Chronic stress and the adrenal steroids secreted in response to stress (e.g. cortisol, corticosterone) are associated with hippocampal atrophy in several conditions including Cushing's Syndrome, recurrent depressive disorder, and aging. Even veterans with posttraumatic stress disorder, a condition with reduced cortisol at the time of diagnosis, display reduced hippocampi, leaving open the possibility that cortisol was elevated during the period of hippocampal shrinkage. A recent study suggests that cortisol elevations contribute to hippocampal shrinkage because reducing chronically elevated cortisol in Cushing's patients reverses hippocampal atrophy. Given the breadth and significance of these cortisol-related afflictions, the long-term objective of this proposal is to understand the consequences and mechanisms by which chronic stress and cortisol hypersecretion cause hippocampal atrophy. Dendritic retraction of CA3 neurons in rats provides a useful model to study the effects of chronic stress and elevated corticosterone on the hippocampus. Chronic stress-induced changes in CA3 dendrites parallel the human condition by shrinking after chronic stress/corticosterone treatment and reversing when the stress subsides. Thus, the mechanisms underlying stress-induced dendritic retraction are conserved across species. The objectives of this proposal are to determine the effects of chronic stress or elevated corticosterone on mechanisms of CA3 dendritic retraction and their functional significance. To achieve this goal, this proposal has three specific aims. First, to determine whether chronic stress-induced CA3 dendritic retraction is indicative of neuronal degeneration or a protective response. Second, to ascertain the levels of corticosterone that are sufficient to cause CA3 dendritic retraction and memory impairment. Third, to determine whether psychosocial stress produces CA3 dendritic retraction and to reveal the components of hippocampal-dependent memory (such as acquisition, consolidation, retrieval) that are disrupted. In all studies, corticosterone, corticosterone binding globulin, and dehydroepiandrosterone will be measured to determine whether other components of the hypothalamic-pituitary-adrenal axis are disrupted by chronic stress and whether they correlate with CA3 dendritic retraction and memory deficits.
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