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Effects of Early Adverse Experiences on Brain

Structure and Function: Clinical Implications
Joan Kaufman, Paul M. Plotsky, Charles B. Nemeroff, and Dennis S. Charney

Child abuse is associated with markedly elevated rates of countless other cases never come to the attention of author-
major depression and other psychiatric disorders in adult- ities (e.g. Wolfner and Gelles 1993). In clinic (Brown and
hood. This article reviews preclinical studies examining the Anderson 1991; Windle and Houston 1995), community
effects of early stress, factors that modify the impact of these (Bifulco et al 1991), and representative epidemiologic sam-
experiences, and neurobiological changes associated with ples (Holmes and Robins 1987), experiences of early child
major depression. Preclinical studies demonstrate that early
maltreatment have been associated with elevated rates of
stress can alter the development of the hypothalamic-pitu-
major depression (MDD), anxiety, and other psychiatric
itary-adrenal axis, hypothalamic and extrahypothalamic cor-
ticotropin releasing hormone, monoaminergic, and ␥-ami- disorders.
nobutyric acid/benzodiazepine systems. Stress has also been Preclinical studies suggest that stress early in life can
shown to promote structural and functional alterations in promote long-term changes in multiple neurotransmitter
brain regions similar to those seen in adults with depression. systems and brain structures implicated in the etiology of
Emerging data suggest, however, that the long-term effects of MDD (Arborelius et al 1999; Heim et al 1997). It is
early stress can be moderated by genetic factors and the hypothesized that neurobiological changes associated with
quality of the subsequent caregiving environment. These adverse early experiences can confer a vulnerability for
effects also can be prevented or reversed with various the development of MDD and other psychiatric disorders.
pharmacologic interventions. Preclinical studies of early It is also suggested that preclinical studies of early stress
stress can provide valuable insights in understanding the can provide a valuable model for understanding the patho-
pathophysiology and treatment of major depression. They
physiology of MDD, even when it occurs independent of
also can provide an important tool to use to investigate
interactions between genes and environments in determining early childhood trauma (Charney and Deutch 1996).
an individual’s sensitivity to stress. More research is needed This article is organized into five sections. The first section
to understand how inherent factors interact with experiences reviews functional connections among key structures and
of abuse and other psychosocial factors to confer vulnera- neurotransmitter systems involved in the initiation and con-
bility to develop depression. Biol Psychiatry 2000;48: trol of the stress response. The second section reviews
778 –790 © 2000 Society of Biological Psychiatry preclinical studies examining the long-term effects of early
stress on hypothalamic-pituitary-adrenal (HPA) axis function
Key Words: Depression, corticotropin-releasing hormone and central corticotropin releasing hormone (CRH), mono-
(CRH), child abuse, animal models aminergic (norepinergic, dopaminergic, serotonergic), and
␥-aminobutyric acid/benzodiazepine (GABA/BZ) systems.
Structural and functional brain changes associated with early
Introduction or severe stress are also reviewed. The next section reviews
factors that modify the impact of early stress, and pharma-
C hild abuse is a pervasive social problem that is fre-
quently associated with long-term significant psychiatric
sequelae. Each year there are more than one million substan-
cologic interventions that can prevent or reverse the neuro-
biological alterations are delineated. Lastly similarities in the
tiated reports of child maltreatment (U.S. Department of neurobiological correlates of stress and depression in adults
Health and Human Services, National Center on Child Abuse are highlighted, and the clinical implications of the research
and Neglect 1997), and numerous studies indicate that are discussed.

From the Department of Psychiatry, Yale University School of Medicine, New Key Structures and Neurotransmitter
Haven, Connecticut (JK), the Department of Psychiatry and Behavioral
Sciences, Emory University School of Medicine, Atlanta, Georgia (PMP, Systems Involved in the Stress Response:
CBN), and National Institute of Mental Health, Bethesda, Maryland (DSC). Overview
Address reprint requests to Joan Kaufman, Ph.D., Yale University School of
Medicine, University Towers, Suite 2H, 100 York Street, New Haven CT
06511.
The brain appears to respond to stress in a complex and
Received May 17, 2000; revised July 12, 2000; accepted July 25, 2000. orchestrated manner, with both general and stimuli-spe-

© 2000 Society of Biological Psychiatry 0006-3223/00/$20.00
PII S0006-3223(00)00998-7

locus coeruleus. inhibitory inputs. ergic inputs are primary in promoting the synthesis and thalamus and amygdala via inputs to the periaqueductal release of CRH into the median eminence and hypophysial gray and parabrachial nucleus (An et al 1998. Not shown in the diagram are indirect connections from these prefrontal structures to the hypothalamus and amygdala via inputs to the periaqueductal gray and parabrachial nucleus. The medial and orbital PFCs provide direct inputs to the hypothalamus and are reciprocally connected with the amygdala. prefrontal cortices also provide direct inputs to the hypo- nents of the stress system is still evolving. and orbital PFC currently un. and brainstem autonomic nuclei. sive connections with the ventral tegmental area. the hippocampus. substantia nigra. anterior cingulate. mus. Krout et al 1998). substan- nents of the stress system. NE. It is secreted tical structures involved in the stress response (Lopez et al from the paraventricular nucleus (PVN) of the hypothala- 1999). Bandler 1998. of information between the different brain regions. cific components to the stress response (Lopez et al 1999). There is growing appreciation of the subcortical structures involved in the stress response and role of cortical inputs. raphe. The medial prefrontal cortex (PFC). and each has indirect connections with the hypo. noradren- nected. and HPA axis are detailed in Figure 2. The medial PFC is also reciprocally connected with the mediodorsal thalamic nucleus and has extensive connections with the ventral tegmental area. stimulatory inputs. and orbital PFC relay information from primary sensory and association cortices to subcortical structures involved in the stress response. The review of thalamus and are reciprocally connected with the amyg- the stress response included in this section is not exhaus. with medial prefrontal cortex the neurotransmitter systems involved in the transmission (PFC). These prefrontal regions appear to tive. The main noradrenergic . It focuses on key components of the stress system and be critical in restraining the acute stress response and emphasizes the structures and neurotransmitter systems facilitating negative feedback inhibition of the system most extensively studied in preclinical studies examining (Herman and Cullinan 1997). Bernard and portal system (Plotsky et al 1989). locus coeruleus. raphe. The medial and orbital Knowledge about the structural and functional compo. initiates the endocrine response to stress. The medial and orbital PFCs are reciprocally interconnected. dala (Ongur et al 1998). tia nigra. dotted line. amygdala. Among the numerous inputs to the PVN.Early Adverse Experience BIOL PSYCHIATRY 779 2000. Connections among brainstem nuclei. The reader is referred (mPFC) also is reciprocally connected with the mediodor- to Chrousos (1998) and Lopez et al (1999) for a more sal thalamic nucleus (Groenewegen 1988) and has exten- detailed discussion of the central and peripheral compo. and the autonomic response to stress that is promoted by the locus coeruleus. different cortical and subcortical brain regions involved in Figure 2 depicts in more detail the relationships among the stress response. The medial prefrontal cortex the long-term effects of early stress. and Figure 1 depicts the functional connections among the brainstem autonomic nuclei (Drevets et al 1998).48:778 –790 Figure 1. Medial and orbital PFC are reciprocally intercon. These connections facilitate initiation and regulation of the endocrine response to stress that is mediated by the hypothalamic–pituitary–adrenal (HPA) axis. Key cortical and subcortical structures involved in the stress response. Solid line. anterior cingulate. nucleus accumbens. Corti- derstood to play an important role in relaying information cotropin releasing hormone is the neurohormone that from primary sensory and association cortices to subcor. nucleus accumbens. norepinephrine.

Glucocorticoids regulate energy locus coeruleus (LC). association cortex. which initiates the release of glucocorticoids from the adrenals. The release of corticotropin- releasing hormone (CRH). CRH appears to act centrally as a neurotrans- Corticotropin releasing hormone then binds to receptors at mitter to initiate the autonomic and behavioral changes the anterior pituitary gland and. Glucocorticoids provide positive stimulation to the CnAmy. found to produce physiologic and behavioral changes similar derived peptides such as adrenocorticotropin and ␤-endor. among other sites. Then CRH promotes the release of adrenocorticotropin (ACTH) from the pituitary. ventrolateral medullary oblongata (Pacak et al 1995). thalamus. tyrosine hydroxylase mRNA in the (Arborelius et al 1999). . In addition. Glucocorticoids provide negative feedback at the pituitary and PVN. which promotes the synthesis and release of CRH. increases pro-opiomelanocortin central nervous system administration of CRH has been (POMC) gene expression and the release of POMC. Kaufman et al 2000. through a cascade of observed in response to stress (Valentino et al 1998). BNST. Septum. amygdala. a neurohormone. bed nucleus stria terminalis. Solid lines. corticosterone in rats) from the adrenal cortex plasma catecholamines. from the paraventricular nucleus (PVN) of the hypothalamus initiates the endocrine response to stress. stimulatory inputs. hypothala- sources. Centrally administered CRH antagonists synthesis and release of glucocorticoids (cortisol in pri. as intracellular events. to those reported in animals subjected to stress (Owens and phin. and amygdala. The release of CRH from the PVN is modified by multiple neurotransmitters. and CRH mRNA and type 1 CRH substrate availability and utilization and provide negative receptor mRNA in the PVN (Jezova et al 1999). inputs into the PVN appear to be derived from medullary feedback to the stress system at the pituitary. In addition. CRH acts as a neurotransmitter to initiate the autonomic response to stress. dotted lines. GABAergic interneurons located at each of the structures likely further modify stress reactivity. Adrenocorticotropin (ACTH) then promotes the Nemeroff 1991). Key subcortical structures and neurotransmitter systems involved in the stress response. but norepinephrine (NE) inputs from medullary nuclei provide the primary stimulus for CRH synthesis and release. the nucleus of the solitary tract (NTS) and the mus. and other central sites involved in the stress response. inhibitory inputs. The stress response is further modified by serotonin (5-HT) inputs from the raphe nuclei to the PVN. lateral septum. as do connections from multiple other brain regions including the prefrontal cortex.48:778 –790 Figure 2. also have been found to reduce stress induced increases in mates. and mesocortical and mesolimbic structures. The hippocampus serves to inhibit the stress response via multiple direct and indirect ␥-aminobutyric acid– ergic (GABAergic) inputs to the PVN. epinephrine.780 BIOL PSYCHIATRY J. hippocampus. EPI. and locus coeruleus. L. The autonomic component of the stress response is initiated by CRH inputs from the central nucleus of the amygdala (CnAmy) to the locus coeruleus.

This profile is associ- ated with decreased GABA binding (Wilson 1996). LC. and the frontal paminergic (DA) system (Chrousos 1998). serotonin inputs from deprived rats also is associated with a decrease in tone of the dorsal raphe to the PVN. see Francis et The stress response is further modified by serotonin al (1999) and Ladd et al (2000). with multiple systems implicated in the pathophys- catecholamine response to stress because local application iology of depression affected by these investigational of exogenous CRH in the LC has been found to increase manipulations. For example. et al 1999b). inputs from the dorsal and median raphe to the basolateral The increase in CRH and NE drive in maternally and central nucleus of the amygdala. For reviews. In addition. BnAmy. They also have been found to have reduced central tical system includes DA neurons of the ventral tegmen. The LC receives endogenous CRH these experiences associated with increased CRH and NE inputs from the central nucleus of the amgydala (CnAmy). The amygdala is activated during stress by ascending Liu et al 2000). These effects were associated with decreased ex- and the mesolimbic system consists of DA neurons from pression of mRNA for the ␥2 subunit that encodes for the the same region that innervate the nucleus accumbens. cortex. neurobiological effects of early maternal separation. creased CRH concentration in the median eminence The hippocampus. The hippocampus also ghi et al 1993). Extensive research has been conducted examining the and prefrontal cortex (Page and Abercrombie 1999. Ladd et al 1996. mesocortical system is involved in anticipatory and cog. Maternal deprivation has also cotropin releasing hormone neurons of the CnAmy re. analogous to the mPFC in humans and other primates. Rat pups separated from their mothers 6 catecholamine neurons originating in the brainstem and by hours per day during the first 3 weeks of life have been cortical association neurons involved in processing stress. eral nuclei of the amygdala (BnAmy). In a set of related experiments (Braun et al 2000. drive in adulthood (Francis et al 1999a. and increased NE concentration in the PVN (Menza- pus (Owens and Nemeroff 1991). numerous investigators have demonstrated long-term neu.Early Adverse Experience BIOL PSYCHIATRY 781 2000. Val. adult rats subjected to These latter serotonin (5-HT) neurons terminate on inhib. and tum that send projections to the medial prefrontal cortex. Similar neurobiological the development of efferents to frontal areas believed to be alterations have been reported across experimental condi. Levine et al 1993. several of the brain structures activated during stress increased CRH content in the parabrachial nucleus (a (Lopez et al 1999). norepinephrine (NE) release in the PVN. subunit mRNA (Caldji et al 2000). adult rats separated from their mothers during the first 3 nitive functions and exerts a suppressive effect on the weeks of life also had increased mRNA expression for the stress system. LC. NTS. median raphe to the hippocampus (Lopez et al 1999). hippocampus. The benzodiazapine site of the GABAA receptor. It is likely that the dampened GABAergic tone in rats exposed Neurobiological Effects of Early Stress: to maternal separation animals contributes to the enhanced Preclinical Studies CRH expression in the amygdala and the increased stress- Building on the seminal work of Levine and colleagues induced activation of the noradrenergic systems (Francis (Coe et al 1978. robiological changes in animals subjected to multiple Poeggel et al 1999). basolat- the mesocortical and mesolimbic components of the do. It also has been associated stress response via multiple direct and indirect links with with increased CRH mRNA expression in the CnAmy. stressor (Kraemer et al 1989). Francis et al 1999b). pituitary (Ladd et al 1996). and serotonin inputs form the the inhibitory GABA/BZ system (Caldji et al 2000. Nonhuman primates subjected to maternal inhibits the LC via direct connections and inhibits the separation early in life have also been found to have PVN via indirect inputs through the lateral septum and bed elevated cerebral spinal fluid NE in response to an acute nucleus of the stria terminalis. been associated with increased CRH mRNA expression in spond positively to glucocorticoids and activate the the hypothalamic paraventricular nucleus (PVN) and in- LC/NE component of the stress system (Lopez et al 1999). repeat separations from their mothers during the first 3 itory GABA neurons. Takahashi and Kalin 1991). in contrast. Specifically. . Wiener et al 1987). benzodiazapine binding in the CnAmy. with entino et al 1998). Braun and colleagues examined the prenatal and postnatal stress paradigms (Graham et al impact of early maternal separation and social isolation on 1999.48:778 –790 The LC appears to be the critical site in initiating the tions. increased CRH binding in the CnAmy is inhibited by GABA inputs from the hippocam. and the mesolimbic system is involved in ␣2 and ␣3 subunits and decreased expression of the ␣1 processing motivation and reward aspects of experience. CRH synthesis in the region that adjoins the LC. Corti. serves to inhibit the (Plotsky and Meaney 1993). found to have increased basal and stress induced ACTH ful stimuli via direct and indirect medial and orbital concentrations and decreased CRH binding in the anterior prefrontal cortical connections (Lopez et al 1999). The mesocor. weeks of life have been found in adulthood to have Both the PVN CRH and LC/NE systems also innervate reduced GABAA receptor binding in the CnAmy.

central benzodiazepine receptor levels in the CnAmy. primates in the high foraging demand condi- amine fiber innervation to the frontal areas was examined tion had to work hard to find food. experimental conditions (Coplan et al 1996). see Ladd et al (2000) and Francis et al (1999b). They showed enhanced negative feedback of information processing. In addition. Because some NADPH. The neu- infralimbic. Mansi et al 1996). . food supply were predictable. the deprived macaque infant–mother dyads to variable foraging demands. with these animals as adults showing en- the substantia nigra did not differ between the groups. core region of the nucleus accumbens. to suppressed axonal sprouting and aborization. receptor mRNA expression and glucocorticoid receptor tions from 8 weeks of age also have been found to exhibit number in the hippocampus and the frontal cortex. in addition to provided positive stimulation via 15 minutes of han- having altered DA/5-HT balance in the mPFC. involved in the inhibitory control of CRH synthesis in creased social interaction. hanced behavioral response to yohimbine. maternally deprived and socially isolated rats maternal deprivation rodent studies discussed above. sites enhanced anxiety. body regions of the LC and NTS. anterior cingulate. Specifically. The number of foraging condition was also associated with over activity of TH-positive somata in the ventral tegmental area and in the NE system. After weaning. and prelimbic cerebral spinal fluid CRH concentration than did monkeys cortex subdivisions of the mPFC and increased 5-HT. reared under the two other more predictable and less stressful positive fiber densities in the infralimbic cortex (nomen. which sors. also had reduced CRH mRNA concentrations in the probably reflecting a reduction in the number of cross. increased self-directed behaviors. consistent with the conditions. precentral medial. as well as increased ing the role of central CRH oversecretion in the patho. are essentially the opposite of those reported in mater- containing neurons have been found to be GABAergic. Coplan et al (1996) subjected day 1 to postnatal day 21. de. compared with nonhandled or maternally separated rats reactive neurons in the anterior cingulate cortex and the (Plotsky and Meaney 1993). Ladd et al 2000). acute restraint stress (Liu et al 2000). The nursery. They also had attenuated CRH reared animals also exhibited increased CRH1 receptor induced activation of the LC and smaller resulting binding sites in the dentate gyrus of the hippocampus and increases in extracellular NE levels in the PVN after the orbital prefrontal cortex. Octodon Degus rodents were separated from neglectful parenting and exposure to stressful environments their mothers three times a day for 1 hour from postnatal in young human infants. 1999b. Handled rats showed reduced reduced NADPH-diphorase neurons may represent a loss ACTH and corticosterone response to exogenous stres- of inhibitory interneurons in this cortical region. foraging demand condition experienced changing and unpre- When compared with rodents reared under undisturbed dictable access to food. with increased CRH2 recep. The variable clature according to Groenewegen 1988). handled rats had reduced mance when tested at 18 to 24 months of age (Sanchez et CRH mRNA levels in the PVN and reduced basal CRH al 1998). and primates in the variable ylase (TH) and 5-HT.48:778 –790 Specifically. Handled rats medial and caudal midbody corpus callosum volume. They were then sacrificed. mediated cognitive tasks (Meaney et al 1991. as well as a trend rats handled in the first 3 weeks of life showed for reduced NADPH-diphorase-reactive neurons in the decreased fearfulness in novel environments. in adulthood. physiology of depression because peptide oversecretion LC. Accordingly. Mater. 1993). access to food. Kaufman et al 2000. the nally separated rats. and NTS (Francis et al 1999b). were also dling per day during the first 3 weeks of life have been found to have a significant decrease of nicotinamide found to have reduced stress reactivity in adulthood adenine dinucleotide phosphate (NADPH)-diphorase. mon- had significantly reduced TH-positive fiber innervation in keys reared in the variable foraging condition had higher the precentral medial. but foraging demands and using immunocytochemical detection of tyrosine hydrox. For In an attempt to more closely parallel the experience of reviews. handled does not always result in receptor down regulation and has rats had attenuated age-related cell loss in the hip- been found to cause upregulation in certain brain regions pocampus and improved performance on hippocampal (Imaki et al 1996. and impaired cognitive perfor. and mono. and prelimbic prefrontal robiological alterations associated with early handling areas (Poeggel et al 1999). animals were reared in isolation in single cages until Primates in the low foraging demand condition had easy postnatal day 45. In adulthood. with quicker return of corticosterone to baseline plays a critical role in integrating affective and cognitive levels. CnAmy and lower CRH content in the LC (Francis et al hemispheric fibers (Sanchez et al 1998). circulating glucocorticoids and increased glucocorticoid Rhesus monkeys reared under isolated nursery condi.782 BIOL PSYCHIATRY J. These animals also have shown reductions in concentration in the median eminence. an ␣2 adrenergic suggesting that the reduced fiber densities were likely due antagonist (Rosenblum et al 1994). increased GABAA receptor levels in noradrenergic cell These findings do not contradict the hypothesis concern. rats nally deprived and socially isolated animals. Handled rats had tor binding in amygdala subregions (Sanchez et al 1999). In contrast. PVN neurons. to the negative effects of early stress.

the handled pups cross-fostered to dams assigned to the Factors Moderating the Impact of Early maternal separation condition reacted to novel stressors Stress like rats subjected to maternal separation during the The studies reviewed in the prior section demonstrate neonatal period. enhanced glu- structural plasticity: neuronal atrophy. and a reversible decrease in number of apical dendritic branch decreased stress induced NE secretion from the PVN. and nonhandled rats. Reductions in hippocampal volume may also be maternal separation experiences were cross-fostered with affected by decreases in neurogenesis (Gould and Cam. Meaney. Similar McEwen for further discussion of these topics. rat pups exposed to early handling or 1994). the maternal separation condition appeared similar to unpublished observations). tactile .48:778 –790 The maternal deprivation and postnatal handling studies reared without any experimental manipulations showed clearly highlight the importance of early experience on the greater exploration in novel environments and had reduced development of the brain and multiple neurotransmitter plasma ACTH and corticosterone response to acute stress. More sustained stress or glucocor. Rats exposed to high studies raised questions as to whether the neurobiological concentrations of glucocorticoids for approximately 12 changes associated with handling were due to the early hours per day for 3 months experience a 20% loss of experimental manipulation or to subsequent differences in neurons specific to the CA3 region of the hippocampus maternal behavior. Jans. In dams assigned the handling and maternal separation con- conducting the handling experiments. Francis et al. In a second set of experiments (Gonzalez et al 1999). In the initial set of hippocampus continue to proliferate into adulthood. These nent loss of hippocampal neurons. They found that with emerging data delineating the seminal role of differ- the adult offspring of high licking and grooming mothers ent components of mother–infant interaction (e. The granule cells in the dentate gyrus of the condition (Gonzalez et al 1999). cross-fostering was performed on pups exposed to the maternal separation condition. These results are consistent unpublished data. increased stress or stress levels of glucocorticoids (Sapolsky 1996. When tested as adults. decreased CRH receptor density in the LC. however. 1996. and assigned to the maternal separation condition. To determine if the neurobiological changes associated toxicity of cells in this region has been reported in with early handling could be altered by subsequent care- nonhuman primates as well (Sapolsky 1996. and the adult offspring that had been assigned to the latter group (B. mediate reactivity to stress (Caldji et al 1998). dams whose pups were assigned the same or opposite eron 1996). Woodside. other dams assigned to the handled condition or to dams See articles in this volume by Sapolsky. maternally separated pups that early life experiences can have profound effects on reared by dams assigned to the handling condition were brain structure and function. Gould. The stress effects on hippocampus development The animals also showed increased hippocampal glu- are likely mediated by a minimum of three forms of cocorticoid receptor mRNA expression. points and length of apical dendrites of sufficient magni. Maccari et al 1995). ior by the dams whose pups were separated for 180 cantly more time licking and grooming their offspring than minutes. systems. These results parallel the findings observed in handled rats tude to impair hippocampal dependent cognitive processes and suggest that maternal licking and grooming behaviors (Watanabe et al 1992). ment can moderate the adverse effects of early stress. handled animals rather than similar to maternally sepa- To determine if the differences in maternal behavior rated animals. and cocorticoid negative feedback sensitivity. Meaney and col. neurotoxicity. glucocorticoids produce and LC. Evidence of stress-induced neuro. M. may “program” the development of the neural systems that ticoid exposure can lead to neurotoxicity—actual perma. Uno et al giving experiences. This maternal behavior of the mothers of handled and non. central benzodiazepine receptor number in the CnAmy Woolley et al 1990). and experiments. J.. They also had de- hippocampus can be caused by 3 weeks of exposure to creased CRH mRNA expression in the CnAmy. and decreased neurogenesis. C. These findings are consistent with the were related to differences in stress reactivity of handled results of studies examining the effects of prenatal stress. simple manipulation seemed to normalize maternal behav- handled pups. (Sapolsky et al 1985).Early Adverse Experience BIOL PSYCHIATRY 783 2000. with the former group spending signifi. Meaney and colleagues examined In these studies “adoption” with “optimal parenting” also multiple indices of stress reactivity in adult rats reared by has been found to reverse the HPA axis alterations mothers with similar naturally occurring differences in typically observed in these experiments (Barbazanges et al maternal behaviors (Caldji et al 1998. J. there is emerging more similar to handled animals.g. Liu et al 1997) 1999). data to suggest that the subsequent caregiving environ. Neuronal atrophy in the CA3 region of the hypothalamic CRH mRNA levels. Conversely. ditions were provided with an age-matched foster litter leagues noted that there were marked differences in the during the period when their own pups were away. At this level. handled pups were either cross-fostered to neurogenesis in this region is markedly reduced by stress.

Kaufman et al 2000. on maze performance.g. imipramine) treatments have also measures.. or Paroxetine. As outlined in Table 1.48:778 –790 stimulation) in regulating physiologic systems involved in as gene chips that permit the simultaneous analysis of the stress response (Caldji et al 1998. also reverses already established hip- hyperactivity and performance deficits. however. The reduced negative feedback as evidenced by dexametha- Human Genome Project and evolving methodologies such sone nonsuppression (American Psychiatric Association . cross-fostering BALB/cByJ number of apical dendritic branch points and length of mice with C57BL/6ByJ dams prevented corticosterone apical dendrites. genetic factors or strain effects has been well established in preclinical studies of stress reactivity (Dhabhar et al 1997). Because the influence of (Watson and Akil 1999). etine and fluvoxamine do not block dendritic atrophy ing of the more resilient C57BL/6ByJ mice had no impact caused by repeated restraint stress (Magarinos et al 1999). and C57BL/6ByJ mice to early handling experiences and Emerging data suggest that in addition to glucocorticoids. many of the biological alterations ulations have greater impact on some neurobiological associated with early stress have been reported in adults systems (e. Surprisingly. in addition to preventing reduction in task performance. The BALB/cByJ mice are inherently toxicity. tianeptine). ing of the interactions between genes and environmental interactions in determining an individual’s stress reactivity and vulnerability to depression. LC. acute and chronic stress (Lopez et al 1999. stress-related changes in brain structure question. the cross-fostering studies raise questions as to Neurobiological Effects of Early Stress: whether manipulations in parenting can overcome genetic Pharmacologic Prevention and Treatment and breed differences in stress reactivity. In addi- cross-fostering were only observed in the high-reactive tion. Consistent with these findings.. McEwen et al high reactors and have elevated corticosterone and brain 1997. neuro- Zaharia et al 1996). with depression and other stress-related disorders. or prefrontal cortex.. the antiseizure drug phenytoin the learning impairments seen when mice were tested in (which reduces EAA release). Meaney and colleagues subjected BALB/cByJ can be altered by multiple pharmacologic interventions.. hippocam.g.. reuptake inhibitors (SSRI) in treating depression. adinazolam). Early handling and cross-foster. To address this The long-term.g. Kuhn and Schanberg thousands of genes will help to identify the relevant genes 1998). central NE).and low-reactive adult rodents subject to repeat maternal separation during rat species (Steimer et al 1998). corticosterone stress reactivity. electroconvulsive therapy and chronic tricyclic stress induced corticosterone levels. McEwen et al 1997. similar neurobiology may have distinct etiologies. catecholamine responses to acute stressors. including serotonin Morris water-maze that is exacerbated by foot-shock reuptake enhancers (e. They suggest that species Similarities in the Neurobiological with more intrinsic reactivity are more responsive to the Correlates of Stress and Depression: effects of environmental manipulations than are less in- Clinical Implications trinsically reactive species and that environmental manip. Early handling of BALB/cByJ mice reduced nists (e. Sapolsky 1996). and these experimental manipulations only affected infancy. Likewise. In addition. Tianeptine. several classes of medications have been found to prevent mice of this strain exhibit impaired performance on a dendritic atrophy caused by stress.g. fostering and handling did not alter stress-induced changes given the clinical effectiveness of selective serotonin in NE concentration in the hypothalamus. For The clinical and research implications of these findings are example. Effects of handling and the neonatal period (Plotsky. been found to reverse HPA axis overactivation following These studies highlight the need for a better understand. HPA axis) than on others (e. in adult primates subject to maternal deprivation in rats. and adrenal steroid inhibi- the Morris water-maze as adults and prevented stress. pocampal atrophy (Magarinos et al 1999). not central NE antidepressant (e. unpublished data). A similar set of findings was reported by erties can reverse the HPA axis alterations observed in investigators studying two different high. including to the development of depression and that phenotypes with increased basal cortisol secretion (Schildkraut et al 1989). benzodiazepine ago- application. randomly assigned them to BALB/cByJ or C57BL/6ByJ serotonin and excitatory amino acids (EAA) are involved mothers for subsequent rearing (Anisman et al 1998. They imply that there are multiple pathways have multiple alterations of the HPA axis. in the mechanisms that promote neuronal atrophy. and neurogenesis (Gould 1999. adults with depression have been reported to far reaching. fluox- pus.784 BIOL PSYCHIATRY J. cross. an SSRI with less serotonergic-specific prop- brain NE. Sapolsky induced elevations of corticosterone and disturbances with 1996). that promote hyperstress reactivity and will facilitate the The cross-fostering experiments clearly demonstrate identification of homogenous subgroups of patients with that the effects of early experiences can be moderated by depression for future neurobiological and genetic studies subsequent rearing experiences. Suomi 1991). tors (Magarinos et al 1999.g.

a neurosteroid that potently system. preliminary histopathologic data from the sub- cal GABA measured in vivo using proton magnetic genual PFC suggest that depressed patients have a de- resonance spectroscopy (Sanacora et al 1999). medial prefrontal cortex. and blunted ACTH secretion in lates of stress and clinical findings in studies of patients response to administration of endogenous CRH (Gold et al with posttraumatic stress disorder. Neurobiological Effects of Early Stress: Clinical Implications Preclinical findings Clinical findings The implications 1. GABA/BZ. (Mayberg et al 1997). maltreated children to optimize the likelihood of good long-term outcomes. as Studies of adults with depression have also reported evidenced by reports of elevated concentrations of cere.. Early stress is associated with Studies of adults with depression have Better understanding of the mechanisms altered development of reported structural and functional involved in the development of mPFC monoaminergic fibers in the alterations in the mPFC and in fibers may also identify noval targets for mPFC. 3. major depression. indicate that adults with depression with repeat neurobiological assessments have reduced hippocampal volume. see Arborelius et al 1986. MDD. CSF. Specif- bral spinal fluid CRH (Nemeroff et al 1992). Effects of early stress can be Twin studies suggest that individuals at The human genome project and evolving moderated by genetic factors. allopregnanolone. Depressed adults vets et al 1997). depression following stressful life events than are individuals at low genetic risk. Early stress is associated with Clinical investigations utilizing MRI Longitudinal studies of depressed patients hippocampal atrophy. total duration of illness. Holsboer et al 1987.g. Many new class of antidepressant and NE drive in adulthood.48:778 –790 Table 1. high genetic risk for affective technologies will help to identify the disorders are more likely to develop relevant genes that infer risk. pharmacologic treatments for MDD. mPFC. Early stress promotes Adults with depression have reduced Medications that selectively modulate in decreased tone in the cortical GABA. They also 1999. connected brain regions (e. amygdala). Plotsky et al 1998). recurrence. effective antidepressants downregulate anxiolytic medications. 5. as well as decreased blood flow and also have been found to have higher cerebral spinal fluid glucose metabolism in this region (Drevets et al 1992). raising questions as to whether these changes Early and aggressive therapeutic represent primary disturbances intervention may be important in associated with depression onset or preventing neurobiological alterations secondary brain changes related to associated with MDD. magnetic resonance imaging. NE. central NE receptors. at different stages of illness are needed Degree of atrophy correlates with (e. These two regions are contained in . 2. Altered crease in glia number in this region without a correspond- DA/5-HT balance also has been reported in adults with ing loss of neurons (Drevets et al 1998).Early Adverse Experience BIOL PSYCHIATRY 785 2000. addition. may be another novel class of antidepressant and anxiolytic medication. ␥-aminobutyric acid/benzodiazepine. first episode vs. 6. cerebrospinal fluid. adults with depression have been found to have CRH receptor binding site number in the frontal cortex of reduced gray matter volume in the subgenual PFC (Dre- suicide victims (Nemeroff et al 1988). structural and functional alterations in the mPFC. Reduced glucose depression (Reddy et al 1992). CRH. norepinephrine. 1987. Carroll 1982). with fluoxetine treatment metabolism in the ventromedial PFC (Buchsbaum et al associated with increases in cerebral spinal fluid DA/5-HT 1997) and decreased blood flow in the dorsal anterior metabolite concentration ratios (De Bellis et al 1993. Effects of early stress can be Clinical studies also indicate that This highlights the importance of clinical moderated by subsequent positive attachment relations can interventions aimed at securing caregiving experiences. 4. third or greater). Early stress is associated with Adults with depression have increased The CRH antagonist drugs may represent a increased central CRH and CSF CRH and NE secretion. and reduced ically. In NE concentration (Wong et al 2000) and decreased corti. facilitates GABA transmission. ALLO. specific brain regions the biosynthesis of inhibitory central GABA/BZ ALLO. for a cingulate also has been reported in depressed patients discussion of the similarities in the neurobiological corre. corticotropin-releasing hormone. ameliorate the deleterious effects of permanent and secure placements for early abuse. MRI. Charney et al 1998).g. have been found to have increased central CRH drive.

No such medications dom 1991). Patchev and Almeida 1998). Preclinical studies highlight the importance of population (Kaufman and Henrich 2000. ication (Guidotti and Costa 1998). Because child abuse is (Bremner et al 1995. availability of a supportive parent or alternate guardian has The finding of central CRH overdrive in preclinical been demonstrated to be one of the most important factors studies of early stress and clinical studies of depressed that distinguishes abused children with good developmen. randomized controlled trials in clinical populations will be sive disorders in maltreated children (Kaufman 1991). different ages also suggests that this is an important focus The section on factors that modify the impact of early of future research because the neurobiological changes stress also discussed the importance of genetic factors in associated with the acute-stress response change with age modifying the impact of postnatal stress. alcohol abuse. CRH1 antagonist drugs are currently being developed. with abnormalities in resting blood flow and genetic and environmental risk factors will help to explain glucose metabolism reported in this area as well (Drevets differences in the clinical outcome of adults with a history et al 1999). and strated in studies examining the development of depres.786 BIOL PSYCHIATRY J. a neurosteroid that potently 1988. Vazquez 1998). individuals at high genetic risk for affective 2000. and secure attachments is compromised for many mal. large. fying the adverse effects of early abuse has been demon. Hauser et al 1989. Shah et al 1998. More research with the onset of disorder or secondary brain changes is needed to understand the manner in which inherent related to recurrence and extended glucocorticoid expo. Pynoos et al 1995). as both parent and child genetic factors influence the Sheline et al 1996). Family and twin (Pihoker et al 1993. depression following stressful life events than were indi- studies of adults with depression. Suomi 1991. long-term impact of early stress on prepubertal.48:778 –790 the mPFC and overlap with the subgenual PFC. Holsboer 1999). ever. postpu- comes for children with a history of early child abuse and bertal. Gurvits et al 1996. For example. Unfortunately. This raises questions as to whether quality of the parent– child relationship and subsequent these changes represent primary disturbances associated environmental experiences (Kendler 1996). Data examining developmental changes in the acute ef- treated children by failures in the child protection system fects of stress in rodents and nonhuman primates of (for further discussion. Stein et al associated with an increased risk for a range of disorders 1997). tions in response to a wide array of stressors (Pynoos et al There are currently few preclinical studies examining 1995).g. the development of positive stress reactivity (Bagdy 1998. and the severity of posttraumatic stress reac. Genetic studies. a better understanding of the relevant et al 1998). of early child abuse. but not all disorders were found to be more vulnerable to develop (Axelson et al 1993. the forthcoming. adults suggest that CRH antagonists may represent a novel tal outcomes from those with more deleterious outcomes and effective antidepressant and anxiolytic medication for (Kaufman and Henrich 2000. currently exist. and available data are often is an important focus for intervention with this clinical conflicting. 1997.. in a recent. Kaufman et al 2000. The section on factors that modify the impact of early Many of the medications found to prevent or reverse the stress discussed the importance of subsequent positive behavioral and neurobiological effects of early stress rearing experiences in ameliorating the deleterious effects discussed in the section on pharmacological interventions of postnatal stress. Drugs that selectively modulate the biosyn- intergenerational transmission of abuse (Egeland et al thesis of allopregnalone. As in the preclinical studies. Altered studies of adults with depression have highlighted the glutamatergic transmission also has been reported in the importance of genetic factors in understanding individual anterior cingulate of depressed patients (Auer et al 2000). the are effective agents in the treatment of adult depression. posttraumatic stress disorder. Vakili et al 2000). Kaufman and Zigler 1989). factors interact with experiences of abuse and other sure. how- correlate with total duration of illness (Bremner et al 2000. differences in stress reactivity and vulnerability to develop Structural changes in the hippocampus have also been MDD. may represent antisocial behavior from adolescence to adulthood in another novel class of antidepressant and anxiolytic med- maltreated youth involved with protective services (Wi. see Kaufman and Zigler 1996). Hippocampal volume reductions also have been psychosocial stressors to confer a vulnerability to develop reported in adults with posttraumatic stress disorder depression (Kaufman et al 1998). The the treatment and prevention of stress-related mood and importance of positive attachment relationships in modi. Adults with depression also have been found to (e. and mature rats. anxiety disorders (Arborelius et al 1999. the persistence of facilitates central GABA transmission. population-based reported in several (Bremner et al 2000. degree of hippocampal atrophy was found to and environmental effects are not easily separated. In . antiso- have a reduced volume of core amygdala nuclei (Sheline cial personality). Facilitating the formation of permanent and secure possible gender and developmental differences in the positive relations is essential in promoting adaptive out. In two of the positive viduals at low genetic risk (Kendler et al 1995). Larrieu and gender factors in understanding individual differences in Zeanah 1998). Sheline et al 1996). Mervaala et al twin study.

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