.. 1997). cortex (4–12 months) compared to prefrontal cortex (after but it is present in children older than 10 years of age 12 months) (Huttenlocher. An example of these developmental improvements is planning. terns of action (Kelso. 2001). Although opment in healthy children using focal transcranial magnetic accepting a wide distribution and multiple representations stimulation (TMS). and to some structural support for neurons. 1996). brain has reached a certain level of maturity. 1982. For instance. namely. changes in the volume and erwise healthy. brain important to note that myelination does more than improve development is a dynamic process. along with the basal ganglia and To this point we have focused on brain areas involved cerebellar cortex are most active at 3 months of age (Chugani. higher activity (represented by glucose uptake) in the basal but other motor behaviors such as bilateral hand movements state in newborns are the sensorimotor cortex. and more functional relevance in recent years. For example. They demonstrated that the corticospi- of motor skills in the young brain may seem problematic. 1995). similar to the organization seen areas of the brain. For instance. 2000). the basal areas in the newborn phase are those that underlie motor ganglia and the cerebellum. 1998). 1994.. is its White matter within the nervous system has gained more capacity to self-organize and therefore generate stable pat. 1997. motor memory. where these levels surpass those of adults. 1997). addition. are also relevant to cognitive execution. and Greenough. Kettner. including a temporary phase larly. circuitry) and another for cognitive–emotional processing Further changes in brain connectivity and metabolism (cortico-caudate-thalamo-prefrontal cortical circuitry). However. and occipital cortices. neuroscientists Interestingly. Additionally. and mirror movements are affected by the corpus callosum brain stem. in addition to aiding neuro- extent self-organizing system” (p. denotes the developmental myelination stage.. and pathways is summarized in figure 10.

and Output PM. motor timing (lateral hemispheres. CB. afferent component of action).1 Motor systems: components. Prefrontal cortical areas and BG (striatum): when attention demands increase in the movement. i. Table 10. Output to SC Execution. bimanual coord. and direction of Cortices input from PM. spatial-visual attention Note: Additional functions CB: motor coordination. sensorimotor integration. PM. fine Sensory info to lemniscal pathway touch Convey sensory info from action to BS-cortex and Anterolateral pathway Coarse touch. SMA. and functions (only most relevant are highlighted) Motor Systems Function Muscles Executors of action Motor unit = motor neuron Developmentally: from Functionally: better motor control and (as internal forces. hemisphere To red nucleus and Initiation. motor area (SMA) sequential movements. posture. involved when decision about next movement. Homotopic connections Perception of somatosensory Cortex input via thalamus Output to MI. visual-motor (PPC) limbic areas of cortex lateral CB transformation. timing of (dentate nucleus) premotor cortex movement Cognitive components of motor action Basal Motor loops Putamen Direct: Facilitation of Selection of movement. motor imagery. BS Planning. preparation for next SMA movement. SI. VC. SMA. coordination. sequential (BG) dopamine) movements Indirect: Inhibition of movement (inhibited by dopamine) Emotion-cognitive Caudate Cognitive-emotional components of loops movement Motor Primary motor (MI) Somatotopic organization. (corticospinal) movement CB (reticulospinal) Premotor (PM) Input from PPC. PPC information Areas Posteriorparietal Input SI. 1991). MN Units also impact initially less capacity motion) for fine motor control) Spinal Efferent: Corticospinal and many other Reflexes. balance. Activated when selection of movement (efferent component of action).e. and Axial and proximal motor control.. balance. sensory discrimination. CB and BG: improving motor performance. BG: bimanual coordination and sequential movements (planning series of actions). execution of movement. fine adjustment of muscle tone. Both. planning. hemisphere To red nucleus and MI Distal motor control. CPGs Assist in coordination. ongoing (lateral) (interposed nucleus) execution Cerebrocerebellar Lateral part.. (MN) and muscle fibers more to less muscle implies fewer muscle fibers per Motor but external forces that innervate fibers per MN (i. and Output to MI. postural orientation Supplementary Input from PPC and BG Output to PM and MI Planning.e. force. Optimizing movement by monitoring outcome of movement (sensory information processing. Primary and premotor cortical areas: movement force and direction. (medial) (fastigial nucleus) MI ongoing execution Spinocerebellar Intermediate part. cognitive aspects of motor behavior. motor learning. anticipation (feed-forward control). higher order aspects of visual processing.. bimanual Ganglia movement (excited by coordination. Keele and Ivry. afferent and efferent pathways. inhibitory Execution of motor action Cord Motor from cortex spinal efferents (see BS) interneurons. . locomotion (SC) Afferent: Dorsal column–medial Proprioception. cognitive and emotional aspects of motor behavior. 1990).. (BS) Reticulospinal skilled arm/hand movement (cortico) Rubrospinal Afferent To cortex Spinocerebellar Convey somatosensory info from To cerebellum (see CB) action to cortex and CB Cerebellum Afferent Efferent (CB) Vestibulocerebellar Flocculonodular To axial MN Axial motor control and balance (lateral vestibular nucleus) Spinocerebellar Vermis To reticular form. comparison of intended versus actual movement (Ghez. and movement Other Primary sensory (SI) Somatotopic organization. motor learning. pain cortex and CB cerebellum Spinocerebellar (see CB) Somatosensory Brain Stem Efferent To SC and cortex Vestibulospinal Flexor and extensor tone. Motivation to move.

In addition. largely putamen]. periods or when the task demands increase drastically. The vestibular influences in movement have been ignored in this while CB receives input mainly from sensorimotor areas. a constant high level anterior to more posterior cortex activation as the learning of synaptic formation was found in the entire basal ganglia consolidates (Shadmehr and Holcomb. start myelinating control of movement (Schwartz. 1995). These areas are PM (premotor). the last trimester of pregnancy and lasts until beyond the In such cases. As motor actions are explored and tion and sequential movements are thought to be affected selected. For instance. Extrapolation from animal models the motor action becomes skilled and well learned. joint) Figure 10. the brain dedicates multiple. SMA (sup. MI (primary motor area). skin.3 Motor systems: A simplified version is presented with in motor motivation and visual-motor transformations. the development Relative increases in the activation of all motor cortices of the cerebellar cortical circuitry closely parallels motor and association areas seem to occur during rapid learning coordination and motor learning (Swinny. so deactivation of nonmotor cortical areas is synaptic formation suggest a significant increase during expected (Muller et al.. large learning component. and VC (visual cortices). (spinal cord). Pathways of the visual system are clearly incomplete. concomitant changes in neural substrates also by BG dysfunction (Ronald et al. BS (brain stem). pathways have been represented with thicker arrow lines. SC pathways. 2005). and cerebellum. 1999). BG (basal only the most relevant connections of both afferent and efferent ganglia). PM SI SMA (Eyes) L via TL BG vi aT Eye MI Muscles CB via TL Corticospinal via T via TL L BS SC Sensory receptors Muscles (muscle. subthalamic nucleus. van der Want. 1998). These two tion of connectivity. Temporal Parietal Prefrontal PPC Sensory Cortices Motor Cortices via TL L TL VC vi aT via Sensory recept. Also note diagram. In contrast. As the infant and child mature. (Passingham. evidence shows a shift from more thalamus.. Chugani. parietal cortex has been highlighted because of its important role ontogeny. Finally. the posterior. and sub. 1997). and Redundancy and interconnectedness in the neuromotor Mazziotta. tasks that involve bimanual coordina.. The basal ganglia (striatum [caudate/ As we have seen. information. Georgopoulos. the cognitive and even emotional load is first year of life (Gramsbergen. occur. prenatally (Chugani and Phelps. interconnected. (Pouwels et al. SI (primary note the important role of the thalamus as a hub to relay sensory areas). Cerebral cortex is represented in the top layer of the the rapid efferent path between MI and neurons in SC activating diagram with the exception of five important sensorimotor areas muscles (corticospinal) and the fast afferent path from SC to CB that have been placed lower and separated to facilitate representa. Note that BG receives input from most cortical areas. CB (cerebellum). Indirect estimates of reduced. plementary motor area). 1987). and in some ways redundant areas to the stantia nigra) are differentiated at birth. Because the basal ganglia send output to the supple. allowing consequences of action to be processed quickly. Martin and associates (2004) showed 154 fundamentals of developmental neurobiology . are multiple ways to achieve a given motor behavior mentary motor area. 1993). 1986. As and Gramsbergen. and mature rapidly over early postnatal system at the cortical and subcortical level mean that there years. 2003). Phelps. 1980). When the motor task has a infancy and childhood in the gray matter of the cortex. TL (thalamus). the acti- indicated that cerebellar cortex circuitry starts developing in vations of the primary/premotor cortex seem to take over. 1994. globus pallidus.

When the object is hidden at B. a In the same way that ongoing activity may change a neural process that is very inefficient. Bertenthal and coupling. infants would state. Results showed that young infants involved in planning movements. Kermonian ated from perceiving and acting exist (Edelman. Briefly. The idea was that crawling has suggested that both the prefrontal cortex and cerebellum angulo-barroso and tiernan: motor systems development 155 . plasticity is a basic process that. infants with more locomotor experience were that underlies not only neural but also motor and cognitive more likely to use allocentric coding (Enderby. infants were first trained to locate an object in a tally simulated actions closely mimics actual movement window to either their right or left side. It should be noted that the role of locomotor experi- Motor–Cognitive Relationships Based on observations ence in development of spatial cognition is deemed to be one of his children. Jones. This cyclical process is known as perception–action task (Acredolo. cognition. trials (Bertenthal and Campos. In a comprehensive review of this topic (see renewed interest in the possibility that locomotor experience Decety. Bell and Fox. 1990.. a shift from egocentric to nitive and motor behaviors and their neural bases has been allocentric coding seemed to coincide with established suggested by others as well. and Campos. Campos. Further support for the interrelatedness between cog- (allocentric coding). Further. such as hidden in one of two locations in front of them (A or B). 2003). 1977). on the aforementioned spatial orientation task and found although to a lesser extent. The perceptual information generated hidden at B. According to Decety almost always looked to the incorrect window (egocentric (1996). and Schallert. Therefore. It has been argued centrate on the relation between the motor domain and that locomotor experience may enhance spatial search capa- two domains more relevant to psychology—cognition and bilities in infants because it both demands and sets up con- emotion.e. it appears that providing Gibson. infants were repositioned so they were facing the appear to rival those during motor imagery. an egocentric behavior is bidirectional (Kleim. The relationship between neural substrates and motor coding because once infants begin locomoting. Furthermore. In her been determined. cognitive. neural plasticity is not unique manipulated locomotor experience while controlling for age to the postnatal period. 1986. 1990). locomotion was related to the development of spatial In addition to the link between locomotion and spatial cognition. the reorganization of the neural structures may also begin to adopt allocentric strategies that are independent have an impact on behavior. capacity to reorganize and change (i. Bertenthal. experience might facilitate the development of allocentric ence. Piaget (1954) proposed that self-produced of facilitation. these results suggest that imagined and actual move- coding). more direct evidence has strengthened cognition. where correlations between the information gener. cerebral opposite direction and then asked to search for the object blood flow increases were observed in the motor cortices in the original window. Findings from Acredolo (1978) motor imagery. it is also quite intuitive and well motor infants using artificial walkers increases success on B documented. Similarly. However. 1987. and Barrett. the abundance of research suggests that experience with self- motor activity we generate also influences our perceptual produced locomotion correlates with success in the A-not-B skills. plasticity) is crucial to Bremner and Bryant. Eventually. Researchers have subsequently neural development. While this phenomenon is important for infants with experience in locomotion in otherwise preloco- understanding development. Finally. 1984. 1978. Similar conclusions regarding locomotion and spatial Motor activity is interrelated with several domains. rather than one of necessitation. in fact. tingencies that teach spatial discriminations (Smith et al. the traditional A-not-B perception. Diamond (2000) locomotor trajectories.that corticospinal development depends on motor experi. According to Stiles (2001). 1992. and fine motor skills like taking a object is first repeatedly hidden at A and then eventually cap off of a pen. One example involves studies regarding search-performance tasks. we will con. 1984). functioning (Stiles. and emotional spatial orientation is impacted by infants’ experience with domains locomotion. 1996). 1999). the of the infants’ orientations in space (see Bremner. For the purpose of this chapter. at least to some much more successful in looking to the correct window extent. functional correlates of motor imagery have may influence the development of spatial orientation. However. and emotion. the literature in this area suggests that the development of Interconnectedness between motor. including search have also been drawn. Campos.. Following the times. The walking down the street. 1988).” An our finger force to uncap a pen efficiently. young infants allows us to adapt our step length to clear a puddle or adjust often fail to search at B. For example. 1985. autonomic responses during actual exercise training. We use perceptual task requires infants to sit at a table and search for an object information to execute both gross motor activities. It was concluded that the timing of men- study. 2001). fied in other areas. motor–cognitive relationships have been identi- this postulation by means of spatial-orientation and spatial. 1988). Since then. coding strategy would have to be continuously updated. making the “A-not-B error. It is preserved during adulthood. whereas infants in their second year of life were ments share the same neural substrates. Horobin and Acredolo. In fact.

day-night periodicity of cortisol release (Gossel-Symank. from iron deficiency and other nutritional insults (Lozoff and Among lower risk groups. and prefrontal cortex in numerous studies (Berquin et al. 2001. Campos and colleagues concluded that experiences which these two areas influence each other and in what generated by locomotion (both self-generated and artificial) manner warrants further investigation. high cortisol levels at 4 years of age (Kagan and Snidman.. In (Hoover and Strick. abnormal development and activity in both the cerebellum emotional tone. infants who had high levels of Black. research suggests that there is a con. 1994). For example. Bowlby. and look toward physiological correlates—heart rate and cortisol responses. in the basal decreased motor activity (Angulo-Kinzler et al. and Thisted.. Since the time of Darwin. 1997). and Kermonian. early problems between motion quality and rated personality characteristics of overactivity. Kiess et al. 2002a. show more its neural pathways in addition to some of its primary distress during separation from them. facial) and heart rate responses of known to be involved in motor and emotional development 4-month-old infants appear to be correlated such that infant problems. Motor–Emotional Relationships The word emotion locomotion is believed to be important for the development comes from an old French word. 1973. 1987) as well as and mental health conditions. motor activity has also been linked to behavioral gait (Montepare. The same children were also motion and emotion have been argued to stem from over- delayed in their general motor development and showed lapping pathways in the brain—specifically. Further. Manta- in conjunction with the well-documented cognitive deficien. several links have been made between emotion and Finally. The dopaminergic newly acquired patterns of activity may have implications system and prefrontal cortex involvement in ADHD-related for arousal and a developing sense of self-control (Robertson. ganglia and the hypothalamus. Castellanos et al. Collectively. 1972). 1992). 1998. which means “to of attachment because it provides infants with physical set in motion. Fear in infancy has often been 1993). emotion. make possible the development of wariness of heights (Campos.are important for both cognitive and motor tasks based on better establishment of the activity/sleep circadian rhythm. Motor activity is an important component situations. and Vagenakis. and Siegmund. infants’ negative expressions and heart rate increased. and Juette. Watson. Moustogiannis. Campbell. and Guides for therapeutic interventions in the motor domain Sullivan. emotions can be understood as a proximity to the caregiver and allows them to move inde- drive for the generation of action and thought (Thelen and pendently toward novel and possibly away from frightening Smith. the extent to studies. and Clausen. 2004) that children who have such nutritional defi. 2000.. 1994.. such as ADHD. Campos. 1966. 2004. children with ADHD have been shown to have important links between motor activity. a number of links between motion 1978.. esmovoir. 1996. 1995. Similarly. Early intervention programs designed to ameliorate motor trated. Bertenthal. 1991). and emotion have been proposed. which rely on intact involve- Lozoff. Developmentally speaking. 1993. Berger and emotion have rarely been examined. After a series of degree than previously thought. In the adult literature on 1992). The latest 156 fundamentals of developmental neurobiology . tive” disorders. particularly ADHD (Barkley. 1998). Schmidt et al. Goldstein. and physiological activation. 2004). This locomotor experience also causes infants to of behavioral expression that shares with emotion many of be more in tune with their caregivers’ locations. appear (Grammer. Hitchcock. behavioral (arm. 314). emotional relationship. the evidence collected increasing degree of organized periodicity of movement and thus far from such studies is largely inconclusive. it is possible that ment of the dopaminergic pathways.. motor problems discussed earlier have long been suspected Bacher. However. Amen. These types of relations between wide range of situations. studied by examining infants’ wariness of heights during nectedness between motor activity and cognition to a higher their performance on the visual cliff. gos. and the establishment of this rhythmicity coincides with imaging. the close activation of these two areas in functional neuro. In our research behaviorally inhibited toddlers and described as “shy” with together with Lozoff and her colleagues. Paldi. there was an inverse relation- ship between facial expression and heart rate—when frus. Honda. However. and March. to be risk markers for a broad range of externalizing prob- In infants or children.” In fact. 1999). them more often in ambiguous situations (Ainsworth et al. co-occurring links between motion lems later in life. iron-deficient chil. Swanson et al. Pierce. in addition to the fact that children with “cogni. motor development. motor activity and negative affect in response to novel audi- ciencies have both motor and emotional characteristics that tory and visual stimuli at 4 months of age were likely to be differ from normally developing children. 2000) and are addition. learning led to increases in operant arm responses and expressions of positive emotions (Lewis. developmental delays in infants and children have been During the first few months of life. Bertenthal. and Huntington. In this study. along with impulsivity and aggression. Thus there are cies. we know and Posner. infants also show an applied for many years. dren were less engaged emotionally with flatter affect to a 1991. Additional infancy research provides support for a motor- 1998.. demonstrate motor deficits Grimmer. However. and Kermonian.

movement. advances in motor showed the greatest positive effects at 24 days of age (Zion development are impossible. Thisted. Learning in the development of infant loco- motion. M. Paldi. Diverse and challenging opportunities for exploration should 115–140. Such studies could have a tremendous stability are very resistant to change. In R. when assessing the functional quality of performance. Soc.. the following theoretical guidelines to better what type of intervention is most beneficial or when to start understand motor development are proposed: First. stable (more flexibly organized).. A. E. NJ: Lawrence Erlbaum. Wall. Child Adolesc. 1. The Development of Spatial Cognition. Santhouse. Program (NIDCAP) during the newborn intensive care unit emotional) that constrain or facilitate change in movement (NICU) period. then a rest period of a few days after the injury. imaging. that underlie the emergence of new behaviors. these animal models have also mutually exclusive. Res. A. In such cases. Active participation in therapy should be promoted to facili. Thus stable movement patterns must be identi- tional research is needed to further delineate the link between fied in normal populations for comparative purposes. Focus on periods/phases when motor patterns are less Alasady. Jones. cognitive. the authors claim early intervention programs designed to enhance motor that further research is necessary to address issues such as development. 1995). 62(3):i–vi. which yielded positive effects on motor development outlined in this chapter. Murray. Additionally. weight gain was critical in the program. Blehar. intervention. The NIDCAP is a holistic and naturalistic patterns (both intrinsic and extrinsic). Measure movement patterns in a natural environment Anderson. L. orientation. Dev. Brain 124:60–66. C. Xing. extrinsic factors may play important roles to drive change. Monogr. pre. 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one for example. topic in humans and higher order nonhuman primate tures such as the amygdala. animal model is appropriate for the analysis of several equally dramatic and neurobiologically based species differ. elegans will not con- Insel et al. 28). on the neurobiology of the social brain was published by Even the terms “social behavior” and “social cognition” Brothers in 1990. in an animal tion would require a number of levels of analysis. milieu that it seems only natural that large portions of their As impressive as these examples of neural control of social brains would be dedicated to mediating social behavior and behaviors are. 2005) have positions are related to evaluations of the identity of other demonstrated that certain wild-type Caenorhabditis elegans individuals. others in order to predict their intentions and actions. in attempting to carefully deconstruct biological functions such as eating. While one would ences in social behavior have been observed (Insel. In addi- model with a nervous system consisting of only 302 neurons. 2004). the tribute much to the understanding of human social cogni- neuropeptides oxytocin and vasopressin play important tion. any.11 Neurodevelopment of Social Cognition MELISSA D.. The activity of these neurons and thus Premack and Woodruff (1978) in the course of studying of feeding behavior is determined by a single polymorphism cognition in chimpanzees referred to this ability of modeling in the neuropeptide receptor npr-1. In her view. and affiliation but on the perception and interpretation tion. accurate perception of the dispositions and intentions of Bargmann and colleagues (de Bono and Bargmann. their posture. Beyond identifying the appropriate species for study. an early step would be to decide what. The monogamous prairie voles. 1990. cognition increases dramatically when one considers the temporal. 2001). Brothers stated. is the processing of information which culminates in the At one level. Even more fundamentally. ronmental conditions. developing a neurobiology of human social cogni- active allele promotes solitary feeding. as well as incorporating potentially relevant research of social signals for the accurate performance of subtle social such as on the “mirror neuron” system. as well as subcortical struc. there is still ample debate about the contribution of roles in social behaviors such as pair bonding. found in animals that feed in clusters. 2002. if In species such as the vole. Thus. eating of bacteria. the definition and interactions. and direction of their movements. The less active allele is the mind of another as Theory of Mind (ToM). have a higher density of oxytocin receptors in would need to determine whether certain brain regions are the nucleus accumbens than the nonmonogamous montane selectively responsible for the perception of social signals 161 . ing. AMARAL PART 1: A BRIEF OVERVIEW OF THE vole. In these animals. Evidence that blockade of receptors in this important NEUROBIOLOGY OF SOCIAL BEHAVIOR reward-related portion of the brain interrupts partner pref- AND SOCIAL COGNITION erence formation in the prairie vole indicates that this neu- ropeptide system plays an important role in orchestrating Humans are so embedded in. other individuals” (Brothers. whereas the more Thus. and nonhuman primate studies (Gottlieb and Lickliter. de Bono and Maricq. Young et al. their social this social behavior. and parietal cortices. 1997. The choice of whether to eat in groups social cognition relies on the ability of an individual to build or to eat alone is dependent on the activity of a few nocicep. BAUMAN AND DAVID G. nematode colonies demonstrate either social or solitary as well as their facial expression. with many more neurons. “Primate social cognition have many layers of complexity. social cognition.. affiliation. However. components of human social cognition. parent- the component processes of social behavior and social cogni. probably receive little argument that C.. sexual behavior. have been associated with social species. A seminal paper in the evolution of research independence of the “social brain” become less apparent. social behavior is akin to togetherness. 1998. the complexity of social behavior and social social cognition. an internal representation of the psychological states of tive neurons that are responsive to stressful or adverse envi. Here the interest is not so much in the area of basic function. paternal care of offspring. It is true that large portions of the frontal. tion to the direct approach of using imaging and lesion substantial genetically determined differences in social techniques to study neurobiological correlates of human behavior can be observed. 1997. and dependent on. dis- de Bono et al.

. an appropriate social fashion. the expression must first be perceived as an complexity and awareness of social interactions across important source of information. one would identify brain regions particularly associated with Our ability to study social cognition is clearly limited by social cognition. motivated to engage in social interactions or to interpret the especially those closely related to ourselves. the form of thought or deed. Macaque monkeys. for example. and finally how chimpanzee compete for food. and non- human primate models of social processing. tion in action (Tomasello et al. and (3) whether the context is on a macaque monkey’s typical evaluation of the location conducive to a social response. 2004). Beyond this a unique capacity to perceive psychological facts (disposi. we have meant by the terms “social behavior” and “social cognition. interpretation and production of social behavior into com- specifics (members of the same species). obligatory social impetus. and finally an appro- behavior from social cognition. Consequently. Since the publi. 2003). non-primates (for example. and such.” found it useful to generate a schematic of social information Broadly defined. Given adequate perception. perspective. Tomasello and colleagues appropriate social responses are generated. motivation. Brothers states. the expression cal or physiological development and the emergence of of overt social behavior is the level of analysis that we can social cognition. it is important to attempt to define what is Given the complexity of primate social behavior. Chimpanzees. Thus several sections understanding of attention. a food item) in order to successfully “steal” such as fear are generated that might modulate the response. and (3) production of social experiences that differentiates social behavior from a species-appropriate response. and context. 1990.and third-person (2) evaluation of its social significance. there is considerable variability in the expression. it is important to note ties. emotion. it is clear that they understand almost no published information on the development of much about the behavior of conspecifics and can respond in these brain regions and of the correlation between anatomi. can use whether a response will even be generated) will depend on information about where an experimenter is looking (at. vocalizations.. Our schematic breaks down the facial expressions. What is social behavior and social cognition? Model of social processing Before we attempt to outline the neural components of the social brain. 162 fundamentals of developmental neurobiology . Through a other brain regions are involved in the evaluation of these series of experiments in which a dominant and subordinate social signals to determine intentionality. there is cal states of others. young child. social behavior is the use of species-typical processing in order to clearly define the component pro- social signals. body postures. There is. it is clear that chimpanzees do not have the same ToM that there remains enormous ambiguity about the neural capabilities that are seen in young children that require an circuits that underlie social cognition. This task capitalizes (2) the motivation to respond. have developed gestures of others as social communication. However. and communicative of this chapter deal with fundamental issues such as how intentions. It is also important to point out that while our inability to directly ask nonhuman primates (and even there is certainly a literature related to candidate brain young children) what they understand about the psychologi- regions for social processing in the mature brain. In spite of these abili- fied (Adolphs. The species-appropriate social cognition (Gallese et al. However.such as facial expressions. and candidate brain regions have been identi. 1999. the food (Flombaum and Santos. of course. “While many priate social response must be generated. such as a facial network. whether demonstrate some forms of social cognition. for the purpose of interaction with con. Social behavior ponent processes in order to more clearly define the essential relies on the ability of the individual to recognize species. The meaning of that par- species. The nature of that response (or chimpanzees. In order to process the understanding of their relationships within the social information conveyed in a social stimulus. It is this capacity to link first. 2005). and here lies the basis for the differentiation of social ticular expression must be evaluated. 28). have demonstrated that chimpanzees have knowledge of cation of Brothers. response could be either the production of a social response Elements of social cognition have been described in gesture or the interpretation of the disposition or intention nonhuman primates ranging from macaque monkeys to of the other individual. ants) can interact in highly spe. and modulatory brain functions underlying social interac- typical social signals and to have at least a rudimentary tions (figure 11. the fundamental components of tions and intentions) about other individuals” (Brothers. including body postures. However. a number of authors have addressed what others see and that they know something about inten- these issues. it appears that primates. and cesses of social interactions. 2003). and attention of conspecifics to determine its chances of evaluation. the brain gaining food in a normal social situation. several modulatory factors including (1) whether emotions versus away from.1A and plate 18). most readily relate among adult. the overarching precondition that the individual must be cific ways with others of their kind. social processing include (1) perception of the social stimulus. must then execute an appropriate response that may take perhaps more than any other nonhuman primate species.

where an evaluation of the potential danger of the stimulus is lus has been perceived. in identifying regions of the brain that are involved in other More than 15 years ago. An organ. is attuned to but also on whether modulatory influences are consistent with the facial stimuli such as fear expressions. This approach has been useful would dramatically alter normal social behavior. Once the social stimu. input may provide context information that is utilized to determine teristics of the particular conspecific. there must be an evaluative process in order carried out. conspecifics. Internal connections within the amygdala convey to determine its intent.1 Model of social processing. This place. one would specialized for processing social information and can there. (See plate 18. expect that the elimination of candidate social brain regions fore be identified and studied. 2004). Brothers proposed that the social complex cognitive processes such as learning and memory. A central question for the field Our discussion of the neurobiology of social development is of social neuroscience is to determine whether the social based on the assumption that regions of the brain are indeed brain is organized in a similar fashion. role that these structures play in social processing. temporal lobe are essential for forming declarative memories and temporal cortex (Brothers. Given this proviso. However. The intent of the social stimulus will have information from the lateral to the basal nucleus. It is not surprising that executed will depend not only on the development of a motor plan the amygdala. a social stimulus through sensory processing. in turn. orbitofrontal cortex. anterior cingulate cortex. A combination of both neuroanatomical studies and these structures are essential for social behavior. (B) Amygdalocentric network of the component processes essential for social behavior. which. (A) Simplified diagram implementation of the behavior.. including the For example. brain was composed of several brain regions. Context includes situational variables as well as the charac. A variety of sensory stimuli indicative ism must first have an overarching motivation to interact with of dangers are perceived by the ventral visual processing system. the brain must be able to perceive This information is directed to the lateral nucleus of the amygdala. or even if 2004). Whether a social behavior is whether an escape behavior is executed. different consequences depending on the context in which it takes receives a prominent input from the orbitofrontal cortex. remains lesion research has specifically identified the hippocampal unclear to this day. 1990). it is well accepted that structures in the medial amygdala.Figure 11. If it is. recent evidence indicates that formation along with the perirhinal and parahippocampal regions of the brain not previously implicated in social bauman and amaral: neurodevelopment of social cognition 163 . as a multipurpose danger detector.) Is there a social brain? cortices as key structures mediating declarative memory (Suzuki and Amaral. the exact (conscious memories for facts and events) (Squire et al. Moreover. mediating danger detection.

This reasoning raises the question of whether the same or is rendered somewhat more intelligible. display visual preferences for a century later. Later. 1998. and D+E−. These innate social predispositions networks evolved to facilitate the accurate processing of suggest that components of the human and nonhuman this information. Nearly human infants. This acquiring resources.g.. Darwin’s work on emotional expressions. macaque monkeys and the poker face in humans. In the following section. (3) that there is a correct and incorrect equally often.. Although transitive tively disrupted in disorders such as autism or following inference has been demonstrated in several primate species damage to specific brain regions. These included evidence (1) for a C+D−. evolution of ever more sophisticated social cognitive process- cessing. and (4) that social behavior can be selec. was overlooked for many years. What remains unknown is the precise primate genetic endowment generate brain regions that relationship between pressures from the social domain and are specialized to mediate complex social interactions. beginning with the following quote from Charles ing. participants who well-defined developmental progression for the emergence choose B over D when presented with novel pair BD are of social behavior. A+B−. Sophisticated social interactions form the basis for cifics as the “terms” of a transitive inference paradigm and primate societies and are necessary for forming and main. 1971. many primate of a social brain. are clearly much more adept at performing these complex taining long-lasting relationships with other group members.. of interacting with conspecifics (Cheney et al. the ability to interpret able to quickly and accurately determine the status of other accurately and produce appropriate social behavior is of group members in relation to one another (Cheney and paramount importance for humans and other group-living Seyfarth. 1872. in the laboratory using inanimate objects as the “terms. and ultimately ensuring propagation of intelligence evolved specifically to solve the challenges one’s genetic material (Cheney et al. tion of these regions as portions of the “social brain.. 1977. social smiling is present suggests that these behaviors are innate components of our even in blind infants. if we believe in different brain region(s) subserve the affiliative lip smack in their descent from a common progenitor” (Darwin. mirror neuron system of the ventral premotor and inferior Reader and Laland.. In her review. as in the movements of the same facial expertise for manipulation and deception of conspecifics. It is reasonable to presume that producing and inter- Darwin: “The community of certain expressions in distinct preting social gestures was a first step to subtly applying this though allied species.. 1977). During training. incorrect choices). 2002.processing may indeed play an important role (e. The Brothers highlights the phylogeny of facial expressions in increasing complexity of social groups may have forced the primates as evidence of a common evolution of social pro. 1991. that a set of emotional expressions are universal to the Morton and Johnson. She suggests that certain cognitive functions. Moreover. 164 fundamentals of developmental neurobiology . they are using conspe- primates. Brothers. ments supporting the existence of neural networks special. Interestingly. operate most strongly Brother’s seminal review included a summary of argu. Barrett et al. overlapping pairs of items are trained (e. 2005). logical operations within a naturalistic social context. and in trajectory that characterizes primate social development is particular his emphasis on biological determinants of socio.. said to demonstrate transitive inference. adult facial gestures immediately after birth (Meltzoff and The commonality of emotional expression across cultures Moore. In transitive inference. muscles during laughter by man and by various monkeys. 1990). terms B and D are edge is distinct from other knowledge. 2006). 1975. where + and − indicate correct and common evolution of social behavior.. 2003). Before delving into the roles that these Another line of evidence proposed by Brothers is that specific structures may play in social processing. of knowledge. 1986). ized for social processing. Despite the accuracy of his observa. the corresponding changes in neural circuitry (Dunbar. Newborn emotional behavior. 1991) and are capable of imitating human species (Ekman and Friesen. 29). Brothers suggests that as this capacity similar to the transient abilities reported in human infants to produce social signals evolved. adding further support to the notion behavioral repertoire. It has recently been dem- facial muscular structure and produce facial expressions onstrated that infant monkeys display a transient ability to believed to be homologous to several human expressions imitate facial gestures in the first week after birth that is (Parr et al. Ekman and colleagues provided evidence facelike stimuli (Goren et al. it is first social knowledge is operationally distinct from other domains important to reconsider the logic that led to the identifica. in the context of social processing. In contrast. parietal cortices). 1990. it appears that closely that there is an innate mechanism for mediating early social related species of nonhuman primates display similarities in predispositions (Freedman. B+C−. Brothers also argued that the distinctive and characteristic tions. Ekman. species live in well-defined dominance hierarchies and are From an evolutionary perspective. maintaining protection from predators difference suggests that at least some aspects of primate (and competitors). Johnson et al. it is likely that neural (Ferrari et al.” such as making transitive inferences. 1986). 1993).g. (2) that social knowl. In a very real sense. also evidence for the existence of a social brain.. 1983).” it we will briefly summarize these main lines of evidence and requires an enormous amount of training to reach criteria incorporate new findings that lend support to the existence (McGonigle and Chalmers. 1964). for example.

1972. regions of the brain stem.Maestripieri and colleagues have provided compelling evi. support the existence of a social brain. and some band 7q11. 1954) suggested diagnosis must include a qualitative impairment in social that the amygdala might be essential for normal social interaction. (3) a lack of spontaneous seeking to share enjoy. and activities. 2000). Here is the ments.2). 1987. social contact and aggression) that resembles their biological Leonard et al. The neuroanatomical connections of the amyg- can selectively be disrupted and therefore supports the exis. lending further identified. 1994). wide range of behavioral and psychological processes. a genetic alteration provide additional evidence of a genetic/ and extensive projections from the central nucleus of the biological basis of social development (Doyle et al. gaze.. In turn. 1984. 1999). The amygdala can influence relatively early stages et al. mothers develop a pattern of social behavior (e.. and the Functional studies. information concerning which brain regions priate behavioral responses (Emery and Amaral. Perrett et al.. our own work has marked impairment in the use of nonverbal behaviors that questioned the notion that the amygdala is an essential regulate social interactions. But. and (4) lack of social or background evidence: emotional reciprocity (APA. Ring.. The amygdala is a cytoarchitectonically that the “inborn selective absence of social cognition” that complex structure located in the anterior temporal lobe (see characterizes autism provides evidence that social processing figure 11. 1990. including medial and orbitofrontal social brain. DSM-IV criteria for autism lesion studies in primates (Rosvold et al. patients numerous brain areas capable of influencing behavioral with Williams syndrome display hypersociability (Bellugi output. tory influence on social and other behaviors. 1992) and in the amygdala (Rolls. For example.23. rates of 1989.. Brothers proposes that neurons ioral response to a provocative stimulus.. bauman and amaral: neurodevelopment of social cognition 165 . superior temporal cortex. removed from their biological mothers and reared by foster Desimone et al. In contrast to the diminished social anterior cingulate cortex. 2005). which is further processed through the complex cognition. what types of responding to social stimuli have evolved to enable the inter. Even early the “hallmark” feature. Williams syndrome is a rare regions of the frontal lobe. Brothers and mothers rather than their foster mothers (Maestripieri. (FFA). component of the social brain. anterior portions of inferotempo- genetic disorder caused by a hemizygous deletion in chromo. including the mirror neuron system and a region support to the notion of biological predispositions for social of the human fusiform gyrus known as the fusiform face area behavior.. concentrated in both the inferior temporal gyrus and on the dence to support this view. In the following section we will briefly summarize Brothers further argues that selective changes in social neurobiological and functional evidence implicating certain behavior as a result of a developmental disorder. Brothers (1990) suggests Neuroanatomy. Taken Brothers concludes her paper with a more direct line of together. perirhinal cortex. to the striatum and the hippocampal formation. Indeed. and restricted patterns of behaviors. intrinsic connections of the 13 amygdaloid nuclei (Amaral Recent research on other neurodevelopmental disorders et al.. interests. 1984. including two of the following characteristics: (1) behavior in macaque monkeys.. interests or achievements. additional regions of 2003). These changes in social behavior resulting from in cortical sensory processing (Freese and Amaral. body movements. However. cells that respond to faces. such as brain regions in social function. Of these three Amygdala The amygdala has long been implicated in the domains. The are impaired in autism may ultimately provide suggestive amygdala receives high-level information from all sensory evidence concerning what regions subserve normal social modalities.. There are additional projections After establishing the plausibility of a social brain. ral cortex. 1985. Indeed. Brothers et al. We view it as a modula- tionships. stimuli does the amygdala respond to? pretation of information about other individuals. This study highlights a mode of direct genetic the brain that may contribute to social processing have been inheritance of complex behavioral traits. impaired communication. the neuropathology of autism is still quite information needed to evaluate stimuli and to elicit appro- uncertain. sensory information from all modalities with contextual Unfortunately. dala give it a unique position to combine highly processed tence of a specialized neural substrate of social behavior. infant monkeys banks of the superior temporal sulcus (Gross et al. the amygdala projects to interest that is characteristic of patients with autism. For example..g. 2004) and amygdala innervate many autonomic and visceral control support of the notion that there is indeed a social brain. the amygdala is capable of interacting with wide- evidence—the existence of socially responsive cells in the spread brain regions to orchestrate an appropriate behav- macaque monkey cortex. the alteration in social behavior is often considered mediation of emotional and social behavior. Baylis et al. But. In the past two decades. autism. (2) failure to develop peer rela. 1993). The amygdala has been implicated in a like are found throughout the adult macaque temporal lobe. Hasselmo et al. 1992). Autism is a neurodevelopmental disorder characterized by deficits in What are the putative structures of the social brain? social interactions. The amygdala receives projections from a that alter social behavior may provide further insight into the variety of cortical areas..

memory modulation (Cahill and McGaugh. suggesting that global activation in the dala in other behaviors. 1992. reward association (Malkova primate amygdala have indicated that it is responsive to et al.. The orbitofrontal rior frontal gyrus and adjacent ventral premotor cortex. et al. 2000. Leonard Canli et al.. bounded by the collateral sulcus medially and the lateral social processing. The fusiform gyrus forms the posterior portion of the occipitotemporal amygdala is located in the anterior portion of the temporal lobe. (A) Lateral view: Anterior and posterior compo. Brothers and Ring. (C) Medial view: Anterior cingulate cortex of the inferior parietal lobule. Gottfried et al. remains controversial. expressions and direct eye contact (Rolls. and social behavior (Brothers. 166 fundamentals of developmental neurobiology ... 1998. 1984. Cortex surrounding the superior (ACC) is the frontal part of the cingulate cortex and includes temporal sulcus (STS) is also highlighted. A region of the fusiform gyrus. 1990. 2000). 2002. Baxter and Murray. 1993). 1992.2 Schematic overview of neural regions implicated in gyrus. including faces.. Brothers et al. The specific contributions of the amygdala are often marked by significant decreases of firing rates. many socially relevant stimuli. Electrophysiological recordings from the nonhuman 2000.. 1990. specific facial 2003). including fear processing (Davis. (B) Ventral view: The Brodmann’s areas 24 (ventral ACC) and 32 (dorsal ACC). However. 1985. neural responses to appeasing faces Amaral. Adolphs.Figure 11. 1997. 2000). LeDoux.. fear processing) have been whereas responses to threatening faces are associated with well characterized. 1999. 2001). 1998. Emery and In nonhuman primates. 2007). FFA) is generally anterior area with mirror neuron properties is located in the infe. located in the middle lateral fusiform gyrus. A posterior cortex (OFC) lies on the ventral surface of the frontal lobe just area with mirror neuron properties is located in the rostral portion above the eye orbits. Bachevalier.g. Kling. An selective for face stimuli (the fusiform face area. such as reward evaluation and social amygdala might be larger to threatening faces (Gothard behavior. the precise role of the amyg. nents of the human mirror neuron system (MNS) are shown. Davis and Whalen. to some of these processes (e. increased firing rate. et al. occipitotemporal sulcus laterally.

simple geometric shapes (R. et al. developed her lesion during adoles- vated by a variety of meaningful social signals. thus leaving open the possibility that the amygdala may play a Lesion studies. 2003)... viewing pictures of fear. Ohman. patient S.M. activation has also been reported during nonsocial testing it is important to note that patient S.1B).. patient S.M.. 1996. atrophy. the results of neonatal lesions of the amygdala in part 2 of tion regarding the function of the amygdala. particularly facial expressions depict. The amygdala is also activated when subjects make complex 1994) and was impaired in judging how much to trust social judgments. the amygdala would evaluate a vast array of poten. is married. does One unifying hypothesis is that the amygdala. has shown abnor- paradigms.M. Amygdala Though her deficits are primarily related to fear processing. and sadness (Morris.. 1992). patient S. For example. as well as several positive emotions (Breiter general... 2004)... In this role as a danger another famous example of an individual who has a com- detector.g.e.. Thus ready activation of the techniques combined with quantitative behavioral assess- amygdala by fearful faces (which convey the fact that there ments have found that amygdala damage in adult monkeys is a proximal danger) or when evaluating whether another does not preclude social interactions (Emery et al. 1998). Yet.. One would not expect.. damage. holds a job.g. bauman and amaral: neurodevelopment of social cognition 167 . It uses produce the majority of social signals. normal. Friston. expressions may be explained by an inability to make or evaluating social content during a social attribution task normal use of information from the eye region of the face. 2002). Schultz et al. 2002). generally resulting in danger signals.’s deficits in identifying fearful what someone may be thinking (Baron-Cohen et al. is for potential threats (figure 11. shows the most consistent deficits et al. it would not be surprising studies indicated that bilateral amygdala lesions dis- that the amygdala is particularly attuned to these “social” rupt species-typical social behavior. functions as a danger detector (Amaral. behavioral changes appeared more closely be consistent with its acting as a danger detector. suggesting that the amyg- amygdala do not remove social function. Canli et al.g. Other facial expressions depicting negative emotions. snakes or fire) to species. Human patients with bilateral amygdala role in acquiring social behavior at earlier ages. One of the this chapter. that involves perception of humanlike interactions among which is critical for identifying fear (Adolphs et al.M. 1998). another person after viewing the person’s face (Adolphs vidual is trustworthy (Winston et al. that the decreased affiliative behavior and subsequent social isolation evaluations carried out by the amygdala deal with the general when tested in socially complex environments (Kling. 2003). such lives independently. remarkably intact (i. 2001). despite his dramatic and near common to most vertebrates (e. anger. tions of danger are conveyed socially through facial expres. Patient H. malities in her ability to assess social stimuli not related to LaBar et al.. she does have areas of impaired function.e. 1998. have also resulted in amyg. 2003). 1998.. et al. was dala activation. can interpret and part.... In this case. It is clear related to deficits in fear processing rather than specific from lesion studies in humans that bilateral lesions of the impairments in social behavior.’s social behavior remains ing fear (Morris et al. Noninvasive functional neuroimaging experiments have most extensively studied patients with bilateral amygdala indicated that the human amygdala is preferentially acti. Patient S. 1996. 1999). but not as consistently as fearful expressions. category of others’ intentions or dispositions but only those However. yet they provide invaluable informa. 1997). One caveat to this interpretation is that dispositions of others. Cheng et al. and fails to normally attribute social intentions to videos of viewing threatening and fearful nonsocial stimuli (Hariri inanimate objects. such as determining whether an indi. nor do they gravely dala plays a modulatory rather than an essential role in impair an individual’s ability to judge the intentions or social behavior. related to fear processing. 2001).. While the reason for this failure is et al.. at least in not demonstrate autistic symptomatology. she has a high school education. 1998. however.. 2003).M. not able to recognize fearful expressions (Adolphs et al. Since indica. including fear conditioning (Buchel et al. cence from Urbach-Wiethe disease—a rare syndrome asso- sions are one of the most replicable elicitors of human ciated with selective bilateral amygdala calcification and amygdala activation.M. complete loss of the ability to form new episodic mem- specific displays of social aggression (e. a family).M. Morris. 1999). and is at least fairly incoming sensory information to evaluate the environment astute at engaging in social cognition.. 2005). of aversive stimuli (e. not likely to cause harm) would these animals. 2003). In individual is trustworthy (i. it does seem to be clear that patient S. his daily social interactions have been generally quite threat facial expressions of macaque monkeys). shock) (Phelps et al.. patient S.. discerning et al. recent studies utilizing more selective lesioning that might present a danger. anticipation (Heberlein and Adolphs. and is raising as disgust. Although patient S. plete bilateral loss of his amygdala and hippocampal forma- tially fear-inducing stimuli. these experiments were conducted in mature animals. open-mouthed ories. We discuss damage are very rare. such as the social attribution task described earlier phobia-related stimuli (Dilger et al.. unknown. The collective results from previous nonhuman primate sions and other biological gestures. ranging from threats that are tion (Corkin et al.M. Facial expres. In Blair et al...M.

2006). 2002). it tion. 1972)... is also affected by OFC damage. using facial expressions to guide this impairment leads to deficits in judging the disposi- behavior in a reversal learning paradigm (Kringelbach and tions and intentions of others. thereby influencing a wide range of relevant information combined with indicators of positive socioemotional behaviors (Kringelbach and Rolls. data from functional imaging studies action that supports both self-interest and social compati- indicate that the OFC is activated in response to complex bility. ligence tests. such as rating the attractiveness of a face following damage to the OFC. in social function remains equivocal. The cingulate cortex is recognized as a support the role of the OFC in social processing. A case study of a patient sustaining damage While there are intriguing neuroimaging and behavioral to the OFC reported profound changes in personality data indicating that the human amygdala is responsive to a that resulted in the patient engaging in risky behavior. viously high ranking macaque monkeys that received damage cingulate cortex. 1999. A more orbital cortex is similar in humans and nonhuman primates recent study utilizing selective OFC lesions found that (Petrides and Pandya. 1992. 2002). there is a substantial Converging evidence from nonhuman primates with and converging body of evidence that the orbitofrontal experimentally induced damage to the OFC support the role cortex is a central component of the social brain. chapter. The amygdala has been proposed to play an 2004. Data from human lesion studies further Neuroanatomy. of the OFC in complex social interactions. More potential danger. and Functional studies. deficits in self-regulation and an inability to use affective and social information to guide social behavior and social Orbitofrontal Cortex Whereas the role of the amygdala decisions. Deficits in these types of Rolls. 2004). Angrilli et al. aggressive behaviors and increased avoidance behaviors pies a larger percentage of total cortical volume as compared (Butter et al.. Human complex collection of cortical subregions that subserve a patients with bilateral lesions of the OFC show deficits in variety of cognitive. making social judgments of emotionally damage in other brain regions discussed later in this evocative or morally conflicted statements (Moll et al. Pre- This brain area has strong connections to the amygdala.Summary. 1994). Social dominance. Yet it is not clear whether (O’Doherty et al. emotional. Traditionally the OFC has been impli- atypical responses to specific social signals (Machado and cated in processing a variety of sensory information relating Bachevalier. Anterior Cingulate Cortex Lesion studies. The orbitofrontal cortex (OFC) lies on the which serves as an important indicator of social competency ventral surface of the frontal lobe just above the eye orbits. and negative conseq