Experience Effects on Brain Development Possible Contributions to Psychopathology
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Transcript of Experience Effects on Brain Development Possible Contributions to Psychopathology
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Experience eects on brain development: possiblecontributions to psychopathology
Aaron W. Grossman,1,2,3
James D. Churchill,1,2,4
Brandon C. McKinney,1
Ian M. Kodish,1,2,3 Stephani L. Otte,1 and William T. Greenough1,2,3,4,51Beckman Institute, 2Neuroscience Program, 3Medical Scholars Program, 4Departments of Psychology, 5Psychiatry,
and Cell and Structural Biology, University of Illinois at Urbana-Champaign, USA
Researchers and clinicians are increasingly recognizing that psychological and psychiatric disorders are
often developmentally progressive, and that diagnosis often represents a point along that progression
that is defined largely by our abilities to detect symptoms. As a result, strategies that guide our searches
for the root causes and etiologies of these disorders are beginning to change. This review describes
interactions between genetics and experience that influence the development of psychopathologies.
Following a discussion of normal brain development that highlights how specific cellular processes may
be targeted by genetic or environmental factors, we focus on four disorders whose origins range from
genetic (fragile X syndrome) to environmental (fetal alcohol syndrome) or a mixture of both factors(depression and schizophrenia). C.H. Waddingtons canalization model (slightly modified) is used as a
tool to conceptualize the interactive influences of genetics and experience in the development of these
psychopathologies. Although this model was originally proposed to describe the canalizing role of
genetics in promoting normative development, it serves here to help visualize, for example, the effects of
adverse (stressful) experience in the kindling model of depression, and the multiple etiologies that may
underlie the development of schizophrenia. Waddingtons model is also useful in understanding the
canalizing influence of experience-based therapeutic approaches, which also likely bring about organic
changes in the brain. Finally, in light of increased evidence for the role of experience in the development
and treatment of psychopathologies, we suggest that future strategies for identifying the underlying
causes of these disorders be based less on the mechanisms of action of effective pharmacological
treatments, and more on increased knowledge of the brains cellular mechanisms of plastic
change. Keywords: Mood disorders, schizophrenia, fragile X syndrome, fetal alcohol syndrome,
learning, memory, psychosis, treatment-based hypotheses, neuronal plasticity, glial plasticity, myeli-
nation, angiogenesis, canalization, kindling.
Some psychological disorders have a root cause that
has been relatively well characterized. The etiologies
of other disorders, however, are less well understood.
Comparisons of monozygotic and dizygotic twins
have illuminated the etiology of disorders that fall
into this latter category, such as schizophrenia and
depression. Despite a substantial genetic contribu-
tion, a large proportion of the variability in pheno-
typic expression and symptom severity across
individuals cannot be accounted for by genetics
alone. Non-genetic factors must therefore contribute
considerably to the etiology of these disorders. Non-
genetic factors largely refer to interactions between
an organism and its environment; we use the term
experience to broadly describe these interactions.
The past 3035 years have seen an increased ap-
preciation for the roles that experience can play both
in molding brain function in development and in
continuing to sculpt the brain throughout adult-
hood. A consistent finding indeed a principal
message in these studies is that experience has its
effects via activation of genes and modification of
their products. Visual experience, for example, altersgene expression in the developing visual system,
resulting in physiological and anatomical changes in
brain organization (Prasad et al., 2002). Many brain
enzymatic processes are regulated in various ways
by activity, as reflected by alterations in mito-
chondrial energy metabolism (e.g., Zhang & Wong-
Riley, 2000), and mitochondrial size/number (e.g.,
Isaacs, Anderson, Alcantara, Black, & Greenough,
1992). Because some of the effects of visual experi-
ence involve proteins that contribute to cell struc-
ture, this is a mechanism through which experience
may have lasting effects on neural function. In ad-
dition to discussing organic mechanisms through
which experience can affect the developing nervous
system, and in light of evidence that abnormalities of
central nervous system development can contribute
to psychopathology, we evaluate the role of experi-
ence in the development and treatment of psycho-
pathologies, even in cases in which a substantial
genetic basis is evident.
Appropriate experiences are critical for normal
psychological development, and several theories now
propose that many adult-onset psychological dis-
orders actually have an early developmental phase
during which symptoms are not observed or are
minimally expressed. These theories also suggestthat early adverse experiences can have dramatic
effects on the developing nervous system, the extent
of which depends in part on the individuals
Journal of Child Psychology and Psychiatry 44:1 (2003), pp 3363
Association for Child Psychology and Psychiatry, 2003.
Published by Blackwell Publishing, 9600 Garsington Road, Oxford OX4 2DQ, UK and 350 Main Street, Malden, MA 02148, USA
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genetically influenced sensitivity to these experi-
ences. Post (1992) theorized, for example, that
stressful experiences early in the progression of de-
pressive disorder may result in altered gene expres-
sion that could lead to changes in brain organization
and to potentiated stress reactivity. Future depres-
sive episodes could then be triggered by progres-sively less stressful experiences until depressive
episodes occur spontaneously. Because this theory
shares many characteristics with kindling, in which
repeated seizures are triggered by progressively
smaller stimuli, Posts theory became known as the
kindling model of depression. This model is des-
cribed in more detail below (see Depression).
Distorted or inappropriate experiences can lead to
psychopathology, and the resulting pathologies can
in turn distort subsequent experiences. These con-
cepts are central to the study of developmental psy-
chopathology and have been described in detail by
Rutter and Sroufe (2000). The brain substrates uponwhich these adverse experiences act to cause psy-
chopathology are the processes studied by develop-
mental neurobiologists. Evidence of the plasticity of
these processes in response to experience suggests
that appropriate modification of the types and levels
of an individuals experiences might be able to nor-
malize abnormal brain organization and thus
ameliorate mental dysfunction. The potential role for
experiences beyond those traditionally used in psy-
chological and psychiatric remediation therefore
deserves increased attention. In general, a broader
understanding of how experience affects brain or-ganization is needed to appreciate its potential con-
tribution to the development and treatment of
psychopathology.
One reason why the role of experience in the de-
velopment of psychopathology has received little at-
tention may be historical. As recent reviews have
noted (Martin, 2002; see also Kandel, 1998), psy-
chiatry diverged from neurology and from a primary
focus on brain pathology during the 20th century. As
neurology focused on disorders for which an organic
basis was evident, psychiatry focused on behavioral
disorders that lacked a discernable neuropathologi-
cal basis. Although most psychiatrists and neurolo-
gists would view this distinction as artificial, Martin
(2002) argues that significant differences in diagno-
sis and treatment approaches reflect the underlying
biases of these two fields. Neurology tends to focus
on treating the organic causes of the disorder,
whereas psychiatry tends to focus on behavioral
treatments and to base hypotheses about the origins
of a disorder on the currently proposed mechanisms
of action of successful treatments, and particularly
on drug efficacy findings since therapeutically valu-
able drugs have been available. With regard to major
depressive disorders, for example, implementation ofthe first antidepressant treatments, including
monoamine oxidase inhibitors and the tricyclic
antidepressants, led to a focus on norepinephrine
and other monoamine systems that the drugs were
primarily thought to affect. As the efficacy of sero-
tonin reuptake inhibitors became evident, serotonin
took center stage or at least a share of it, in combi-
nation with norepinephrine (for a review, see Nestler
et al., 2002). Likewise, the effectiveness of antipsy-
chotic (or neuroleptic) drugs that targeted dopaminereceptors was the basis for the dopamine hypothesis
of schizophrenia. Modifications in the dopamine
hypothesis first paralleled the discovery of novel re-
ceptor subtypes and then paralleled the progression
from typical antipsychotics such as phenothiazines
to the more preferred atypical antipsychotics that
have a different dopamine receptor affinity profile
from the previously dominant drugs (reviewed by
Strange, 2001).
There are several widely acknowledged reasons to
be cautious about these treatment-based hypotheses
regarding the etiology of psychopathologies. Re-
search aimed at demonstrating abnormalities inpharmacologically relevant neurotransmitter sys-
tems from patients with psychiatric illnesses has
been less than convincing (Nestler et al., 2002).
Moreover, it seems nave to believe that the mech-
anisms of therapeutic action of these and other
pharmacotherapies are limited to simple effects on
neurotransmitter receptors and transporters. The lag
between the time these drugs act on their target
synaptic enzymes, receptors and transporters and
the time a therapeutic response is observed in patient
behavior strongly suggests that the amelioration of
symptoms reflects long-term consequences of somecompensatory response to the treatment, rather than
the immediate pharmacological response. Although
treatment-based hypotheses about the etiology of
schizophrenia and depression may have enhanced
the focus on development of new drugs, research
strategies that are formed on these hypotheses lar-
gely restrict theoretical consideration of alternative
pharmacological and clinical approaches. More im-
portantly this may limit creative investigation of the
root causes and the factors influencing the etiology of
these and other disorders. With increasing know-
ledge of the brain correlates of psychopathology, in-
vestigators may be inspired to explore more closely
the role of genetic and experiential factors in psy-
chopathology development and not restrict their ap-
proaches to those emphasized by drug treatment-
based hypotheses.
A useful model for understanding how genetic and
environmental influences interact to affect the
course of development is provided by the old, but still
valuable conceptualization of canalization provided
by Waddington (1957). Waddington conceived of
normal development as represented by a groove in a
model surface representing the normative develop-
ment process over time (see Figure 1). Certain in-fluences, arising from genetic or environmental
sources, could operate on a process of brain
development and therefore on an individuals
34 Aaron W. Grossman et al.
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developmental progression either in a restorative or
canalizing manner, returning the trajectory toward
normative development, or in a disruptive manner,
leading the process away from the normative devel-
opmental pathway. The value of this representation
is that contributions of individual genes or experi-
ences can be recognized, and yet the continuing in-
teractive nature of the developmental process is
evident in the overall representation. This model
helps to conceptualize the interactions that might
occur with respect to a psychopathology whose de-
velopment reflects both genetic and environmental
contributions. We will return to this model as we
discuss specific aspects of pathological development.
Within this context, a non-comprehensive set of
experiences that may affect psychological develop-
ment is discussed here, largely because at least
some mechanisms through which they act have been
delineated experimentally. The quality of an organ-isms developmental environment, for example, is
among the experiences proposed to play a role in the
etiology of psychopathology. Certain components of
the developmental environment, such as learning
and physical exercise, interact with the animals
genome to affect brain organization and behavior.
Additionally, the effects of a number of extrinsic in-
fluences, including prenatal and postnatal stress,
toxins, and nutrition, that have cellular and mo-
lecular consequences are considered. Finally, gender
is considered both as a modulator itself, for example
in cases where gonadal steroids appear to directly
influence developmental organization of the nervous
system, and as a variable in determining how these
experiences differentially affect males and females.
In this review, we outline some basic mechanisms
of brain organization, highlighting ways in which
these mechanisms can be affected by experience.
This is followed by a discussion of the role of ex-
perience in the development of specific psychopa-
thologies whose root causes range from solely
environmental (e.g., fetal alcohol syndrome) toknown genetic abnormalities (e.g., fragile X syn-
drome), and finally to disorders whose etiology re-
flects a mixture of genetic and non-genetic
Figure 1 View of development, modified from C.H. Waddingtons (1940; 1957) concept of canalization. The normal
developmental trajectory can be viewed as the progression of an individual (represented by a ball) along a canal
initially specified by the genome. The form of the surface represents the concept that genetic influences collectively
tend to promote the normal developmental trajectory. Over time, genetic factors (black bar) and non-genetic
experiences (white bars) can influence the direction of the developmental trajectory, yet any given individual will not
encounter all of these influences. Adverse experiences can push the individual up the slopes of the canal toward the
thresholds for symptom expression (represented by the dotted lines) whereas canalizing experiences that have a
positive effect on the developmental course push the trajectory back toward the middle of the canal (the normal state).
Early in development, the slope of the canal banks is gentle such that even a relatively mild adverse experience can
push the trajectory beyond the threshold for psychopathology. As development progresses, the banks become steeper
and progressively more resilient to adverse experiences. The intrinsic value of this general model is that it permits a
number of disorders to be conceptualized in a manner that considers the interactive influence of genetics and
experience (see also Woolf, 1997)
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influences (e.g., schizophrenia and depression). The
clinical manifestation of these psychopathologies,
even the disorders whose etiologies are largely either
environmental or genetic, depends on the interac-
tions among these factors. While disorders such as
schizophrenia are generally considered to be adult-
onset disorders, it is becoming increasingly evidentthat the roots of this pathology, and others, lie in
early development. We conclude with a discussion of
the role of experience in treatment of several psy-
chopathologies, because it is the development of this
arena that is potentially most beneficial to patients
and their families.
Experience and the processes of neuraldevelopment
As has been repeatedly demonstrated, different or-
gan systems develop on different time courses, suchthat an environmental insult at a particular devel-
opmental stage may interfere with the development
of some organs but not others. Likewise, brain re-
gions develop at different times and the series of
orchestrated processes by which each brain region
develops also follows a discrete time course. These
processes include the basic mechanisms of neuro-
genesis, neuronal migration and differentiation,
synapse formation and remodeling, the development
of critical non-neuronal components (glia, myelina-
tion, cerebrovasculature), and neurodegeneration.
Early in normal development, these processes areguided largely by genetic influences, and experience
plays an increasingly important role over the course
of development. Even a minor genetically or envir-
onmentally induced deviation from the intended di-
rection of a single process, however, can have
dramatic effects on the outcome, and critical or
sensitive periods of vulnerability appear to exist
during which each process is particularly suscept-
ible to perturbation (reviewed by Rice & Barone,
2000). Due to space restrictions, the discussion of
each of these processes will be limited to a brief de-
scription of the normal developmental course, fol-
lowed by several examples of how experience can
affect each process. Far from exhaustive, this section
is intended to familiarize the reader with the role
experience plays in brain development; where poss-
ible the reader is referred to more complete reviews
on each topic.
Neurogenesis
The development of the nervous system begins with
induction of the neuroepithelium, the embryonic
source of the central nervous system, from a region
of ectodermal tissue due to trophic effects of under-lying tissue on the ectoderm. In an early phase, the
flat sheet of neuroepithelium folds into a neural tube
with a cavity, the central canal, that develops into
fluid-filled spaces of the spinal cord and brain such
as ventricles. As the anterior neural tube swells to
give rise to basic elements of the brain, a variety of
transcription factors and other genes induce the
generation of new neurons; neurogenesis continues
prenatally in a number of proliferative zones. The
proliferation of these cells follows a well-character-ized time course such that the timing of adverse ex-
periences or other environmental insults determines
where they most negatively affect the rate of devel-
opmental neurogenesis and the functional integra-
tion of these cells (Altman & Bayer, 1997; reviewed
by Rice & Barone, 2000). For example, in utero ex-
posure to methylmercury, which has been linked to a
form of infantile cerebral palsy, has been shown to
impair neurogenesis (Choi, 1989; Matsumoto, Koya,
& Takeuchi, 1965). In addition, prenatal exposure to
ethanol detrimentally affects neurogenesis in the
cerebral cortex, hippocampus and cerebellum,
leading to developmental delay (Miller, 1996; seeFetal alcohol syndrome).
Most neurons in the brain proliferate during pre-
natal brain development and early infancy; neuro-
genesis beyond the developmental period has been
controversial with respect to some brain regions, but
there is wide agreement that in several regions the
brain appears to efficiently and continuously gener-
ate small numbers (relative to glial cells and total
neuron numbers) of specific neuronal populations
throughout life (Alvarez-Buylla & Garcia-Verdugo,
2002; Eriksson et al., 1998; Gould, Reeves et al.,
1999). Various forms of experience have been foundto influence cell proliferation and survival rates
during the post-developmental period. In the com-
plex environment paradigm, animals are housed
communally in a cage that includes a variety of ob-
jects such as childrens toys and often a running
wheel. The behavior, neuroanatomy, and other
characteristics of animals exposed to this complex
environment condition are then compared with ani-
mals that were housed in standard laboratory cages
(without these extra objects). It has been reported
that exposure to a complex environment enhances
survival of newly generated neurons in the dentate
gyrus of adult rodents (Kempermann, Kuhn, & Gage,
1998). Because the effects of complex environment
exposure on neuroanatomy in weanling animals are
typically more pronounced than in adult animals,
one might predict that exposure to a complex envir-
onment would have even greater effects on the sur-
vival of new neurons in younger animals.
In the complex environment, animals are exposed
to a broad, non-specific range of experiences. Among
these experiences, physical activity appears to in-
duce neuron proliferation while learning enhances
the survival of new neurons in the post-develop-
mental brain. In adult rodents that had opportunityfor physical exercise on a running wheel in their
cage, neurogenesis in the dentate gyrus was signi-
ficantly increased compared to control animals
36 Aaron W. Grossman et al.
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(van Praag, Christie, Sejnowski, & Gage, 1999). With
regard to the viability of these new cells, it has been
reported that survival rates of new cells in the den-
tate gyrus were found to be higher following an as-
sociative learning task that required activation of the
hippocampal formation (Gould, Beylin, Tanapat,
Reeves, & Shors, 1999). These data suggest thatphysiological consequences of exercise, such as in-
creased blood flow, glucose uptake, angiogenesis,
and neurotrophic factors could be mediators of cell
proliferation, and these findings are consistent with
the hypothesis that physical activity often results in
brain changes that differ from those caused by
learning (Black, Isaacs, Anderson, Alcantara, &
Greenough, 1990; Oliff, Berchtold, Isackson, &
Cotman, 1998). Although there has been some dis-
cussion of the relative impact of learning and phy-
sical activity on post-developmental neurogenesis
(e.g., Greenough, Cohen, & Juraska, 1999), further
research is needed to delineate the specific effects ofthese two components of behavioral experience.
In contrast to the findings that certain behavioral
experiences generally increase the rate of post-
developmental neurogenesis, other experiences can
decrease neurogenesis. In both developing and adult
animals, stress reduces proliferation of dentate
granule cell precursors (Gould, Tanapat, McEwen,
Flugge, & Fuchs, 1998; Tanapat, Galea, & Gould,
1998). Among other effects, stress activates the hy-
pothalamic-pituitary-adrenal (HPA) axis, resulting in
the secretion of corticotropin releasing factor (CRF)
from cells in the hypothalamus into the portalbloodstream. CRF stimulates the release of adreno-
corticotropic hormone (ACTH) from the anterior pi-
tuitary, leading to glucocorticoid release from the
adrenal cortex (reviewed by Hiller-Sturmhofel &
Bartke, 1998). Bypassing the HPA axis and directly
administering glucocorticoids also decreased neuro-
genesis in the adult hippocampus, indicating that
the HPA-mediated response is central to the effects
of stress on neurogenesis (Cameron & Gould, 1994).
Maternal stress also reduces neurogenesis in the
dentate gyrus of the offspring, when later evaluated
as adults (Lemaire, Koehl, Le Moal, & Abrous, 2000).
Although the functional relevance of long-term im-
pairments in neurogenesis has yet to be defined,
these observations provide empirical support that
stressful events cause lasting neurobiological chan-
ges. In light of Posts (1992) kindling model of de-
pression (described in more detail in Depression),
these changes may alter the response to subsequent
stressors, resulting in more easily triggered depres-
sive episodes. Clearly the recognition that some re-
gions of the brain undergo post-developmental
neurogenesis that is sensitive to stress and to ac-
tivity has opened up a new potential avenue for un-
derstanding the basis of psychiatric syndromes,particularly depressive disorders, and these findings
also suggest routes for pursuit of potential thera-
peutic interventions.
Post-developmental neurogenesis is also influ-
enced by factors such as sex hormones and trau-
matic brain injury. During the estrous cycle,
neurogenesis fluctuates, increasing with higher es-
trogen levels (Tanapat, Hastings, Reeves, & Gould,
1999). Ischemia or other causes of focal brain lesion
also increase cell proliferation (Tzeng & Wu, 1999).In addition to these reactive responses in the hippo-
campal formation, cerebral cortical neurogenesis
appears to be triggered by experimentally induced
neurodegeneration, suggesting that trophic events
initiated by trauma may induce neurogenesis in re-
gions in which it is not routinely observed or occurs
only at much lower levels (Magavi, Leavitt, & Mack-
lis, 2000). These data suggest that signals evoked by
neuronal perturbation may permit neuroregenera-
tion to occur (Kuhn, Palmer, & Fuchs, 2001). The
compensatory nature of injury- and trauma-
enhanced neurogenesis in the cerebral cortex points
to a potentially important avenue for therapeuticintervention, as well.
Migration and differentiation
During development, the mammalian cerebral cortex
is formed by the radial and tangential migration of
successive waves of newly generated neurons.
Proper timing and guidance of migration is critical
for the appropriate organization and function of the
cortex. Many of the earliest-formed neurons migrate
from the proliferative zones toward either the surface
of the developing cortex along radial glial cells tooccupy the superficial-most layer of the mature
cortex or they may become displaced beneath the
developing cortex to become subplate neurons (Lu-
skin & Shatz, 1985). The remainder of the cerebral
cortex is formed in an inside-out fashion. First, the
deep layers of the cortex are formed from a wave of
migrating cells; a subsequent wave of cells migrates
past the deep layers of cortex to occupy more su-
perficial layers (Rakic, 1974). After reaching the ap-
propriate cortical layer, cells may also migrate
tangentially to their destination (see Nadarajah &
Parnavelas, 2002).
As precursor cells migrate, intrinsic and extrinsic
signals interact to trigger the expression of genes
that will impart a neuronal or glial phenotype (re-
viewed by Price & Willshaw, 2000). Many intrinsic
signals such as transcription factors can activate or
suppress expression of specific genes. Extrinsic sig-
nals such as extracellular matrix proteins, cell ad-
hesion molecules and growth factors, by contrast,
exert their effects primarily by activating signal
transduction cascades, many of which also regulate
gene expression. It has been suggested that both
intrinsic and extrinsic signals influence cortical de-
velopment by directing migration of pluripotent cells(capable of multiple paths of differentiation) that give
rise to multiple lineages of unipotent cells (Reid, Li-
ang, & Walsh, 1995). Although relatively little is
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known about the underlying mechanisms of cortical
cell differentiation, it seems clear that intrinsic and
extrinsic cues interact to determine the fate of each
cell, as has been observed in several model systems
(e.g., Livesey & Cepko, 2001).
Because normal development of the cerebral cor-
tex depends on the proper distribution of neurons,disruption of neuronal migration and differentiation
can have dramatic effects on cortical organization.
Environmental factors such as exposure to methyl-
mercury and in utero viral infections can impair
neuronal migration and differentiation (Barone,
Haykal-Coates, Parran, & Tilson, 1998; Lauder &
Schambra, 1999). Likewise, exposure to lead has
been shown to induce premature cellular differ-
entiation (Crumpton, Atkins, Zawia, & Barone,
2001). Maternal ingestion of alcohol during gesta-
tion (see Fetal alcohol syndrome) impairs formation
of basal forebrain neurons in the developing fetus,
leading to abnormal development of the cerebralcortex (Lauder & Schambra, 1999). For each of
these environmental toxins, the effects on brain
development and ultimately on behavior depend on
which subsets of neurons were undergoing active
migration and differentiation at the time of ex-
posure.
As reviewed by Pomeroy and Kim (2000), several
disorders of neuronal migration may have a genetic
basis; lissencephaly, a hallmark of Miller-Dieker
syndrome, has a substantial genetic component, as
does double cortex syndrome (Gleeson et al., 1998;
Reiner et al., 1993). More subtle disruptions of mi-gration and differentiation may play a significant role
in a number of disorders with unknown etiologies
such as epilepsy, schizophrenia, and mental retar-
dation (Bunney & Bunney, 2000; Chee, Chee, & Hui,
1995; Marin-Padilla, 1975). As with teratogens that
affect migration, migratory disorders of genetic origin
may have general or selective effects that reflect the
cells in which the genes are expressed and the timing
of their expression.
Synapse formation and remodeling
Following migration and differentiation, dendritic
outgrowth and the formation of synapses (synapto-
genesis) are phenomena that, beginning during early
phases of prenatal development, respond to specific
qualities of an animals environment. By streng-
thening some circuits via synaptogenesis or re-
modeling, and by weakening others through, for
example, synapse removal (synaptosis) or neuro-
degeneration, the brain remains plastic throughout
life. Genetic and environmental factors that guide
the processes of developmental plasticity can be
conceptualized as normative or canalizing influen-
ces, or as negative influences that can guide the in-dividual away from the middle of Waddingtons
developmental surface (see Figure 1). The capacity
for plasticity later in life can, as a result, be positively
or negatively influenced by these factors, making the
brain more or less able to adapt to future demands.
The initial outgrowth of dendrites and the estab-
lishment of synaptic contacts can occur without
synaptic activity (Verhage et al., 2000), and subse-
quent organizational changes may be driven by in-
trinsic activity not modulated by sensory input (Shatz& Stryker, 1988). Beyond this, the maturation and
maintenance of these contacts depends on patterned
neural activity. This is what Black and Greenough
(1986) referred to as an experience-expectant pro-
cess, in which particular sensory experiences guide
development at a particular point in time, at least
partially by selecting synapses to be preserved and
others to be pruned from a superfluous population of
synapses. The kinds of experiences that became in-
corporated into the development process were those
that were reliable in the evolutionary history of the
organism and available in the typical experience of all
species members, such that experience could achievea greater precision of fine-tuning of individuals
sensory systems than could be achieved by intrinsic
mechanisms alone. The well-characterized visual
system serves to illustrate this concept.
In most mammals, by birth or when the eyes open,
the visual cortex is already organized to begin pro-
cessing evolutionarily expected stimuli such as pat-
terned light. Initially, axons innervate the visual
cortex in an overlapping fashion. During develop-
ment, these axons are partially retracted or pruned
such that alternating columns of cells emerge, called
ocular dominance columns because their input isdominated by one eye or the other (Hubel, Wiesel, &
LeVay, 1977). Although recent data suggest that the
initial establishment of ocular dominance columns
can occur in the absence of visual input (Horton &
Hocking, 1996), the organizational fine-tuning of the
visual cortex appears to require patterned visual
input.
The development of ocular dominance columns
appears to involve competition between axons car-
rying input from each eye, as studies in which one
eyelid is sutured shut at birth have demonstrated
that ocular dominance columns innervated by the
open eye were wider than columns innervated by the
closed eye (e.g., LeVay, Wiesel, & Hubel, 1980). In
addition, synapses in the column that received nor-
mal patterned light stimulation (from the open eye)
exhibited a mature morphology and received multi-
ple axonal innervations, whereas synapses in the
deprived column had a more immature morphology
(Friedlander, Martin, & Wassenhove-McCarthy,
1991; Tieman, 1991). In terms of Waddingtons
model, phenomena that result in abnormal visual
input, such as monocular deprivation often caused
by muscular abnormalities that deviate one eye in
children (Horton, 2001), may push the trajectory ofbrain development out of the normal groove and, in
the absence of normalizing events, into a persisting
trajectory of abnormality (see Figure 1).
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In human cortical development, there is evidence
for a similar overproduction and pruning process, as
reflected in an initial proliferation of synapses during
early development, followed by a plateau and an
overall reduction in synapse number at later ages
(Huttenlocher & Dabholkar, 1997). As with experi-
ence-expectant processes in animals, altered inputsuch as sensory deprivation or disruption of pat-
terned stimulation alters the developmental traject-
ory in an increasingly irrevocable manner, as has
been observed in both basic and clinical cases (re-
viewed by Horton, 2001). Abnormalities in this
pruning process, as appear to exist in the case of
fragile X syndrome (see discussion below), may un-
derlie specific deficits in cognitive and behavioral
development.
Brain changes that depend on an organisms in-
dividual experience (not necessarily common to the
species) have been referred to as experience-
dependent plasticity (Black & Greenough, 1986). Inexperience-dependent plasticity, experiences asso-
ciated with learning appear to trigger the formation
of new synapses as opposed to selecting from syn-
apses already in existence. As a model of experience-
dependent plasticity, differential complexity of
housing has been used to characterize structural
plasticity in cortical neuroanatomical substrates.
Animals exposed at weaning (or later) to a complex
group environment exhibit enhanced dendritic ar-
borization, increased spine density, and more syn-
apses per neuron compared with animals housed in
standard laboratory housing conditions (as reviewedby Greenough & Chang, 1988). Exposure to a com-
plex environment also alters the morphology of
synapses, including shape of the dendritic spine,
size of the synaptic contact zone, and curvature of
the pre- and post-synaptic membranes.
Although it is clear that neural activity can alter
synaptic and dendritic morphology (e.g., Toni, Buc-
hs, Nikonenko, Bron, & Muller, 1999), it is less ob-
vious which components (learning or physical
activity) of an experience such as exposure to a
complex environment produce the patterns of neural
activity required to induce these morphological
changes. The necessary and sufficient factors gov-
erning experience-dependent plasticity have been
studied by comparing the brains of rats trained on a
motor-skill learning task with those of animals al-
lowed to exercise freely but with little opportunity for
learning. These studies have shown that the number
of synapses per neuron in both motor and cerebellar
cortices was greater in animals trained on the motor
skill learning task than in those that simply ex-
ercised or were inactive (Black et al., 1990; Kleim,
Lussnig, Schwarz, Comery, & Greenough, 1996).
Thus, a pattern of neural activity specifically related
to the motor skill learning component of the task wasnecessary to induce synaptic plasticity, whereas the
pattern of neural activity associated only with
physical activity involved in the motor skill task
(represented by the exercise-only animals) was not
sufficient to induce synaptic changes. By contrast,
animals that exercised had more capillaries, a
change not evident in the learning or inactive groups.
In a different skill learning paradigm, functional re-
organization parallels synapse formation in the mo-
tor cortex following learning of a skilled reachingtask (Kleim et al., 2002).
Thus experience-dependent plasticity represents a
different variety of brain adaptation from experience-
expectant plasticity, and it includes the common
forms of learning and memory, both declarative and
non-declarative (Eichenbaum & Cohen, 2001) and
other forms of long-term brain adaptation to the or-
ganisms environment and experience. These forms
of specific learning still find a home in the Wad-
dington developmental scheme (Figure 1): learning
can both facilitate future learning, which can have a
normative effect, and encode negative experiences
that can affect future behavioral reactions andchoices. That is, experiences that change dendritic
or synaptic morphology can also be detrimental to
cognitive and behavioral ability neural plasticity
defines the ability to incorporate the effects of
experience, whether or not that experience has a
positive or normative influence.
These influences are not, of course, limited to those
arising from learning. Inadequate nutrition during
postnatal development, for example, is associated
with lasting dendritic and neuronal abnormalities
and has been associated with behavioral deficits later
in life (Crnic, 1984; Leuba & Rabinowicz, 1979).Postnatal exposure to lead causes diminished den-
dritic arborization in areas such as the hippocampus,
cerebral cortex, and cerebellum (Kiraly & Jones,
1982; Lorton & Anderson, 1986; Patrick & Anderson,
2000), and broad spectrum behavioral deficits have
been associated with developmental lead exposure
(Dietrich, Ris, Succop, Berger, & Bornschein, 2001).
Likewise, prenatal exposure to ethanol may cause
brain region-specific changes in dendritic morphol-
ogy (Smith & Davies, 1990). These findings may
partially account for the cognitive and behavioral
deficits observed following perinatal exposure to
these and other toxins (e.g., Mattson & Riley, 1998).
Again, the specific effects of each of these disruptive
events reflect the developmental processes occurring
at the time of the insult.
Region-specific alterations in neural morphology
and brain anatomy have also been observed in re-
sponse to stress. Dendritic arborization in specific
hippocampal subfields is reduced following pro-
longed restraint stress or administration of gluco-
corticoids (Magarinos, McEwen, Flugge, & Fuchs,
1996; Woolley, Gould, & McEwen, 1990). Hippo-
campal volume is also reduced following prolonged
psychosocial stress, although evidence that thisvolume reduction involves dendritic atrophy is
lacking (Lucassen et al., 2001). Stress-induced
alterations in neuronal connectivity appear to have
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behavioral correlates, as impairments in spatial and
short-term memory have been associated with ele-
vated adrenal steroid levels (reviewed by McEwen,
1999). The remodeling of dendritic arbors in the
hippocampus in response to stress appears to be
transient, yet the potentiated hormonal response of
animals that were stressed early in life and exposedlater to a different stressful stimulus suggests that
specific, persistent neurobiological changes (e.g.,
decreased post-developmental neurogenesis; see
above) must result from stressful experiences (Ladd,
Owens, & Nemeroff, 1996; Luine, Villegas, Martinez,
& McEwen, 1994; Plotsky & Meaney, 1993; Post &
Weiss, 1997). These observations lend credence to
Posts (1992) concept that initial stressors may po-
tentiate the stress response to future adverse ex-
periences, ultimately leading to recurrent depressive
episodes.
The persistent nature of some neuronal changes
following experience may either be maladaptive inthat an experience potentiates the response to future
adverse experiences or it may establish an adaptive
response profile enabling the brain to respond more
efficiently to behavioral demands. The increased
dendritic arborization and synapse number that
result from exposure to a complex environment, for
example, persist for at least 30 days following
termination of this experience (Camel, Withers, &
Greenough, 1986; Briones & Greenough, unpub-
lished observations). Neuroanatomical effects of
motor skill training also persist in the absence of
continued training, as the number of synapses perneuron in the motor cortex remained elevated for at
least 4 weeks after training (Kleim, Vij, Ballard, &
Greenough, 1997). These observations suggest that,
even in the absence of continued levels of heightened
stimulation, the brain maintains the residue of past
experiences in these structural and functional
refinements, perhaps in expectation of future
experiences.
It should also be noted that enhanced neuronal
connectivity is not always adaptive. Experimental
induction of seizures in the hippocampal formation,
for example, is associated with increased synapse
number (Hawrylak, Chang, & Greenough, 1993).
Excess synaptic connectivity can have negative ef-
fects from a developmental perspective as well. In
post-mortem tissue from patients with fragile X
syndrome (FXS), dendritic spine density was higher
in two cortical regions than in control subjects (Irwin
et al., 2001). The excess synapses in FXS may be
developmentally left behind due to the failure of
normal pruning processes, and might simply add
extra noise to information processing activity in the
brain (see Weiler & Greenough, 1999). In fact, about
2025% of patients with FXS exhibit seizures, at
least during development, suggesting a parallel tothe synapse addition associated with experimental
induction of seizures in adult animals. This reminds
us that neural reorganization resulting from experi-
ence reflects the nature of the experience and may
have either positive or negative functional effects.
Thus one can see a broad variety of influences
interacting in ways that may be easier to visualize in
principle in terms of Waddingtons model than they
are to predict in practice with regard to their specific
effects on development. Experience-expectant pro-cesses require specific normative environmental in-
puts early in the progression along this surface, and
fragile X syndrome can be seen as an example of
experience-expectant mechanisms gone wrong the
failure to prune and possibly the failure to store
appropriate developmental information from experi-
ence. Experience-dependent mechanisms are more
frequently encountered as development moves down
Waddingtons surface, again having both normal-
izing and diversionary effects. Genetic mechanisms
guiding the formation of neural networks and their
plastic incorporation of information are largely nor-
malizing. In fragile X syndrome, and possibly inschizophrenia and depression, the genetic abnor-
malities may be amplified by the normal plastic
properties of the brain through repeated storage of
abnormal experiences.
Modification of non-neuronal componentsby experience
To the extent that psychologists and psychiatrists
have been interested in the effects of experience on
brain organization, the focus has generally been on
neuronal development and synaptic connectivity.Less attention has been directed to non-synaptic
aspects of brain organization including glial cells
and cerebrovasculature. Experience-induced chan-
ges in these components may affect brain function to
an extent not previously suspected (reviewed by
Grossman, Churchill, Bates, Kleim, & Greenough,
2002). Astrocytes, for example, are responsible for
regulating the synaptic environment and for main-
taining appropriate levels of neurotransmitters and
neurotrophins. Astrocytic hypertrophy following be-
havioral experience may merely reflect the increased
demand of maintaining the synaptic microenviron-
ment under increased load, or it may reflect altera-
tions that affect neural information processing in
more specific and selective ways, modifying func-
tional organization on a relatively transient or even
on a more lasting basis. Oligodendrocytes, through
axon myelination, enhance the conduction velocity
of nerve impulses, and altered myelination is an-
other way the brain changes in response to beha-
vioral demands. These changes in myelination are
substantial up to approximately 20% in adult an-
imals providing the opportunity for significant ef-
fects on functional neural circuitry. Thus the specific
information processing functions of both astrocytesand oligodendrocytes, heretofore largely overlooked,
could be very significant, as could their contribu-
tions to the etiology of mental disorders. It may be of
40 Aaron W. Grossman et al.
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particular significance that, whereas experience-
induced changes in astrocyte morphology appear to
be relatively transient, those changes in oligodend-
rocyte myelination of axons appear to be relatively
stable (see below). Cerebrovasculature may also play
a more important role in brain adaptation to be-
havioral demand than historically has been appre-ciated and, quantitatively, shows greater plasticity in
response to rearing in a complex environment than
any other element of the brain thus far described.
The nature of plasticity in these non-neuronal com-
ponents depends, as with neurons, on the nature of
the experience, and many of these changes persist
after the experience has been discontinued. Al-
though data are limited, there is growing evidence for
involvement of all of these components in psycho-
pathology.
Astrocytes. Gliogenesis in the developing nervous
system follows a well-characterized time course that,in the case of astrocytes, begins prenatally but can
persist throughout life (Lee, Mayer-Proschel, & Rao,
2000). Radial glia are the predominant glial cell type
during embryonic cerebral cortical development and
play a key role in neuronal migration. Once migration
is complete, many radial glia differentiate into mul-
tipolar astrocytes (Mission, Takahashi, & Caviness,
1991). The molecular mechanisms underlying
astrocytic development appear to be intrinsically
defined, yet also receptive to extrinsic cues from the
neural environment (Sauvageot & Stiles, 2002). Once
thought to play merely a supportive or nutritive roleto the function of neurons, astrocytes are now
believed to play a much more critical role in brain
development and synaptic plasticity (Lemke, 2001).
Astrocytes can modify synaptic function through re-
uptake and metabolism of neurotransmitters (Bezzi,
Vesce, Panzarasa, & Volterra, 1999), through mod-
ulation of synaptic activity (Araque, Parpura, Sanz-
giri, & Haydon, 1998; Smit et al., 2001), and through
assisting in synaptic remodeling (Hatton, 1997).
Following early reports that astrocytes and other
glial cells can be affected by experience (e.g., Szeligo
& Leblond, 1977), a number of studies have shown
that exposure to a complex environment causes
astrocytic hypertrophy (e.g., Jones, Hawrylak, &
Greenough, 1996), an effect that varies by cortical
layer and exposure duration (reviewed in Jones &
Greenough, 2002). Ultrastructural analysis reveals
that following exposure to a complex environment,
astrocytic processes more completely ensheathe
synapses, perhaps to optimize the synaptic micro-
environment in response to and in preparation for
increased neural activity (Jones & Greenough, 1996).
A possible human correlate of these animal findings
is that in postmortem tissue from individuals with
high professional status, the proportion of mito-chondria was higher in astrocytic somata in the
dorsolateral prefrontal cortex (a region involved in
executive function) compared with individuals of low
professional status, while there was no difference in
primary visual cortex (Black et al., 2001). Astrocytic
changes, in contrast to the persistent nature of syn-
aptic changes induced by motor skill training (Kleim
et al., 1997), appear to fade rapidly following the
discontinuation of training (Kleim, Ballard, Vij, &
Greenough, 1995).An alternative form of experience, neural damage,
results in reactive gliosis, or a proliferation of astro-
cytes and other glial cells near the site of damage.
Astrocytic proliferation during this process appears
to play an important role in neural repair (Ridet,
Malhotra, Privat, & Gage, 1997) and has been ob-
served following exposure to a variety of environ-
mental toxins, including ethanol and lead (e.g.,
Goodlett, Peterson, Lundahl, & Pearlman, 1997).
The elevated levels of glucocorticoids associated with
stress have also been implicated in alteration of as-
trocytic structure and function (Crossin, Tai,
Krushel, Mauro, & Edelman, 1997).Interestingly, stress effects on hippocampal as-
trocytes and complex environment effects on cere-
bral cortical astrocytes can be observed in the same
animals; the surface density of astrocytic processes
in the dentate gyrus (a stereological measure of their
amount) was highly correlated with adrenal weight
across experience groups (increasing as adrenal
weight increased), but uncorrelated with housing
condition (complex, social and individual cages).
Surface density of astrocytic processes in the visual
cortex, on the other hand, was highest in animals
exposed to a complex environment, but uncorrelatedwith adrenal weight (Sirevaag, Black, & Greenough,
1991). These observations suggest that astrocytes
may play many roles in the brains adaptive response
to behavioral experience. Effects of adverse experi-
ence on astrocytes may be involved in the develop-
ment of psychopathology as well (Coyle & Schwarcz,
2000). Several groups have reported glial cell loss in
the frontal cortex of patients with depression, and
although similar reductions in astrocytic measures
have been noted in patients with schizophrenia, the
reports are less consistent (reviewed in Cotter, Pari-
ante, & Everall, 2001). In the superficial dorsolateral
prefrontal cortex of schizophrenia patients, there
was a decreased proportion of astroglial processes
and a reduction in astrocytic ensheathement of syn-
apses compared with control subjects (Uranova,
Orlovskaya, Zimina et al., 2001).
Myelination. Myelinating glia share many char-
acteristics with astrocytes in their development (re-
viewed in Price, 1994). Once differentiated, Schwann
cells begin to myelinate axons in the peripheral
nervous system by approximately the 4th fetal
month in humans (Yakovlev & Lecours, 1967). Oli-
godendrocytes begin to myelinate fibers in some re-gions of the central nervous system prenatally, as
well, but most myelination in the central nervous
system occurs during the first two decades of life and
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in some brain regions, this process continues
throughout adulthood (Benes, Turtle, Khan, & Farol,
1994; Wiggins, 1986). The time course and extent of
central nervous system myelination appears to be
positively influenced by certain forms of behavi-
oral experience and negatively affected by many
environmental factors.An early account by Szeligo and LeBlond (1977)
described increased white matter myelination in rats
reared in a complex environment. Several studies
subsequently reported that exposure to a complex
environment caused an increase in myelination of
axons in the splenial corpus callosum, the area that
carries visual information between hemispheres
(e.g., Juraska & Kopcik, 1988). Effects of experience
on oligodendrocytes are evident in gray matter, as
well; complex environment exposure resulted in an
increased number of oligodendrocytes in the visual
cortex (Sirevaag & Greenough, 1987). These results
indicate that the brain responds to increased de-mands imposed by behavioral experience by myeli-
nating previously unmyelinated axons or by
extending new, myelinated axons. Unlike the relat-
ively transient nature of astrocytic changes induced
by behavioral experience, the increase in myelina-
tion observed in adult rats following 30 days of
complex environment exposure is maintained across
a subsequent 30-day period of individual, standard
laboratory housing (Briones, Shah, Juraska, &
Greenough, 1999). This persistence, paralleling that
of experientially induced synapses, suggests a
greater value of specifically localized myelination,as if enhancement of the speed of conduction in
particular circuits may play very specific behavioral
roles comparable to those believed to be played by
synapses in learning.
Myelinating glia appear to be preferentially tar-
geted by many environmental toxins, in part because
lipophilic substances accumulate in the cellular
membranes that make up myelin (Wiggins, 1986).
Ethanol exposure during development affects the
synthesis of myelin and proteins that are critical to
its normal function (Zoeller, Butnariu, Fletcher, &
Riley, 1994). These effects may account for some of
the abnormalities observed in the corpus callosum of
children prenatally exposed to alcohol (Riley et al.,
1995). With many of these environmental insults,
the time at which the insult occurs dictates the ef-
fects on the brain. It appears, for example, that
malnutrition impairs myelin development most pro-
foundly during the period of oligodendrocyte pro-
liferation and not during the period of active axon
myelination (Wiggins, 1982).
There is some evidence for myelin pathology and
abnormalities in myelin-associated proteins in schi-
zophrenia (Foong et al., 2000; Hakak et al., 2001).
Recent work has also discovered morphological evi-dence of elevated levels of myelin pathology in cor-
tical autopsy samples from schizophrenia patients
(Uranova, Orlovskaya, Vikhreva et al., 2001). Of
particular interest is that the pathology was not re-
stricted to regions of the dorsolateral prefrontal
cortex that are traditionally associated with schizo-
phrenia; equivalent myelin pathology was evident in
primary visual cortex of patients with schizophrenia
compared with matched controls, suggesting that at
least some schizophrenia-related pathology may oc-cur throughout the brain. Whether these myelina-
tion effects are primary in schizophrenia or
secondary consequences of other factors remains to
be determined, but these data clearly indicate that
searches for cellular pathology underlying schizo-
phrenia and other psychiatric conditions should in-
clude non-neuronal elements of the brain, as well as
brain regions not thought to be involved directly in
the disorders.
Cerebrovasculature. Despite literature that argued
that the brains capillary system was not plastic (e.g.,
Diamond, Krech, & Rosenzweig, 1964; Rowan &Maxwell, 1981), cerebrovasculature appears to be
quite responsive to experience. Functional magnetic
resonance imaging has revealed that vascular ca-
pacity is elevated in response to increased demand in
the motor cortex of animals allowed to exercise freely
(Swain & Greenough, in press). Likewise, capillaries
are both larger, on average, and more elaborately
branched in rats following exposure to a complex
environment that begins at weaning than in indi-
vidually caged animals (Black, Sirevaag, & Gre-
enough, 1987). It appears that angiogenesis is driven
more by the repeated performance of unskilledmovements such as those produced during exercise
than by skill learning, which causes synaptogenesis
(Black et al., 1990). The fact that experimentally in-
duced hypoxia can similarly drive relatively rapid
angiogenesis (Harik, Hritz, & LaManna, 1995) sug-
gests that some physiological feedback from blood
oxygen levels or a related metabolic demand may
activate vascular proliferation.
As noted above, experience-induced changes in
the number of synapses and myelinated axons ap-
pear to be relatively stable in the absence of contin-
ued environmental demand or training, whereas
astrocytic effects of motor skill training in the cere-
bellum disappeared relatively rapidly when training
was discontinued. Although the persistence of the
experience-induced changes in cerebrovasculature
has yet to be tested, one might speculate that added
synapses and myelin are relatively stable because
they represent information-based additions to the
functional wiring diagram of the brain that have
significant survival value. In contrast, astrocytic and
possibly vascular changes are general, easily initi-
ated responses to immediate demands of experience
that can be discarded, conserving valuable metabolic
resources in the absence of continued environmentalpressure. To date there have been remarkably few
studies of vascular changes associated with psy-
chopathology, possibly because the above work
42 Aaron W. Grossman et al.
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suggests that vascular responsiveness reflects rather
than drives levels of physiological and metabolic
activity. It is possible, however, that the relative in-
activity of typical hospitalized patients could lead to
vascular insufficiency that exacerbates symptoms of
otherwise unrelated disorders; the merits of in-
creased activity or exercise in such cases might be afruitful avenue of investigation.
Neurodegeneration
The development and refinement of neural networks
often, if not always, involves the removal of a subset
of neurons in the brain through a process of pro-
grammed cell elimination known as apoptosis (Kerr,
Wyllie, & Currie, 1972). This sequence of intrinsic
and extrinsic signals that triggers apoptotic events
has been differentiated from other forms of neuro-
degeneration such as necrosis and excitotoxic cell
death caused by elevated levels of glutamate or itsanalogs (Olney & Ishimaru, 1999; Wyllie, Kerr, &
Currie, 1980). Over half the neurons in the mam-
malian nervous system are ultimately eliminated by
apoptosis, which occurs not only in mature, func-
tionally connected neurons, but also reflects the fate
of many newly generated cells before they become
integrated into active neural networks (Rakic &
Zecevic, 2000). Apoptosis among precursor cells is
thought to assist in selecting regionally appropriate
phenotypes and to aid in the elimination of cells with
genetic abnormalities (Voyvodic, 1996). In rodents
and other mammals, later periods of widespreadapoptosis serve to remove cells that no longer con-
tribute to active cortical networks, and to more se-
lectively match appropriate patterns of synaptic
connectivity (Rakic & Zecevic, 2000). Post-develop-
mental neurogenesis, in turn, may function to add
cells to these cortical networks.
In addition to triggering cellular elimination,
apoptotic enzymatic cascades at the level of den-
drites and individual synapses may serve to remove
selected connections that no longer play a necessary
role in efficient communication between neurons.
This process and the removal of synapses through
yet undefined mechanisms are defined collectively
here as synaptosis, and appear to be critical for
normal neural plasticity. Clearly synaptosis plays a
role in those examples of experience-expectant
plasticity discussed above where synapse over-
production is involved; whether synapse overpro-
duction followed by synaptosis also plays a role in
experience-dependent plasticity that is, in the
brains response to discrete learning-related experi-
ences remains unclear but possible. The loss of
some synapses and the maintenance of others may
share many features with apoptosis, in which the
process appears to be balanced by protective anti-apoptotic signals, creating an adaptive system that
regulates the trophic response to synaptic activity
and the spread of apoptotic enzymes through the
neurites to the nucleus (Mattson & Duan, 1999).
Activation of these cascades in restricted dendritic
regions at levels that do not cause whole-cell death
may help regulate local synaptic plasticity by cleav-
ing proteins such as actin (Kayalar, Ord, Testa,
Zhong, & Bredesen, 1996), spectrin (Wang et al.,
1998), and subunits of AMPA-type glutamate re-ceptors (Chan, Griffin, & Mattson, 1999). For proper
neural function, a balance must seemingly be
maintained between neurogenesis and neurodegen-
eration, as well as between synaptogenesis and syn-
aptosis. It is possible that impaired synaptosis is
involved in fragile X syndrome (see below).
Whether synaptically active or expressed in the cell
nucleus,neurodegenerativeprocessesoftenrepresent
mechanisms by which experience may affect brain
development. Prenatal exposure to ethanol, for ex-
ample, induces apoptosis and alters neuron number
and function in multiple brain regions, causing sig-
nificant cognitive impairments (Ikonomidou et al.,2000). Exposure to other environmental toxins such
as methylmercury and lead also appears to cause
neurodegeneration via apoptosis, the location of da-
mage varying with the timing of exposure (Nagashima
et al., 1996; Oberto, Marks, Evans, & Guidotti, 1996).
Traumatic brain injury may trigger cell death
through a combination of neurodegenerative mech-
anisms. According to Ishimaru et al. (1999), excito-
toxic cell death is observed quickly around the site of
injury, whereas apoptotic cell death is observed later
and in regions distant from the injury. Neurodegen-
eration via excitotoxicity and apoptosis have alsobeen observed in response to hypoxia-ischemia
(Ikonomidou, Mosinger, Salles, Labruyere, & Olney,
1989) and in response to seizures that model epilepsy
(Covolan, Smith, & Mello, 2000). Glucocorticoids,
secreted during stress, also have neurodegenerative
effects particularly in the hippocampus, which may
contribute to the lasting effects of stressors that
possibly sensitize an individual to onset of depressive
episodes (reviewed in Sapolsky, 2000).
Exposing rats to a complex environment, by con-
trast, appears to reduce spontaneous apoptotic cell
death in the hippocampus to approximately half that
of rats in standard laboratory housing (Young,
Lawlor, Leone, Dragunow, & During, 1999). This
study also demonstrated that excitotoxic injury by
experimental seizure induction was attenuated fol-
lowing complex environment exposure, suggesting
that differential experience can be anterogradely
neuroprotective. In addition to neuroprotective ef-
fects, the brain appears to compensate for neurode-
generative cell loss through generation of new
neurons (reviewed in Kuhn et al., 2001).
Experience and the developmentof psychopathologies
In the preceding discussion of brain development, it
was evident that each developmental process follows
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a well-defined time course that has periods during
which the process is more sensitive to experiential
perturbations than during other periods. As
psychopathologies are increasingly found to be as-
sociated with disruptions in these developmental
processes, it becomes increasingly clear that the
development of these psychopathologies likely alsofollows a well-defined time course. This suggests that
at least some aspects of psychopathology may result
from adverse experiences during one or more of
these sensitive periods of brain development.
Several disorders serve as exemplars of how ex-
perience and genetics can interact to influence the
development of psychopathology. Fetal alcohol syn-
drome (FAS), for example, is a disorder whose root
cause is environmental. The root cause of fragile X
syndrome (FXS), on the other hand, is genetic.
Schizophrenia and depression serve as excellent
examples of disorders in which genetic and
non-genetic factors both play significant roles in thedevelopment and onset of psychopathology. In the
latter two examples, early adverse experiences
appear to have significant effects on the developing
nervous system that may alter the systems response
to subsequent events. In all four examples, however,
the influence of both experience and genetics is evi-
dent. We will consider each disorder in turn, des-
cribing some of the associated neuropathologies and
discussing the disorder from a neurodevelopmental
perspective, stressing the influence of experience on
this psychopathology. Again, the discussions of
these disorders are not exhaustive due to spaceconstraints. Later, we will consider the potential role
of experience in the treatment of these disorders.
Given the ability of the brain to adapt over the course
of a lifetime, certain underlying pathobiologies of
these and other psychopathologies should be
amenable to intervention strategies that may at-
tenuate symptom severity.
Fetal alcohol syndrome
Prenatal alcohol exposure can have permanent ad-
verse effects on the human fetus; one of the most
severe outcomes is fetal alcohol syndrome (FAS).
Children who are affected by prenatal alcohol expo-
sure but do not express all of the features of FAS are
often diagnosed with fetal alcohol effects (FAE) or
characterized as having an Alcohol-Related Neuro-
developmental Disorder (ARND). The clinical and
behavioral correlates associated with FAS and FAE
include microcephaly, growth retardation, deficits in
cognitive functioning, and fine and gross motor im-
pairments. Facial dysmorphologies are additional
characteristics of FAS and are used as a component
of the diagnosis. For a more complete review of these
clinical and behavioral correlates, see Lewis andWoods (1994) and Mattson and Riley (1998). The
most common neuropathologies observed in the
brains of individuals with FAS are a reduction in
overall brain size, with shrinkage of the basal gan-
glia, shrinkage and loss of neurons in the cerebellum
and hippocampus, and thinning to complete agen-
esis of the corpus callosum (reviewed by Roebuck,
Mattson, & Riley, 1998). Neuropathologies in FAS
result largely from ethanol-induced disruption of
neurodevelopmental processes such as proliferation,neuronal differentiation, and neurodegeneration.
The developmental processes that are affected,
and therefore the extent and severity of a childs
condition, depend on several factors including how
much, how often, and during what periods of her
pregnancy the mother consumed alcohol. The effects
of alcohol on brain development are more detrimen-
tal, for example, if a single, large amount of alcohol is
consumed yielding a high peak blood alcohol content
(BAC) than if multiple exposures occur but the BAC
never reaches as high a level (Bonthius, Goodlett, &
West, 1988). In humans, the period of prenatal brain
growth during which the effects of alcohol are mostpronounced is in the latter stages of pregnancy
(West, 1987). As an animal model to study the effects
of alcohol on the developing brain, rats are exposed
to ethanol either during the final days of gestation,
which corresponds to the second trimester of human
brain development (Miller, 1986) or during the first
14 postnatal days, which corresponds to brain de-
velopment during the third trimester of human
pregnancy (West, Goodlett, Bonthius, & Pierce,
1989). In general, the effects of prenatal ethanol ex-
posure on rat brain development differ from those of
postnatal ethanol exposure, supporting the idea thatsensitive periods of vulnerability also exist during
the various stages of human pregnancy.
Perhaps the most detrimental results of alcohol
exposure during development are the loss of neurons
in brain regions such as the hippocampus and neo-
cortex (Ikonomidou et al., 2000; Miller, 1995), and
the profound loss of Purkinje cells and granule cells
in the cerebellum (Bonthius & West, 1990). Ethanol
appears to cause apoptosis in the developing brain
by a mechanism similar to other drugs that act as
glutamate receptor antagonists or GABA receptor
agonists (Olney, Ishimaru, Bittigau, & Ikonomidou,
2000; see Neurodegeneration). In the rat, Purkinje
cells in the cerebellum appear to be more vulnerable
to the detrimental effects of ethanol exposure during
their differentiation, which occurs postnatally (along
with significant continuing cerebellar granule cell
genesis) than during their proliferation, which oc-
curs prenatally (Marcussen, Goodlett, Mahoney, &
West, 1994). After this sensitive period, the effects of
ethanol exposure on Purkinje cell number are less
severe (Goodlett & Eilers, 1997). In humans, the
corresponding period of Purkinje and granule cell
vulnerability occurs prenatally, leading to symptoms
associated with prenatal ethanol exposure. Even inthose Purkinje and granule cells that survive ethanol
exposure, the mean dendritic arbor size is reduced
and synapses exhibit abnormal morphology (Smith,
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Foundas, & Canale, 1986; Volk, 1984). Exposure to
ethanol also affects the development of astrocytes
and radial glia, which are involved in neuronal mi-
gration, although the specific effects depend on the
timing and nature of exposure (Goodlett et al., 1997;
Guerri, Pascual, & Renau-Piqueras, 2001). The
timing of sensitive periods of vulnerability, such asthat observed for Purkinje cell loss, appears to be
brain region-specific, suggesting that the timing of
the mothers alcohol consumption over the course of
brain development influences the range of deficits
observed in the offspring (Maier & West, 2001).
Although the etiology of FAS is environmental, the
existence of discrete periods during which the
brain is highly vulnerable to ethanol toxicity
supports the view that experience interacts with
genetically determined developmental time courses
to affect brain development (reviewed by Rice &
Barone, 2000).
Fragile X syndrome
In contrast to FAS, fragile X mental retardation
syndrome has a well-characterized genetic root
cause, whose symptoms may vary with experiential
factors. Fragile X syndrome (FXS), the most com-
mon inherited form of mental retardation, is caused
by a mutation in the FMR1 gene that prevents its
expression and hence prevents the synthesis of its
protein product FMRP (Pieretti et al., 1991). Stud-
ies in vivo and in vitro suggest that FMRP is in-
volved in synaptic maturation and plasticity(Churchill et al., 2002). For example, autopsy brain
tissue from patients with FXS and the brains of
FMR1 knockout mice that also lack FMRP exhibit
deficits that suggest a failure of the normal neu-
ronal and synapse maturation processes (Irwin
et al., 2001; Irwin et al., 2002). Synapses in both
human FXS patients and in the mouse model of the
disorder appear to retain an immature appearance,
and in humans there is an excess number of
dendritic spines that has been interpreted to reflect
a failure of the normal process of synapse elimin-
ation in development (although it could also reflect
a continuing process of synaptogenesis). Consonant
with the elimination failure hypothesis, normal
developmental withdrawal of inappropriately locat-
ed dendrites is also impaired in the mouse model
(Galvez, Gopal, & Greenough, submitted). FXS is
most commonly associated with mental retardation
and broad-spectrum developmental delay (includ-
ing cognitive, language and motor abilities) but is
also often associated with a variety of symptoms,
only some of which are seen in any individual pa-
tient. Many patients with FXS exhibit autistic-like
behaviors that are indistinguishable from idio-
pathic autism using standard diagnostic instru-ments (Rogers, Wehner, & Hagerman, 2001).
Separate, partially overlapping subsets of patients
may exhibit other symptoms such as seizure sus-
ceptibility, social anxiety, stereotypy, short-term
memory deficits, hypersensitivity to sensory sti-
muli, hyperactivity and attention deficits (Berry-
Kravis, Grossman, Crnic, & Greenough, 2002;
Hagerman, 2002).
The heterogeneity of individual patterns of
symptoms in FXS suggests at least two possibleinterpretations. The first interpretation is compat-
ible with what appears to be the principal function
of FMRP: binding to particular messenger RNAs
and regulating either the degree of expression or
the location in the cell of the protein(s) encoded by
each mRNA (ODonnell & Warren, 2002; Miyashiro
et al., submitted). Differences in the location and
level of FMRP production and polymorphisms in
the genes whose mRNAs are bound by FMRP
would influence the expression patterns and ac-
tions of these proteins. Variability in the expres-
sion patterns of these mRNAs and their proteins in
various brain regions could in turn account for thediversity of behavioral patterns observed across
patients with FXS. Although these features suggest
a high degree of genetic determinism, the contri-
bution of home environment quality to cognitive
ability and to expression of problem behaviors and
autistic symptoms has been noted (Dyer-Friedman
et al., 2002; Hessl et al., 2001). These studies
suggest that improving the home environment
could serve as experiential therapeutic approaches
(see Treatment), and make it clear that differences
in experience can interact with these intrinsic
(genetic) sources of variability, yielding multipleoutcomes.
A second interpretation of the heterogeneity of FXS
is that multiple developmental courses may exist.
Patients may converge from a variety of starting
points onto a generally aberrant developmental state
that, when reached, is difficult to overcome or move
away from developmentally. The symptoms of aut-
ism observed in some patients with FXS suggest that
particular states exist in the brain development
process that can be reached in diverse ways but that
have similar behavioral consequences. Behaviors
such as stereotypy and attention deficits could rep-
resent these stable attractors or absorbing states
in that they are associated with multiple disorders
and are difficult to overcome once expressed. This
phenomenon can be illustrated in the canalization
model of Waddington with the idea that there may be
multiple genetically or environmentally influenced
routes to common developmental outcomes (see
Figure 2), as well as multiple outcomes in a common
genetic syndrome.
The examples of fragile X syndrome and fetal
alcohol syndrome reinforce the view that disorders
whose etiology is primarily genetic may have sig-
nificant environmental components that determinetheir specific expression patterns, and vice versa.
As noted above, other psychopathologies appear to
share such sensitivity to experience. Schizophrenia
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and depression, for example, show greater concor-
dance in monozygotic than in dizygotic twins,
suggesting a strong genetic component. The con-
cordance rates, however, are not 100%, indicating
a significant role for non-genetic factors in their
etiology. Schizophrenia and depression, as well as
many other psychiatric illnesses that have been
typically considered adult-onset disorders, are now
recognized increasingly to have progressive devel-
opmental components (see Lewis & Leavitt, 2002).
That is, with the exception of acute, well-defined
events that may rapidly induce the symptoms of a
disorder (e.g., drug induced psychosis), it could be
argued that the clinical manifestation of these dis-
orders is typically the culmination of a long se-
quence of subtle, neurodevelopmental insults that
may have begun very early in life. As more about
the developmental progression of psychiatric dis-
orders is discovered, it is becoming clear that an
increasing number of mental illnesses have a neu-
rodevelopmental basis and result from the lastingneurobiological effects of early experience that can
set the stage for the later development of psycho-
pathology.
Schizophrenia
The concordance rate for schizophrenia is 50% in
monozygotic twins and 17% in dizygotic twins, in-
dicating a strong genetic component (Tsuang,
2000). It has been suggested that the clinical ma-
nifestation of schizophrenia could be accounted for
by the additive effects of a number of deficient genes
(Risch & Baron, 1984). Indeed, linkage studies have
suggested the existence of susceptibility genes on at
least five chromosomes (Moises et al., 1995). One of
these polygenic theories proposes that diversity in
symptom profiles among individuals with a schizo-
phrenic genotype depends, in part, on the number
of susceptibility genes expressed beyond a thresh-
old (Woolf, 1997). While there is intrinsic value in
polygenic theories, additional non-genetic factors
must influence the symptom expression of schizo-
phrenia to account for incomplete concordance
rates in monozygotic twins. Observations that neu-
ropsychological deficits exist in the unaffectedmonozygotic twin and first-degree relatives of pa-
tients with schizophrenia suggest an interaction
between genetics and the environment that
Figure 2 Absorbing states or stable attractors in the development of psychopathology. Over the course of develop-
ment, multiple etiologies including genetic predispositions (left path) and adverse experiences (right path) may lead
to an individuals progression beyond the thresholds for symptom expression. As appears to be the case for certain
behaviors that are associated with multiple disorders, absorbing states or stable attractors (depicted by a groove in
the developmental surface) appear to exist as we have depicted in Waddingtons model. In the stable attractor model,
many genetic and experiential influences can lead to a common state (e.g., stereotyped behavior in various forms of
autism, fragile X syndrome, and other disorders) and it becomes progressively more difficult for an individual to
progress beyond or move out of that stable attractor. This concept could account for disorders that have multiple
etiologies (e.g., schizophrenia) and also suggests how multiple disorders with different etiologies can yield symptoms
that are indistinguishable (e.g., autistic-like behaviors in children with fragile X syndrome and children with idio-
pathic autism). Conventions are as described in Figure 1
46 Aaron W. Grossman et al.
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influences the expression of psychotic symptoms
(Toomey et al., 1998).
Schizophrenia is viewed increasingly as a devel-
opmental disorder whose presentation represents a
point along a continuum at which effects of the in-
teraction between genetics and experience finally
surpass an individuals threshold for symptom ex-pression (Lewis & Levitt, 2002). Insights into the
developmental progression to psychosis come, in
part, from retrospective studies examining the psy-
chosocial behavior of children who later develop
schizophrenia. Mild deficits in social, motor, and
cognitive functioning indicative of premorbid fea-
tures of schizophrenia were observed in infants
(Walker, 1994), and in children and adolescents
(Cannon et al., 1997) who later exhibited psychotic
symptoms. Attention deficits and inappropriate so-
cial interaction have also been noted in children who
later manifest schizophrenia; the severity of these
abnormalities increases with age through adoles-cence (Walker, Diforio, & Baum, 1999). This period
of emerging symptom presentation commonly de-
velops into a pre-psychosis prodromal state on the
continuum from normal cognition toward schizo-
phrenia (see Moller, 2001). During childhood and
this prodrome, neuropsychological impairments
may be phenotypic markers of increasingly compro-
mised brain organization, eventually leading to psy-
chosis (Rosen, Woods, Miller, & McGlashan, 2002).
Morphological studies of schizophrenic patients
early in their disorders also lend support for devel-
opmental theories of schizophrenia. Minor physicalanomalies, such as low-set ears and abnormal palate
height, which are often observed