Glucocorticoids released by the hypothalamo-pituitary-adrenocortical axis play a major role in mobilization of bodily defenses in response to physiological or psychological threat. Processes initiated by glucocorticoids can have serious deleterious consequences when prolonged; accordingly, excess exposure is normally avoided by glucocorticoid negative feedback regulation, operating at the level of the brain. Substantial evidence has indicated that this feedback mechanism is severely disrupted in affective disease, resulting in a glucocorticoid dyshomeostasis that may play a major role in determining the course and severity of illness. In the present proposal we have assembled a group of investigators to delineate mechanisms of central neurocircuit regulation of the HPA axis under normal conditions and during disease states. Evidence from several of our laboratories suggests that the HPA axis is controlled by multisynaptic limbic-hypothalamic connections that translate psychological stimuli into neuroendocrine output. The proposed network combines investigators from the disciplines of cell biology, electrophysiology, neuroanatomy, molecular biology, endocrinology, and psychiatry into an integrated research team with the central goal of determining the nature and involvement of these limbic-hypothalamic HPA-regulatory circuits in physiological and behavioral consequences of affective illness. Specific Aim 1 creates a mechanism for linking the efforts of the six component labs through a series of conferences, at which broad-based collaborative studies will be designed, results discussed and future directions determined. Specific Aim 2 provides the means for implementing the collaborative process amongst component laboratories, through pilot projects, sample exchange and active physical interaction among component labs. As a result of these collaborative efforts, this network expects to: 1) design and implement critical tests of the hypothesis that HPA dysregulation and behavioral changes seen in stress models of affective disease are fueled by limbic-hypothalamic imbalance; 2) extend testing of the limbic-hypothalamic hypothesis to functional imaging studies in human depressives; and 3) conduct multi-factorial and inter-disciplinary analyses of anatomical, physiological, pharmacological and behavioral data derived from individual experiments. These collaborative efforts should provide novel insights into integrative regulation of the HPA axis and its relationship to mental health disorders.