Molecular Mechanisms of the Stress Response

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SUMMARY Stress is an important factor in either eliciting or exacerbating many neuropsychiatric disorders. The goal of this proposal is to better understand the molecular mechanisms by which stress affects CNS physiology and behavior. Such knowledge will ultimately lead to more effective measures for preventing the deleterious effects of stress on behavior and health. A prominent mediator of stress is the neuroendocrine system that includes glucocorticoid signaling. Classic glucocorticoid signaling modulates gene expression via steroid hormone (glucocorticoid and mineralocorticoid) receptor transcription factors. This genomic mechanism is partly responsible for stress effects observed over hours to days. Acute stress effects occurring over minutes or longer can also be mediated by glucocorticoids. These effects of stress are thought to occur through non- genomic mechanisms~ however, the identity of these mechanisms remains largely unknown. In a recent study examining the acute effects of stress on hippocampus-dependent memory retrieval, we identified the ¿2- adrenergic receptor (¿2AR) as a critical mediator of the impairing effects of stress and glucocorticoids. Based on these and other observations, we now hypothesize that there is a specific interaction between either the glucocorticoid receptor (GR) or its ligand (cort) and ¿2AR, and that many of the acute effects of glucocorticoids depend on this interaction and the downstream signaling activated by ¿2AR. Here we propose to identify additional systems in which this interaction is relevant to the stress response, characterize the interaction between cort and ¿2AR at the molecular level, and define the downstream signaling events that mediate this coincident signaling. Results from these aims will identify specific molecular mechanisms for the non-genomic effects of glucocorticoids and the acute effects of stress that can persist under conditions of chronic stress. Because stress can impair normal CNS physiology and behavior, as well as exacerbate many neurologic and psychiatric disorders, understanding the mechanisms that underlie stress effects may aid in their prevention.