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)

Experience effects on brain development 35


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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



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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



8/31

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



9/31

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



10/31

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



11/31

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



12/31

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,



13/31

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



14/31

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



15/31

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

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Experience Effects on Brain Development Possible Contributions to Psychopathology

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