EARLY EXPERIENCE ALTERS ADULT BEHAVIOR AND THE HPA AXIS

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DESCRIPTION (adapted from applicant's abstract): Both basic and epidemiological studies implicate psychosocial stressors and life events in the development of affective disorders. This stress diathesis model is partially based on the findings that a traumatic stressor often precedes the onset of affective episodes. Accumulating evidence strengthens the concept that the experience of early trauma serves as an important vulnerability factor in this sequelae. Dysfunction of one or more neuronal systems has been postulated in the etiology of major affective disorders, including the noradrenergic (NA) system, the serotonergic (5-HT) system, and the hypothalamic-pituitary-adrenal (HPA) axis. Clinical and animal studies have identified apparent dysregulation of the HPA axis in major depression and its experimental analogs. Dysregulation includes resistance to glucocorticoid negative feedback, elevated concentrations of corticotropin-releasing factor (CRF) in the CSF and/or in specific neuronal structures, and alterations in either peripheral and/or central glucocorticoid receptor density. In animals studies administration of exogenous CRF not only produces activation of the HPA axis, but is associated with many symptoms of depression. Given this burgeoning evidence for a major role for CRF in the pathogenesis of affective disorders coupled with the observed psychiatric impact of early trauma, the investigators hypothesize that early trauma such as that induced by maternal deprivation or abuse may modify hypothalamic and/or extrahypothalamic CRF neurons and may alter inputs to these CRF neurocircuits in such a way as to produce neurochemical, endocrine, and behavioral hyperresponsivity to stressors in adults. Their recent research utilizing neonatal maternal separation in rats has not only verified the existence of alterations in the function of central CRF systems of glucocorticoid receptor density associated with early traumatic experience, but has also uncovered evidence supporting the involvement of adrenergic, serotonergic and GABAergic/benzodiazapine (BZ) systems in either mediating and/or maintaining these maladaptive alterations. In the current application, the investigators propose to further characterize these changes, to elucidate the mechanisms underlying these changes and to evaluate the potential of pharmacological interventions to reverse these dysfunctions. Overall, this research will augment understanding of the role of perinatal life expereince in the development of individual differences in stress responsiveness as well as in identification of neural processes that define this vulnerability.