Journal of Child Psychology and Psychiatry 44:1 (2003), pp 3363

Experience eects on brain development: possible contributions 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. Greenough1,2,3,4,5
1

Beckman 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 dened 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 inuence the development of psychopathologies. Following a discussion of normal brain development that highlights how specic 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 modied) is used as a tool to conceptualize the interactive inuences 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 inuence 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, myelination, 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 contribution, a large proportion of the variability in phenotypic 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. Nongenetic 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 appreciation for the roles that experience can play both in molding brain function in development and in continuing to sculpt the brain throughout adulthood. A consistent nding indeed a principal message in these studies is that experience has its effects via activation of genes and modication of their products. Visual experience, for example, alters gene 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 reected by alterations in mitochondrial energy metabolism (e.g., Zhang & WongRiley, 2000), and mitochondrial size/number (e.g., Isaacs, Anderson, Alcantara, Black, & Greenough, 1992). Because some of the effects of visual experience involve proteins that contribute to cell structure, this is a mechanism through which experience may have lasting effects on neural function. In addition 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 experience in the development and treatment of psychopathologies, 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 disorders actually have an early developmental phase during which symptoms are not observed or are minimally expressed. These theories also suggest that early adverse experiences can have dramatic effects on the developing nervous system, the extent of which depends in part on the individuals

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 inuenced sensitivity to these experiences. Post (1992) theorized, for example, that stressful experiences early in the progression of depressive disorder may result in altered gene expression that could lead to changes in brain organization and to potentiated stress reactivity. Future depressive episodes could then be triggered by progressively 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 described 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 concepts are central to the study of developmental psychopathology and have been described in detail by Rutter and Sroufe (2000). The brain substrates upon which these adverse experiences act to cause psychopathology are the processes studied by developmental neurobiologists. Evidence of the plasticity of these processes in response to experience suggests that appropriate modication of the types and levels of an individuals experiences might be able to normalize abnormal brain organization and thus ameliorate mental dysfunction. The potential role for experiences beyond those traditionally used in psychological and psychiatric remediation therefore deserves increased attention. In general, a broader understanding of how experience affects brain organization is needed to appreciate its potential contribution to the development and treatment of psychopathology. One reason why the role of experience in the development of psychopathology has received little attention may be historical. As recent reviews have noted (Martin, 2002; see also Kandel, 1998), psychiatry 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 neuropathological basis. Although most psychiatrists and neurologists would view this distinction as articial, Martin (2002) argues that signicant differences in diagnosis and treatment approaches reect the underlying biases of these two elds. 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 efcacy ndings since therapeutically valuable drugs have been available. With regard to major depressive disorders, for example, implementation of the rst 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 efcacy of serotonin reuptake inhibitors became evident, serotonin took center stage or at least a share of it, in combination with norepinephrine (for a review, see Nestler et al., 2002). Likewise, the effectiveness of antipsychotic (or neuroleptic) drugs that targeted dopamine receptors was the basis for the dopamine hypothesis of schizophrenia. Modications in the dopamine hypothesis rst paralleled the discovery of novel receptor subtypes and then paralleled the progression from typical antipsychotics such as phenothiazines to the more preferred atypical antipsychotics that have a different dopamine receptor afnity prole 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. Research aimed at demonstrating abnormalities in pharmacologically relevant neurotransmitter systems from patients with psychiatric illnesses has been less than convincing (Nestler et al., 2002). ve to believe that the mechMoreover, it seems na 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 reects long-term consequences of some compensatory 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 largely restrict theoretical consideration of alternative pharmacological and clinical approaches. More importantly this may limit creative investigation of the root causes and the factors inuencing the etiology of these and other disorders. With increasing knowledge of the brain correlates of psychopathology, investigators may be inspired to explore more closely the role of genetic and experiential factors in psychopathology development and not restrict their approaches to those emphasized by drug treatmentbased hypotheses. A useful model for understanding how genetic and environmental inuences 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 development process over time (see Figure 1). Certain inuences, arising from genetic or environmental sources, could operate on a process of brain development and therefore on an individuals

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Figure 1 View of development, modied 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 specied by the genome. The form of the surface represents the concept that genetic inuences collectively tend to promote the normal developmental trajectory. Over time, genetic factors (black bar) and non-genetic experiences (white bars) can inuence the direction of the developmental trajectory, yet any given individual will not encounter all of these inuences. 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 inuence of genetics and experience (see also Woolf, 1997)

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 developmental pathway. The value of this representation is that contributions of individual genes or experiences can be recognized, and yet the continuing interactive 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 development reects both genetic and environmental contributions. We will return to this model as we discuss specic aspects of pathological development. Within this context, a non-comprehensive set of experiences that may affect psychological development is discussed here, largely because at least some mechanisms through which they act have been delineated experimentally. The quality of an organisms 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 inuences, including prenatal and postnatal stress, toxins, and nutrition, that have cellular and molecular consequences are considered. Finally, gender is considered both as a modulator itself, for example in cases where gonadal steroids appear to directly inuence 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 experience in the development of specic psychopathologies whose root causes range from solely environmental (e.g., fetal alcohol syndrome) to known genetic abnormalities (e.g., fragile X syndrome), and nally to disorders whose etiology reects a mixture of genetic and non-genetic

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inuences (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 interactions among these factors. While disorders such as schizophrenia are generally considered to be adultonset disorders, it is becoming increasingly evident that 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 psychopathologies, because it is the development of this arena that is potentially most benecial to patients and their families.

Experience and the processes of neural development

As has been repeatedly demonstrated, different organ systems develop on different time courses, such that an environmental insult at a particular developmental stage may interfere with the development of some organs but not others. Likewise, brain regions 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 neurogenesis, neuronal migration and differentiation, synapse formation and remodeling, the development of critical non-neuronal components (glia, myelination, cerebrovasculature), and neurodegeneration. Early in normal development, these processes are guided largely by genetic inuences, and experience plays an increasingly important role over the course of development. Even a minor genetically or environmentally induced deviation from the intended direction 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 susceptible to perturbation (reviewed by Rice & Barone, 2000). Due to space restrictions, the discussion of each of these processes will be limited to a brief description of the normal developmental course, followed 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 possible 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 underlying tissue on the ectoderm. In an early phase, the at sheet of neuroepithelium folds into a neural tube with a cavity, the central canal, that develops into

uid-lled 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-characterized time course such that the timing of adverse experiences or other environmental insults determines where they most negatively affect the rate of developmental neurogenesis and the functional integration of these cells (Altman & Bayer, 1997; reviewed by Rice & Barone, 2000). For example, in utero exposure 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; see Fetal alcohol syndrome). Most neurons in the brain proliferate during prenatal brain development and early infancy; neurogenesis 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 efciently and continuously generate small numbers (relative to glial cells and total neuron numbers) of specic neuronal populations throughout life (Alvarez-Buylla & Garcia-Verdugo, 2002; Eriksson et al., 1998; Gould, Reeves et al., 1999). Various forms of experience have been found to inuence cell proliferation and survival rates during the post-developmental period. In the complex environment paradigm, animals are housed communally in a cage that includes a variety of objects 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 animals 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 environment would have even greater effects on the survival of new neurons in younger animals. In the complex environment, animals are exposed to a broad, non-specic range of experiences. Among these experiences, physical activity appears to induce neuron proliferation while learning enhances the survival of new neurons in the post-developmental brain. In adult rodents that had opportunity for physical exercise on a running wheel in their cage, neurogenesis in the dentate gyrus was signicantly 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 dentate gyrus were found to be higher following an associative learning task that required activation of the hippocampal formation (Gould, Beylin, Tanapat, Reeves, & Shors, 1999). These data suggest that physiological consequences of exercise, such as increased blood ow, glucose uptake, angiogenesis, and neurotrophic factors could be mediators of cell proliferation, and these ndings 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 discussion of the relative impact of learning and physical activity on post-developmental neurogenesis (e.g., Greenough, Cohen, & Juraska, 1999), further research is needed to delineate the specic effects of these two components of behavioral experience. In contrast to the ndings that certain behavioral experiences generally increase the rate of postdevelopmental 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 hypothalamic-pituitary-adrenal (HPA) axis, resulting in the secretion of corticotropin releasing factor (CRF) from cells in the hypothalamus into the portal bloodstream. CRF stimulates the release of adrenocorticotropic hormone (ACTH) from the anterior pituitary, leading to glucocorticoid release from the adrenal cortex (reviewed by Hiller-Sturmhofel & Bartke, 1998). Bypassing the HPA axis and directly administering glucocorticoids also decreased neurogenesis 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 impairments in neurogenesis has yet to be dened, these observations provide empirical support that stressful events cause lasting neurobiological changes. In light of Posts (1992) kindling model of depression (described in more detail in Depression), these changes may alter the response to subsequent stressors, resulting in more easily triggered depressive episodes. Clearly the recognition that some regions of the brain undergo post-developmental neurogenesis that is sensitive to stress and to activity has opened up a new potential avenue for understanding the basis of psychiatric syndromes, particularly depressive disorders, and these ndings also suggest routes for pursuit of potential therapeutic interventions.

Post-developmental neurogenesis is also inuenced by factors such as sex hormones and traumatic brain injury. During the estrous cycle, neurogenesis uctuates, increasing with higher estrogen 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 hippocampal formation, cerebral cortical neurogenesis appears to be triggered by experimentally induced neurodegeneration, suggesting that trophic events initiated by trauma may induce neurogenesis in regions in which it is not routinely observed or occurs only at much lower levels (Magavi, Leavitt, & Macklis, 2000). These data suggest that signals evoked by neuronal perturbation may permit neuroregeneration to occur (Kuhn, Palmer, & Fuchs, 2001). The compensatory nature of injury- and traumaenhanced neurogenesis in the cerebral cortex points to a potentially important avenue for therapeutic intervention, 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 to occupy the supercial-most layer of the mature cortex or they may become displaced beneath the developing cortex to become subplate neurons (Luskin & 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 supercial layers (Rakic, 1974). After reaching the appropriate 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 (reviewed by Price & Willshaw, 2000). Many intrinsic signals such as transcription factors can activate or suppress expression of specic genes. Extrinsic signals such as extracellular matrix proteins, cell adhesion 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 inuence cortical development by directing migration of pluripotent cells (capable of multiple paths of differentiation) that give rise to multiple lineages of unipotent cells (Reid, Liang, & 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 cortex 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 methylmercury 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 differentiation (Crumpton, Atkins, Zawia, & Barone, 2001). Maternal ingestion of alcohol during gestation (see Fetal alcohol syndrome) impairs formation of basal forebrain neurons in the developing fetus, leading to abnormal development of the cerebral cortex (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 exposure. 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 migration and differentiation may play a signicant role in a number of disorders with unknown etiologies such as epilepsy, schizophrenia, and mental retardation (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 reect 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 (synaptogenesis) are phenomena that, beginning during early phases of prenatal development, respond to specic qualities of an animals environment. By strengthening some circuits via synaptogenesis or remodeling, and by weakening others through, for example, synapse removal (synaptosis) or neurodegeneration, the brain remains plastic throughout life. Genetic and environmental factors that guide the processes of developmental plasticity can be conceptualized as normative or canalizing inuences, or as negative inuences that can guide the individual 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 inuenced by these factors, making the brain more or less able to adapt to future demands. The initial outgrowth of dendrites and the establishment of synaptic contacts can occur without synaptic activity (Verhage et al., 2000), and subsequent organizational changes may be driven by intrinsic 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 process, 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 superuous population of synapses. The kinds of experiences that became incorporated 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 achieve a greater precision of ne-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 processing evolutionarily expected stimuli such as patterned light. Initially, axons innervate the visual cortex in an overlapping fashion. During development, these axons are partially retracted or pruned such that alternating columns of cells emerge, called ocular dominance columns because their input is dominated 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 ne-tuning of the visual cortex appears to require patterned visual input. The development of ocular dominance columns appears to involve competition between axons carrying 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 normal patterned light stimulation (from the open eye) exhibited a mature morphology and received multiple 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 of brain 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 reected 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 experience-expectant processes in animals, altered input such as sensory deprivation or disruption of patterned stimulation alters the developmental trajectory in an increasingly irrevocable manner, as has been observed in both basic and clinical cases (reviewed by Horton, 2001). Abnormalities in this pruning process, as appear to exist in the case of fragile X syndrome (see discussion below), may underlie specic decits in cognitive and behavioral development. Brain changes that depend on an organisms individual experience (not necessarily common to the species) have been referred to as experiencedependent plasticity (Black & Greenough, 1986). In experience-dependent plasticity, experiences associated with learning appear to trigger the formation of new synapses as opposed to selecting from synapses already in existence. As a model of experiencedependent 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 arborization, increased spine density, and more synapses per neuron compared with animals housed in standard laboratory housing conditions (as reviewed by Greenough & Chang, 1988). Exposure to a complex 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, Buchs, Nikonenko, Bron, & Muller, 1999), it is less obvious 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 sufcient factors governing experience-dependent plasticity have been studied by comparing the brains of rats trained on a motor-skill learning task with those of animals allowed 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 exercised or were inactive (Black et al., 1990; Kleim, Lussnig, Schwarz, Comery, & Greenough, 1996). Thus, a pattern of neural activity specically related to the motor skill learning component of the task was necessary 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 sufcient 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 reorganization parallels synapse formation in the motor cortex following learning of a skilled reaching task (Kleim et al., 2002). Thus experience-dependent plasticity represents a different variety of brain adaptation from experienceexpectant 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 organisms environment and experience. These forms of specic learning still nd a home in the Waddington 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 and choices. That is, experiences that change dendritic or synaptic morphology can also be detrimental to cognitive and behavioral ability neural plasticity denes the ability to incorporate the effects of experience, whether or not that experience has a positive or normative inuence. These inuences 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 decits later in life (Crnic, 1984; Leuba & Rabinowicz, 1979). Postnatal exposure to lead causes diminished dendritic arborization in areas such as the hippocampus, cerebral cortex, and cerebellum (Kiraly & Jones, 1982; Lorton & Anderson, 1986; Patrick & Anderson, 2000), and broad spectrum behavioral decits have been associated with developmental lead exposure (Dietrich, Ris, Succop, Berger, & Bornschein, 2001). Likewise, prenatal exposure to ethanol may cause brain region-specic changes in dendritic morphology (Smith & Davies, 1990). These ndings may partially account for the cognitive and behavioral decits observed following perinatal exposure to these and other toxins (e.g., Mattson & Riley, 1998). Again, the specic effects of each of these disruptive events reect the developmental processes occurring at the time of the insult. Region-specic alterations in neural morphology and brain anatomy have also been observed in response to stress. Dendritic arborization in specic hippocampal subelds is reduced following prolonged restraint stress or administration of glucocorticoids (Magarinos, McEwen, Flugge, & Fuchs, 1996; Woolley, Gould, & McEwen, 1990). Hippocampal volume is also reduced following prolonged psychosocial stress, although evidence that this volume 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 elevated 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 exposed later to a different stressful stimulus suggests that specic, 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 potentiate the stress response to future adverse experiences, ultimately leading to recurrent depressive episodes. The persistent nature of some neuronal changes following experience may either be maladaptive in that an experience potentiates the response to future adverse experiences or it may establish an adaptive response prole enabling the brain to respond more efciently 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, unpublished observations). Neuroanatomical effects of motor skill training also persist in the absence of continued training, as the number of synapses per neuron 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 renements, 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 effects 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 to the synapse addition associated with experimental induction of seizures in adult animals. This reminds us that neural reorganization resulting from experi-

ence reects the nature of the experience and may have either positive or negative functional effects. Thus one can see a broad variety of inuences 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 specic effects on development. Experience-expectant processes require specic normative environmental inputs 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 experience. Experience-dependent mechanisms are more frequently encountered as development moves down Waddingtons surface, again having both normalizing and diversionary effects. Genetic mechanisms guiding the formation of neural networks and their plastic incorporation of information are largely normalizing. In fragile X syndrome, and possibly in schizophrenia and depression, the genetic abnormalities may be amplied by the normal plastic properties of the brain through repeated storage of abnormal experiences.

Modication of non-neuronal components by 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 changes 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 maintaining appropriate levels of neurotransmitters and neurotrophins. Astrocytic hypertrophy following behavioral experience may merely reect the increased demand of maintaining the synaptic microenvironment under increased load, or it may reect alterations that affect neural information processing in more specic and selective ways, modifying functional 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 another way the brain changes in response to behavioral demands. These changes in myelination are substantial up to approximately 20% in adult animals providing the opportunity for signicant effects on functional neural circuitry. Thus the specic information processing functions of both astrocytes and oligodendrocytes, heretofore largely overlooked, could be very signicant, as could their contributions to the etiology of mental disorders. It may be of

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particular signicance that, whereas experienceinduced changes in astrocyte morphology appear to be relatively transient, those changes in oligodendrocyte myelination of axons appear to be relatively stable (see below). Cerebrovasculature may also play a more important role in brain adaptation to behavioral demand than historically has been appreciated 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 components depends, as with neurons, on the nature of the experience, and many of these changes persist after the experience has been discontinued. Although data are limited, there is growing evidence for involvement of all of these components in psychopathology.

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 multipolar astrocytes (Mission, Takahashi, & Caviness, 1991). The molecular mechanisms underlying astrocytic development appear to be intrinsically dened, yet also receptive to extrinsic cues from the neural environment (Sauvageot & Stiles, 2002). Once thought to play merely a supportive or nutritive role to 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 reuptake and metabolism of neurotransmitters (Bezzi, Vesce, Panzarasa, & Volterra, 1999), through modulation of synaptic activity (Araque, Parpura, Sanzgiri, & 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 microenvironment in response to and in preparation for increased neural activity (Jones & Greenough, 1996). A possible human correlate of these animal ndings is that in postmortem tissue from individuals with high professional status, the proportion of mitochondria 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 synaptic 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 astrocytes 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 observed following exposure to a variety of environmental 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 astrocytic structure and function (Crossin, Tai, Krushel, Mauro, & Edelman, 1997). Interestingly, stress effects on hippocampal astrocytes and complex environment effects on cerebral 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 uncorrelated with 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 experience on astrocytes may be involved in the development 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, Pariante, & Everall, 2001). In the supercial dorsolateral prefrontal cortex of schizophrenia patients, there was a decreased proportion of astroglial processes and a reduction in astrocytic ensheathement of synapses compared with control subjects (Uranova, Orlovskaya, Zimina et al., 2001).

Myelination. Myelinating glia share many characteristics with astrocytes in their development (reviewed 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). Oligodendrocytes begin to myelinate bers in some regions of the central nervous system prenatally, as well, but most myelination in the central nervous system occurs during the rst 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 inuenced by certain forms of behavioral 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 demands imposed by behavioral experience by myelinating previously unmyelinated axons or by extending new, myelinated axons. Unlike the relatively transient nature of astrocytic changes induced by behavioral experience, the increase in myelination 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 specically localized myelination, as if enhancement of the speed of conduction in particular circuits may play very specic behavioral roles comparable to those believed to be played by synapses in learning. Myelinating glia appear to be preferentially targeted 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 effects on the brain. It appears, for example, that malnutrition impairs myelin development most profoundly during the period of oligodendrocyte proliferation 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 schizophrenia (Foong et al., 2000; Hakak et al., 2001). Recent work has also discovered morphological evidence of elevated levels of myelin pathology in cortical autopsy samples from schizophrenia patients (Uranova, Orlovskaya, Vikhreva et al., 2001). Of

particular interest is that the pathology was not restricted to regions of the dorsolateral prefrontal cortex that are traditionally associated with schizophrenia; 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 occur throughout the brain. Whether these myelination 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 schizophrenia and other psychiatric conditions should include 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 capacity 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 individually caged animals (Black, Sirevaag, & Greenough, 1987). It appears that angiogenesis is driven more by the repeated performance of unskilled movements such as those produced during exercise than by skill learning, which causes synaptogenesis (Black et al., 1990). The fact that experimentally induced hypoxia can similarly drive relatively rapid angiogenesis (Harik, Hritz, & LaManna, 1995) suggests 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 appear to be relatively stable in the absence of continued environmental demand or training, whereas astrocytic effects of motor skill training in the cerebellum 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 signicant survival value. In contrast, astrocytic and possibly vascular changes are general, easily initiated responses to immediate demands of experience that can be discarded, conserving valuable metabolic resources in the absence of continued environmental pressure. To date there have been remarkably few studies of vascular changes associated with psychopathology, possibly because the above work

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suggests that vascular responsiveness reects rather than drives levels of physiological and metabolic activity. It is possible, however, that the relative inactivity of typical hospitalized patients could lead to vascular insufciency that exacerbates symptoms of otherwise unrelated disorders; the merits of increased activity or exercise in such cases might be a fruitful avenue of investigation.

Neurodegeneration
The development and renement of neural networks often, if not always, involves the removal of a subset of neurons in the brain through a process of programmed 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 neurodegeneration such as necrosis and excitotoxic cell death caused by elevated levels of glutamate or its analogs (Olney & Ishimaru, 1999; Wyllie, Kerr, & Currie, 1980). Over half the neurons in the mammalian nervous system are ultimately eliminated by apoptosis, which occurs not only in mature, functionally connected neurons, but also reects 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 widespread apoptosis serve to remove cells that no longer contribute to active cortical networks, and to more selectively match appropriate patterns of synaptic connectivity (Rakic & Zecevic, 2000). Post-developmental 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 dendrites and individual synapses may serve to remove selected connections that no longer play a necessary role in efcient communication between neurons. This process and the removal of synapses through yet undened mechanisms are dened 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 overproduction is involved; whether synapse overproduction followed by synaptosis also plays a role in experience-dependent plasticity that is, in the brains response to discrete learning-related experiences 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 antiapoptotic 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 cleaving proteins such as actin (Kayalar, Ord, Testa, Zhong, & Bredesen, 1996), spectrin (Wang et al., 1998), and subunits of AMPA-type glutamate receptors (Chan, Grifn, & Mattson, 1999). For proper neural function, a balance must seemingly be maintained between neurogenesis and neurodegeneration, as well as between synaptogenesis and synaptosis. It is possible that impaired synaptosis is involved in fragile X syndrome (see below). Whether synaptically active or expressed in the cell nucleus, neurodegenerative processes often represent mechanisms by which experience may affect brain development. Prenatal exposure to ethanol, for example, induces apoptosis and alters neuron number and function in multiple brain regions, causing signicant 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 damage 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 mechanisms. According to Ishimaru et al. (1999), excitotoxic cell death is observed quickly around the site of injury, whereas apoptotic cell death is observed later and in regions distant from the injury. Neurodegeneration via excitotoxicity and apoptosis have also been 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 contrast, 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 following complex environment exposure, suggesting that differential experience can be anterogradely neuroprotective. In addition to neuroprotective effects, the brain appears to compensate for neurodegenerative cell loss through generation of new neurons (reviewed in Kuhn et al., 2001).

Experience and the development of psychopathologies

In the preceding discussion of brain development, it was evident that each developmental process follows

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a well-dened 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 associated with disruptions in these developmental processes, it becomes increasingly clear that the development of these psychopathologies likely also follows a well-dened 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 experience and genetics can interact to inuence the development of psychopathology. Fetal alcohol syndrome (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 signicant roles in the development and onset of psychopathology. In the latter two examples, early adverse experiences appear to have signicant effects on the developing nervous system that may alter the systems response to subsequent events. In all four examples, however, the inuence of both experience and genetics is evident. We will consider each disorder in turn, describing some of the associated neuropathologies and discussing the disorder from a neurodevelopmental perspective, stressing the inuence of experience on this psychopathology. Again, the discussions of these disorders are not exhaustive due to space constraints. 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 attenuate symptom severity.

Fetal alcohol syndrome

Prenatal alcohol exposure can have permanent adverse effects on the human fetus; one of the most severe outcomes is fetal alcohol syndrome (FAS). Children who are affected by prenatal alcohol exposure 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 Neurodevelopmental Disorder (ARND). The clinical and behavioral correlates associated with FAS and FAE include microcephaly, growth retardation, decits in cognitive functioning, and ne and gross motor impairments. 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 and Woods (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 ganglia, shrinkage and loss of neurons in the cerebellum and hippocampus, and thinning to complete agenesis 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 detrimental, 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 most pronounced 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 nal days of gestation, which corresponds to the second trimester of human brain development (Miller, 1986) or during the rst 14 postnatal days, which corresponds to brain development during the third trimester of human pregnancy (West, Goodlett, Bonthius, & Pierce, 1989). In general, the effects of prenatal ethanol exposure on rat brain development differ from those of postnatal ethanol exposure, supporting the idea that sensitive 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 neocortex (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 signicant continuing cerebellar granule cell genesis) than during their proliferation, which occurs 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 in those 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 migration, although the specic 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 as that observed for Purkinje cell loss, appears to be brain region-specic, suggesting that the timing of the mothers alcohol consumption over the course of brain development inuences the range of decits 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 common 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). Studies in vivo and in vitro suggest that FMRP is involved 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 decits that suggest a failure of the normal neuronal 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 reect a failure of the normal process of synapse elimination in development (although it could also reect a continuing process of synaptogenesis). Consonant with the elimination failure hypothesis, normal developmental withdrawal of inappropriately located 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 (including cognitive, language and motor abilities) but is also often associated with a variety of symptoms, only some of which are seen in any individual patient. Many patients with FXS exhibit autistic-like behaviors that are indistinguishable from idiopathic autism using standard diagnostic instruments (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 decits, hypersensitivity to sensory stimuli, hyperactivity and attention decits (BerryKravis, Grossman, Crnic, & Greenough, 2002; Hagerman, 2002). The heterogeneity of individual patterns of symptoms in FXS suggests at least two possible interpretations. The rst interpretation is compatible 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 inuence the expression patterns and actions of these proteins. Variability in the expression patterns of these mRNAs and their proteins in various brain regions could in turn account for the diversity of behavioral patterns observed across patients with FXS. Although these features suggest a high degree of genetic determinism, the contribution 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 multiple outcomes. 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 difcult to overcome or move away from developmentally. The symptoms of autism 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 decits could represent these stable attractors or absorbing states in that they are associated with multiple disorders and are difcult 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 inuenced 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 signicant environmental components that determine their specic expression patterns, and vice versa. As noted above, other psychopathologies appear to share such sensitivity to experience. Schizophrenia

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Figure 2 Absorbing states or stable attractors in the development of psychopathology. Over the course of development, 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 inuences 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 difcult 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 idiopathic autism). Conventions are as described in Figure 1

and depression, for example, show greater concordance in monozygotic than in dizygotic twins, suggesting a strong genetic component. The concordance rates, however, are not 100%, indicating a signicant 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 developmental components (see Lewis & Leavitt, 2002). That is, with the exception of acute, well-dened 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 disorders is typically the culmination of a long sequence of subtle, neurodevelopmental insults that may have begun very early in life. As more about the developmental progression of psychiatric disorders is discovered, it is becoming clear that an increasing number of mental illnesses have a neurodevelopmental basis and result from the lasting neurobiological effects of early experience that can set the stage for the later development of psychopathology.

Schizophrenia
The concordance rate for schizophrenia is 50% in monozygotic twins and 17% in dizygotic twins, indicating a strong genetic component (Tsuang, 2000). It has been suggested that the clinical manifestation of schizophrenia could be accounted for by the additive effects of a number of decient genes (Risch & Baron, 1984). Indeed, linkage studies have suggested the existence of susceptibility genes on at least ve chromosomes (Moises et al., 1995). One of these polygenic theories proposes that diversity in symptom proles among individuals with a schizophrenic genotype depends, in part, on the number of susceptibility genes expressed beyond a threshold (Woolf, 1997). While there is intrinsic value in polygenic theories, additional non-genetic factors must inuence the symptom expression of schizophrenia to account for incomplete concordance rates in monozygotic twins. Observations that neuropsychological decits exist in the unaffected monozygotic twin and rst-degree relatives of patients with schizophrenia suggest an interaction between genetics and the environment that

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inuences the expression of psychotic symptoms (Toomey et al., 1998). Schizophrenia is viewed increasingly as a developmental disorder whose presentation represents a point along a continuum at which effects of the interaction between genetics and experience nally surpass an individuals threshold for symptom expression (Lewis & Levitt, 2002). Insights into the developmental progression to psychosis come, in part, from retrospective studies examining the psychosocial behavior of children who later develop schizophrenia. Mild decits in social, motor, and cognitive functioning indicative of premorbid features of schizophrenia were observed in infants (Walker, 1994), and in children and adolescents (Cannon et al., 1997) who later exhibited psychotic symptoms. Attention decits and inappropriate social interaction have also been noted in children who later manifest schizophrenia; the severity of these abnormalities increases with age through adolescence (Walker, Diforio, & Baum, 1999). This period of emerging symptom presentation commonly develops into a pre-psychosis prodromal state on the continuum from normal cognition toward schizophrenia (see Moller, 2001). During childhood and this prodrome, neuropsychological impairments may be phenotypic markers of increasingly compromised brain organization, eventually leading to psychosis (Rosen, Woods, Miller, & McGlashan, 2002). Morphological studies of schizophrenic patients early in their disorders also lend support for developmental theories of schizophrenia. Minor physical anomalies, such as low-set ears and abnormal palate height, which are often observed in individuals with abnormal central nervous system development, are also exhibited by some patients with schizophrenia (Waddington et al., 1999). At rst symptom onset, neuroanatomical abnormalities such as enlarged ventricles and decreased volume of several brain regions are often already present (e.g., VazquezBarquero et al., 1995). Recent emphasis on schizophrenia as a developmental disorder has focused on characterizing the role of non-genetic factors in the development of symptoms of schizophrenia. Certain prenatal and perinatal environmental factors, including maternal stress and malnourishment, and obstetric complications such as low birth weight, pre-eclampsia, prolonged labor, and hypoxia have been reported to be associated with increased susceptibility to schizophrenia (Hulshoff Pol et al., 2000; Kunugi, Nanko, & Murray, 2001; van Os & Selten, 1998). Increased incidence of schizophrenia was also reported in children born to mothers who experienced infection from inuenza or rubella during the second trimester of pregnancy (see Brown & Susser, 2002). Although direct evidence is lacking, these experiences have the potential to affect neurodevelopmental processes, laying the groundwork for vulnerable neuronal circuits whose presence is masked until these circuits

are taxed by later developmental demands (Arnold, 1999). For example, the demands associated with childhood and adolescence (two stressful periods of social development) likely involve brain adaptation and renement of synaptic connectivity. If developmental perturbations have compromised the integrity of neural circuits or the processes whereby renement occurs (see Synapse formation and remodeling), the stress associated with adolescence could potentially lead to the expression of psychotic symptoms (Lewis, 1997; Walker & Bollini, 2002; see also discussion of stress in Depression). Long before symptom expression, early adverse experiences such as those described above may contribute to disruptions of neurodevelopmental processes such as neuronal migration, neurodegeneration, and synapse formation and remodeling. Decits in each of these processes have been associated with schizophrenia. During normal development, for example, most neurons in the subplate of the cerebral cortex undergo apoptosis, leaving the surviving cells as interstitial neurons of the white matter. In patients with schizophrenia, however, the density of interstitial neurons is increased in the deep white matter of prefrontal cortex, yet decreased in the supercial white matter (Akbarian et al., 1996). Cytoarchitectural abnormalities that could reect similar abnormalities in neurodevelopmental processes have also been observed in both the hippocampus and entorhinal cortex (Jakob & Beckmann, 1986; Kovelman & Scheibel, 1984), although the reliability of these observations has been questioned (see Harrison, 1999). As has been observed following other adverse experiences, even if immature neurons survive early insults, synaptic connectivity will likely be compromised (see Synapse formation and remodeling). Neuroanatomical characteristics reecting abnormal connectivity and therefore a diminished capacity for normal function and plasticity have been observed in patients with schizophrenia (reviewed by Harrison, 1999). Neuron density, for example, is increased in patients with schizophrenia (Selemon, Rajkowska, & GoldmanRakic, 1995), leading the authors to propose the reduced neuropil hypothesis of schizophrenia, while dendritic length and the density of spines on pyramidal neurons in prefrontal cortex are reduced (Black et al., submitted; Garey et al., 1998; Glantz & Lewis, 2000). Taken together, these observations suggest that the reductions in cortical volume in patients with schizophrenia reect loss and/or impaired development of neuronal processes and likely reductions in associated supporting cells including glia and vasculature. Neuronal pathology observed in both prefrontal and primary visual cortices (Kodish et al., in preparation) suggests a pathology that may be distributed across brain regions rather than focused in the frontal lobe regions implicated in these disorders, and is consistent with the broad spectrum of neuropsychological decits in patients

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with schizophrenia (reviewed by Schultz & Andreasen, 1999). One molecular correlate that may underlie these cellular changes and ultimately lead to some of the neuroanatomical anomalies observed with schizophrenia is a reduction in the expression of reelin, an extracellular matrix protein proposed to regulate morphological plasticity (Guidotti et al., 2000). Sex hormones also appear to inuence the development and phenotypic expression of schizophrenia. Schizophrenia onset occurs earlier in men than in women, suggesting that estrogen may have a neuroprotective role in the development of this particular psychopathology (Taber, Murphy, BlurtonJones, & Hurley, 2001). Early onset of menstruation has been associated with a later onset of schizophrenia in women, possibly due to elevated levels of estrogen (Cohen, Seeman, Gotowiec, & Kopala, 1999). Furthermore, psychotic symptoms appear to improve during periods of the menstrual cycle when estrogen levels are high (Riecher-Rossler, Hafner, Stumbaum, Maurer, & Schmidt, 1994). Following menopause, when estrogen levels drop, the incidence schizophrenia increases dramatically, further suggesting a neuroprotective effect of estrogen in the symptomatic expression of schizophrenia (Hafner et al., 1998). The apparent ameliorative role of estrogen with regard to schizophrenia serves to highlight the interactions likely to occur among genetic and experiential aspects of the developmental course of this disorder. A central issue that remains is why the expression of schizophrenia in genetically identical twins can vary, even while both exhibit signs of neuropathology. It seems likely that varying experiences may both contribute to the development of symptoms and mitigate their genetically predisposed expression. The more general issue involves the sources of developmental stability in the face of polygenic and experiential inuences that can promote or disrupt the development process. As noted above (see Figure 1), Woolf (1997) has pointed to the heuristic value of C.H. Waddingtons (1940, 1957; see also J.L. Waddington, 1993) concept of canalization in understanding the interaction between genetic and environmental inuences in the etiology of schizophrenia. Canalizing genes or experiences are those that promote normative development in the presence of genes and other inuences that tend to drive development beyond some collective neuropathological threshold for a disorder, such as schizophrenia (see Figure 2). The value of this conceptualization is that it emphasizes the interaction among multiple genetic and environmental inuences in the determination of the schizophrenia phenotype, as well as the determination of other potentially pathological non-schizophrenic phenotypes. Also, while Woolf (1997) emphasizes abnormalities of early developmental cell migration as the principal neuropathology underlying schizophrenia,

the canalization model allows for, and indeed suggests that multiple forms of neuropathological insult and therefore multiple etiologies may contribute to the development of schizophrenia. This suggestion is compatible with the multiple forms of brain pathology described above that have been related to schizophrenia in empirical work. In principle, of course, any of these pathologies could be either causative or a consequence of schizophrenia, and identication of the causal factors at the neuropathological level is essential to their contribution to treatment strategies.

Depression
Historically, depression was seldom diagnosed in children, yet it has recently become increasingly clear that depression manifests prior to adulthood (Lewinsohn, Rohde, & Seeley, 1998; Rutter & Sroufe, 2000). This paradigm shift has led to a view of the etiology of depression that emphasizes a developmental perspective. Adverse experiences early in life, for example, have been associated with increased incidence of depression in adulthood (e.g., Famularo, Kinscherff, & Fenton, 1992). As with the developmental hypothesis for schizophrenia, the onset of each depressive episode may represent the surpassing of a threshold whose relative position is modied by continuously interacting genetic and experiential inuences. The progression relative to this threshold may be gradual (through the additive effects of several psychosocial stressors) or sudden (through the overwhelming effects of a single event), and likely reects the interaction between the nature and frequency of the psychosocial stressors and an individuals biological response to those stressors. Genetics appear to inuence an individuals response to adverse experience, and may therefore contribute to establishing the threshold for depression onset. In animal studies, some genetic strains of mice exhibit more elevated hormonal stress responses and more pronounced behavioral effects of stress than other strains (Zaharia, Kulczycki, Shanks, Meaney, & Anisman, 1996). In a human study, Kendler, Thornton, and Gardner (2001) reported that for patients with high genetic risk for depression (individuals whose twin had a lifetime history of major depression), a stressor was less often associated with the onset of depressive episodes than in patients with a low genetic risk. These data suggest that, at one extreme, an individual with a genetic predisposition towards high reactivity to stress may have to experience only mild stressors, if any, to exceed the threshold and exhibit symptoms of depression. At the other extreme, an individual with lower reactivity to stress may have to experience several stressors before experiencing a depressive episode. One might therefore hypothesize that some of the genes associated with depression may be involved in determining an individuals sensitivity to

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stress and thus the relative position of the threshold for depression onset. Hypotheses about the progression to and beyond this threshold have emerged from observations of the developmental course of depression. One hypothesis, rst articulated by Kraepelin (1921), suggests that psychosocial stressors play a greater role in early episodes of depression than in subsequent episodes. As noted above, this pattern has been compared to behavioral sensitization and electrophysiological kindling (Post, Rubinow, & Ballenger, 1986). In kindling, seizures that are initially triggered by intense stimulation can eventually be triggered by progressively less intense stimuli, until they occur spontaneously (Wada, Sato, & Corcoran, 1974). By analogy, depressive episodes may be triggered initially by intense psychosocial stressors; over time, these episodes become progressively less dependent on stressors until depressive episodes occur spontaneously (i.e., in the absence of psychosocial

stressors). Although the neurobiology of depression is likely dissimilar to that of electrophysiological kindling, the kindling model of depression provides a framework, especially when viewed in the context of Waddingtons developmental surface, to conceptualize the wealth of data that suggest early adverse experiences can negatively affect neurobiological function and thereby facilitate the development and recurrence of depression. Kindling of depression is visualized in Figure 3 as the repeated diversion of the developmental trajectory such that it becomes permanently diverted. In an effort to establish correlates between the neurobiological effects of stress and the kindling hypothesis, Post (1992; see also Post & Weiss, 1997) suggested that transient gene expression following adverse experience could provide a basis for enduring alterations in brain structure and function. Consistent with this hypothesis, it has been reported that an initial stressor has a lasting inuence on the

Figure 3 Posts kindling model of depression conceptualized on Waddingtons developmental surface. Post and colleagues (1986) theorized, as did Kraepelin (1921), that because psychosocial stressors play a greater role in depressive episodes early in the course of the illness than they do later on, each stressor had lasting effects that potentiated the brains response to future stressors. As depicted along the left bank of the canal, a developmental trajectory may begin in a relatively normal state (in the middle of the canal), but after exposure to a severe stressor (1) early in development (while the slope of the canal banks is still gentle) the individual exceeds a threshold for onset of a depressive episode (the dotted line on the left). In this example, the individual recovers from the initial episode, but the stressor has had an enduring effect on his or her reactivity to stress (the ball fails to return to the middle of the canal). The second stressor (2) need not be as severe as the rst to trigger a depressive episode, and the third stressor (3) may be even milder, until the individual has recurrent depressive episodes that occur in the absence of a stressor. As Kendler et al. (2001) proposed, genetics may inuence some combination of the overall risk for depression (the slope of the canal banks and the height of the dotted lines, as depicted along the right canal wall), the speed of kindling (the number of stressors encountered before the ball begins to oscillate in a state of recurrent depression, independent of stressors), and the severity of the stressor required to trigger an initial depressive episode (the proximity of the ball to the dotted line). Conventions are as described in Figure 1

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HPA axis, the well-characterized stress response system, such that subsequent stressors result in a potentiated response. When tested as adults, rats that had been stressed during development exhibited elevated basal levels of plasma ACTH, and an increased CRF and ACTH response following footshock or restraint stress (Ladd et al., 1996; Plotsky & Meaney, 1993). Initial stressors also appear to affect the recovery of the HPA axis response to baseline following subsequent stressful experiences (Garcia, Marti, Valles, Dal-Zotto, & Armario, 2000). It should be noted that studies using maternal separation as the initial stressor have been interpreted, in light of previous work (e.g., Levine & Mullins, 1966), to suggest that the intensity of the stressor and other factors, such as maternal behavior when she is returned to her pups, govern subsequent responsiveness to stress (reviewed by Francis & Meaney, 1999). Following relatively long separation, a more severe stressor, subsequent responses to stress are maladaptive, whereas a brief separation is associated with adaptive responses to future stressors. Based on this animal literature, developmental stress appears to be a double-edged sword. As the kindling model predicts, early experience affects the subsequent function of the HPA axis, but in the case of early mild stress compared with early severe stress, the directions and outcomes may vary. Several cellular mechanisms that may underlie the lasting effects of stress on the HPA axis have been proposed. An increase in CRF expression levels in hypothalamic neurons of rats has been reported following experimental stress paradigms, as well as a similar increase in the levels of neuromodulators such as arginine vasopressin (AVP) that can enhance CRF-induced release of ACTH (Bartanusz et al., 1993). Alterations in neurotransmitter systems and receptors have also been observed in response to stress (reviewed by McEwen, 1999). These stressinduced changes in gene expression may lead to a potentiated response to future stressors. Because the hippocampus normally has an inhibitory inuence on HPA activity (Jacobson & Sapolsky, 1991), alterations in synaptic connectivity due to hippocampal atrophy (reductions in hippocampal volume and in arborization of pyramidal cell dendrites; see Synapse formation and remodeling) may release this inhibition and contribute to HPA hyperactivity (Herman et al., 1989). These and other region-specic alterations in neuroanatomy that are associated with stress, along with the potentiating effect of initial stressors on the HPA axis and future stress responses, may underlie an individuals progressive sensitization to stressful experiences and a lowered threshold for onset of a depressive episode (reviewed by Sanchez, Ladd, & Plotsky, 2001). If, as the kindling model suggests, early adverse experiences lead to lasting alterations in the stress response, and these alterations underlie the devel-

opment of recurrent depressive episodes, then patients with depression should exhibit abnormal stress reactivity compared with non-depressed subjects. Indeed, a common characteristic of patients with depression is hyperactivity of the HPA axis (reviewed by Plotsky, Owens, & Nemeroff, 1998). It was rst reported that patients with depression have elevated levels of plasma cortisol, a product of HPA activity (Board, Persky, & Hamberg, 1956). Nemeroff et al. (1984) subsequently noted increased CRF levels in the cerebrospinal uid of depressed patients compared with controls, indicating that inhibitory feedback was abnormal. The inhibitory feedback mechanism of the HPA axis normally attenuates the release of CRF in the presence of high levels of cortisol. Patients with depression commonly exhibit a lack of feedback inhibition, as evidenced by continued cortisol release following administration of dexamethasone, a synthetic glucocorticoid (Carroll, Curtis, & Mendels, 1976). Postmortem tissue from patients with depression has revealed neuroanatomical correlates that parallel those observed in rats following stress. Specically, more CRF-expressing neurons in the hypothalamus were observed in tissue from depressed patients, as were more neurons that co-express CRF and AVP, thus having a synergistic effect on ACTH release (Raadsheer, Hoogendijk, Stam, Tilders, & Swaab, 1994). Reductions in hippocampal volume that have been reported in patients with depression are correlated with total lifetime duration of illness and may contribute to plasticity in hypothalamic neurons and ultimately to HPA hyperactivity observed in depressed patients (Bremner et al., 2000; Sheline, 2000). Volume reductions have also been reported in the amygdala (Sheline, Gado, & Price, 1998) and the cerebral cortex (Bremner et al., 2002; Drevets et al., 1997). Rajkowska et al. (1999) measured cortical thickness, neuronal size, neuronal density and glial density, and noted layer-specic decreases in many of these parameters in the orbitofrontal region and dorsolateral prefrontal cortex of patients with depression. Although the hippocampal data provide the strongest evidence for a neuropathological correlate of the enhanced stress response in patients with depression, abnormalities in these other regions may also reect lasting effects of early adverse experiences that facilitate the development of future depressive episodes. For more thorough recent reviews of neuropathologies associated with depression, see Harrison (2002) and Drevets (2001). In light of the evidence supporting the kindling model of depression, and in light of the evidence for genetic factors in the etiology of depressive disorders, it has been proposed that genetics may directly inuence the depression kindling process itself. Kendler et al. (2001) presented three hypotheses that might account for heterogeneity of symptom expression and severity across individuals suffering

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from depression and might specically account for variability in the rate of kindling. In their rst hypothesis, genetics inuences the overall risk for depression but does not affect the kindling process. Their second hypothesis is that genetics inuences the speed of kindling, suggesting that some individuals are at higher genetic risk than others for depression because adverse experiences that trigger depressive episodes lead more quickly to the point at which depressive episodes need no trigger. Their third hypothesis suggests that in some individuals, even the rst depressive episodes may occur in association with a mildly stressful experience or in the absence of a stressor; these individuals are genetically pre-kindled (Kendler et al., 2001). The extent to which stress, broadly conceived, and an intrinsic predisposition can account for depressive disorders remains to be seen. Certainly some forms of depression, such as seasonal affective disorder, involve other contributing environmental causes not directly traceable to stress, yet the etiology of these disorders appears to have a genetic component, as well (e.g., Sher, Goldman, Ozaki, & Rosenthal, 1999). A principal conclusion, however, is that experiential factors are becoming increasingly recognized as signicant contributors to affective disorders, and that their effects and the development of the disorders occur over time. Whether the brain substrates involve plastic mechanisms of the sorts

discussed above also remains to be seen, but the brain structural correlates of depressive disorders that have been reported are certainly in accord with this possibility.

Experience and the treatment of psychopathologies

Just as various forms of experience can affect the structure and function of the brain and, in some cases, adversely affect brain development leading to pathology, therapeutic approaches that modify the nature of an individuals experience also have organic effects on the brain. Knowledge of experiential effects on the brain should therefore be considered in the development of therapeutic strategies. Waddingtons canalization model is useful to conceptualize how experience can modulate development. As depicted in Figure 2, a series of environmentally- or genetically-caused deviations that overcome the canalizing or normalizing genetic and environmental forces may lead to psychopathology. Conversely, some genetic and experiential inuences such as therapeutic experiential strategies counter the aberrant disposition so as to canalize the individual back towards a more normal state (see Figure 4). In fetal alcohol syndrome (FAS), for example, certain alleles of the gene that encodes alcohol dehydrogenase lead to overproduction of an enzyme,

Figure 4 Experience and the treatment of psychopathologies in the canalization model. In this gure, a genetic or environmental perturbation (4) diverts an individuals trajectory during early development beyond the threshold for psychopathology. A series of experiential therapeutic interventions (5) act to alleviate symptoms and to progressively return the deviated path to normality. Conventions are as described in Figure 1

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which may protect against development of the disorder (Viljoen et al., 2001). This potentially neuroprotective allele serves as an example of a restorative genetic inuence on Waddingtons developmental surface. The potential role of experiential intervention as a normalizing inuence and as a (partial) treatment for prenatal alcohol exposure has been supported by ndings in both clinical and basic research. Raising children that were exposed prenatally to alcohol in experientially impoverished environments is associated with a higher incidence of secondary psychopathologies and with increased severity of the effects of alcohol exposure. Two factors that protect against developing secondary psychopathologies are a nurturing household and the quality of the home environment between 8 and 12 years of age (Streissguth & Kanter, 1997; see similar ndings below for fragile X syndrome). In animal models of FAS, exposure to a complex environment improved some of the behavioral abnormalities associated with alcohol exposure, yet this intervention was without detectable effect on the neuroanatomical abnormalities (reviewed in Hannigan & Berman, 2000). More aggressive and proactive strategies such as motor skill training, however, had demonstrable therapeutic value in both behavioral and neuroanatomical realms (Klintsova, Goodlett, & Greenough, 2000; Klintsova et al., 2002). These observations demonstrate that improving the quality of postnatal experience can have rehabilitative effects on both the behavioral and the neuroanatomical outcomes of prenatal alcohol exposure. In an etiologically genetic disorder, there is similar evidence that patients with fragile X syndrome (FXS) can benet from appropriate experience. Patients with FXS exhibit a diverse symptom prole, and the severity of behavioral impairments is variable (see Fragile X syndrome above). While in some cases cognitive capacity may be severely impaired, frequently FXS individuals can learn routines that aid in their adaptation to daily life demands, such as participating in classroom activities. In addition to procedure learning there appears to be a more general environmental enrichment effect on cognition (Dyer-Friedman et al., 2002), as well as an effect of environmental variables on behavior problems and autistic symptoms (Hessl et al., 2001). Dyer-Friedman et al. (2002) report that the quality of the home environment contributed to cognitive outcomes in FXS children, particularly in males. Unaffected siblings, by contrast, showed minimal effects of the home environment and a much larger correlation with parental IQ, indicating a selective therapeutic effect of the home environment on the FXS siblings. It has long been known that parental IQ substantially predicts that of the offspring (e.g., Plomin, DeFries, McClearn, & Rutter, 1997), so a parental IQ effect for FXS children and their siblings was not surprising. In some ways, these observations parallel those in knockout mouse models of FXS in which

genetic makeup (strain differences) affects behavior (Dobkin et al., 2000). Hessl et al. (2001) reported that, in addition to effectiveness of educational and therapeutic services, psychological disorders in parents predicted the degree of problem behavior in children with FXS and that quality of the home environment affected autistic behaviors. These studies emphasize the sensitivity of the phenotype of this genetically based disorder to experience variables, particularly those that serve as canalizing or normative inuences. The use of experiential intervention in treatment has a long history, although little attention has been paid to its organic consequences. Arguably, interpersonal psychotherapy (IPT), and cognitive and behavioral therapies constitute experiential treatments; in light of the organic effects of experiences on the brain, one might hypothesize that each of these therapies has normative effects on brain structure and function (see Kandel, 1998). Several groups have observed effects of IPT or cognitivebehavioral therapy on regional blood ow in the brains of patients with schizophrenia, depression, or social phobias (Furmark et al., 2002; Martin, Martin, Rai, Richardson, & Royall, 2001; Penades et al., 2002). Other groups, studying patients with depression, have noted regional changes in brain glucose metabolism following IPT and changes in thyroid hormone levels following cognitive-behavioral therapy (Brody et al., 2001; Joffe, Segal, & Singer, 1996). Efforts to detect neuroanatomical correlates of these treatments have been less successful, likely due to the inability to detect subtle changes in human neuroanatomy (e.g., Rosenberg, Benazon, Gilbert, Sullivan, & Moore, 2000). For each of these studies, it is unclear whether the structural or functional correlates of treatment are the cause or effect of reduced symptom expression. Nevertheless, there appears to be great potential for development and evaluation of brain effects of these experientially based treatment strategies, especially with an increasingly thorough understanding of how an individuals genetics and environment interact across the lifespan. In learning more about the neurodevelopmental course of diseases such as schizophrenia, we have also come to better understand the importance of early intervention. For example, an association between increasing duration of untreated initial psychosis and poor prognosis following treatment has been established (Waddington, Youssef, & Kinsella, 1995). In fact, it appears that the experiences and adaptations during early symptom expression are critically important for long-term prognosis, suggesting that sensitive periods exist with regard to therapeutic intervention (Harrison et al., 2001). These observations emphasize the importance of early intervention by suggesting that psychoses left unchecked can have progressively debilitating consequences whereby relatively minor abnormalities

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build upon one another. Other critical elements, however, have yet to be thoroughly investigated, such as the duration of the sensitive period for optimal treatment initiation, duration of treatment, the type of treatment strategy, and what symptoms will be most likely affected by treatment. Finally, when sufcient information becomes available, predictive tools such as genetic screening and evaluative tools such as brain functional and structural measures may be of value in determining subject populations that would most benet from implementing suitable preventative measures. As noted above, experience-based treatment strategies can take many forms. Social skills training and family therapy, for example, improve symptoms and relapse rates in patients with schizophrenia (Bustillo, Lauriello, Horan, & Keith, 2001). Greist and colleagues (1979) rst noted that aerobic exercise can play an important role in management of mild to moderate depression. They concluded that, beyond the obvious effects on the cardiovascular system, endurance training (comfortably paced jogging) was as effective as psychotherapy. It was subsequently reported that activities such as cycling, dancing, and racquetball had similar ameliorative effects on depressive symptoms and the cognitive function of patients with depression (Doyne, Chambless, & Beutler, 1983; Pappas, Golin, & Meyer, 1990). These observations, along with ndings that exercise has ameliorative effects on symptoms of attention-decit hyperactivity disorder (Tantillo, Kesick, Hynd, & Dishman, 2002), clearly illustrate the benecial value of routine aerobic activity, which would seem to go beyond merely making up for deciencies in physical condition. A strong case has been made for the use of therapies that increase the level of engagement as treatment for some disorders. At least for the rodent model of FAS, these therapies have discrete neurobiological effects. The combination of these therapies with other forms of therapy, however, has achieved the greatest degree of success. The effectiveness of antidepressant pharmacotherapy was signicantly greater, for example, in women who participated in aerobic exercise than in those who participated in relaxation techniques or in control subjects (McCann & Holmes, 1984). Mounting evidence suggests that antidepressant drug therapies may bring about lasting structural and functional changes in brain organization similar to those documented in response to experiences such as physical exercise and learning. Depression, as mentioned above, is associated with volume loss in several brain regions including the hippocampus; this volume loss correlates with cell loss and dendritic atrophy observed in this region. The proliferation of new neurons, which in principle could reverse atrophy in the dentate gyrus, has been observed following exercise (see Neurogenesis) and antidepressant treatment (Malberg, Eisch, Nestler,

& Duman, 2000). Treatment with antidepressants has also been reported to increase dendritic branching in the hippocampus, and to reverse stress-induced dendritic atrophy (Duman, Heninger, & Nestler, 1997; Magarinos, Deslandes, & McEwen, 1999). Although these data showing neuroanatomical correlates of exercise and antidepressant treatment certainly have heuristic value, as do data suggesting that other pharmacotherapies such as lithium and antipsychotics result in normative structural changes (reviewed by Miguel-Hidalgo & Rajkowska, 2002), it is important to distinguish between the etiology of psychopathologies and the effects of therapeutic interventions. Because a primary characteristic of the nervous system is the tendency to return to homeostasis, manipulating this system without correcting the underlying problems may serve to make subsequent treatment attempts even more difcult (e.g., development of drug tolerance and sensitization). In addition, such an approach may lead to research and therapeutic strategies based solely on symptoms or on specic effects of treatments, as opposed to identifying and targeting the actual pathobiologies underlying the disorder. As noted above, dominance of catecholamine-based and more recently indoleamine-based hypotheses of depression etiology that arise from the effects of antidepressant medications has tended to suppress many promising research directions. One hypothesis that is based on mechanisms thought to underlie a disorder, as opposed to mechanisms thought to underlie treatment, has led to creative, targeted treatments and has resulted in symptom improvement (Tallal, Merzenich, Miller, and Jenkins, 1998). The decits observed in some children with language-based learning impairments such as dyslexia have been attributed to the inability to process stimuli that are presented in close succession, such as in the course of reading or listening to rapid (or even normally paced) speech (Tallal & Piercy, 1973). Decits in temporal integration may impede development of neural representations of phonemes, which are critical for normal language perception. If this mechanism in fact accounts for the learning impairments, and if the ability to process these stimuli can somehow be enhanced, then perhaps the learning impairments in these children can be attenuated. Based on basic research ndings in the sensory system, Merzenich and colleagues (1996) used a game-like computer training system to speed up temporal processing integration, likely modifying cortical maps in the auditory system. This training resulted in lasting improvements in speech discrimination and language comprehension in these children (Tallal et al., 1996), indicating that therapeutic strategies aimed at correcting the underlying pathobiology of a disorder have substantial potential for lasting success.

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Conclusions
A great deal of research, particularly recently, has emphasized that most of the fundamental processes of brain development are sensitive to non-genetic inuences and, in particular, to experience. Forms of cellular plasticity not anticipated a decade ago are now widely accepted and have been demonstrated to be responsive to experience, including astrocytic interactions with neurons, myelination, the formation of new blood vessels, and the generation of new neurons. Because these phenomena are newly recognized, they have received little consideration in theory regarding the etiology of mental disorders. A small but increasingly convincing stream of evidence is also beginning to indicate that pathology of neurogenesis and synaptogenesis, myelination, and perhaps other fundamental processes may be central, or at least ancillary, to psychopathological etiology. Despite variability in their root causes and contributing inuences, the four models of psychopathology chosen as exemplars, FXS, FAS, schizophrenia and depressive disorders, have in common an etiology that involves the interaction of environment, and particularly experience, with genetics. The root causes of FXS and FAS are identied as genetic and environmental respectively, yet the course of FXS is clearly inuenced by experience and the outcome of FAS involves both what appear to be genetic sources of resilience and powerful inuences of the later environment. With regard to schizophrenia, many causal factors have been proposed, ranging from decits in cell migration and synaptogenesis to deciencies in gene expression. Rather than focusing on any of these factors as independent contributors to the etiology of schizophrenia, considering the potential contributions of all the possibilities in an interactive model appears warranted. Waddingtons conceptualization of a developmental landscape and its emphasis on the interactions among multiple genetic and environmental inuences provides a valuable tool to view the progression of schizophrenia and other psychopathologies (see Figures 1 and 2). Normative genetic and environmental forces, those canalizing sources of stability that tend to restore a normal developmental trajectory and resist expression of psychopathology, interact continuously with inuences that promote the expression of psychopathology. Waddingtons model also allows us to visualize and understand the interactions in the kindling model of depression the hypothesized role of stress as initiator of early stages of mood disorder and the importance of differences in resilience to stress along the etiological trajectory for each individual and across individuals (see Figure 3). This representation implies that the effects of stress and other experiential factors are organic, and warrant further incorporation into hypotheses about the develop-

ment of pathobiologies that may underlie mental illnesses. With the effects of adverse genetic and experiential inuences on developmental neurobiology in mind, we also present examples of normalizing inuences, both experiential and genetic, that have positive organic effects on the developing or adult brain (see Treatment; Figure 4). In environments that promote learning and/or activity, cognitive and behavioral decits have been attenuated in clinical or preclinical trials involving FAS, FXS, schizophrenia and depression. Likewise, there appear to be important ameliorative factors with regard to these disorders that are genetically based (i.e., estrogen as a neuroprotective factor in the case of schizophrenia, and the overexpression of alcohol dehydrogenase in the case of FAS). These observations suggest that further investigation into the effects of experiences that fall outside of traditional treatments for psychiatric disorders should be considered. The representation provided by Waddingtons canalization model allows us to visualize how all of these inuences, genetic, environmental, therapeutic and others, may share common mechanisms in determining the course of development. Although traditional treatments (i.e., pharmacotherapies) also have lasting effects on the brain (not all of them positive), emphasizing too heavily the neural effects of these treatments can focus hypotheses regarding the etiologies of psychopathologies on the presumed mechanisms of their pharmacological (or behavioral) treatments. These treatmentbased hypotheses regarding etiology often fail to consider important discrepancies (e.g., drugs that have near instantaneous neuropharmacological effects often take long periods to work on psychiatric symptoms; very different classes of drugs with seemingly different pharmacology have comparable symptomatic benets). Although the focus on pharmacokinetics of effective drug therapies may generally expand knowledge of possible brain mechanisms that underlie psychological-psychiatric disorders, this focus should not be allowed to restrict the generation of hypotheses that are based on a broad consideration of potential organic contributions to the development of psychopathology.

Acknowledgments
Portions of this work were supported by NIH grants HD37175, HD07333 (NICHD); AG10154 (NIA); MH35321 (NIMH), AA09838 (NIAAA), by the McDonnell Foundation, by the FRAXA Research Foundation, by the Illinois Eastern Iowa District of the Kiwanis International Spastic Paralysis Research Foundation, and by the Retirement Research Foundation. The authors wish to extend their deepest gratitude to Jessica J. Stanis for preparing gures and to Anna Klintsova and Paul Ardayo for their

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thoughtful comments on an earlier version of this manuscript.

Correspondence to
William T. Greenough, Beckman Institute, 405 N. Mathews, University of Illinois at Urbana-Champaign, Urbana, IL 61801, USA; Tel: 217-333-4472; Fax: 217-244-5180; Email: wgreenou@s.psych. uiuc.edu

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