Chronic Stress, Glucocorticoids, and Progesterone in Brain Aging

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Evidence indicates that prolonged/ repeated behavioral stress promotes brain aging. This is thought to be due, at least in part, to stress associated glucocorticoid (GC) secretion, which in turn binds to glucocorticoid receptors, exerting transcriptional and other effects. A key downstream mediator in this signaling pathway, serum-and- glucocorticoid kinase 1 (Sgk1) accelerates, and the female sex steroid progesterone (P4) blunts, the effects of GCs. However, despite the negative clinical consequences of chronic stress exposure with aging and/or in female subjects, little work has examined how aging may change the stress response, the mechanisms through which stress may accelerate brain aging, the degree to which stress-accelerated aging is dependent on GC, is driven by Sgk1, or is inhibited by P4. Our preliminary data suggests that hippocampal Sgk1 is upregulated by aging, stress, and GCs in white matter oligodendrocytes, and that the female sex hormone progesterone (P4) blunts the effects of stress/GCs and may serve as an endogenous protectant that is lost with age in females. To address these knowledge gaps, we propose 3 aims to investigate: the age-course of the response to chronic stress or chronic GCs in males and females; whether viral overexpression of Sgk1 exacerbates, or systemic P4 administration ameliorates, stress-accelerated aging; and whether the pharmacologic sensitivity of hippocampal tissue to GC and P4 is shifted with age or chronic stress/GC. Cognitive and anxiety-related behavior, blood hormone measures, and a novel panel of 205 hippocampal genes that are robustly changed with aging across multiple studies, will be used to test for stress/GC-accelerated aging and intervention effects, as will downstream gray and white matter Sgk1 expression and microglial response to microinjury- two processes demonstrated to be glucocorticoid sensitive and exaggerated in white vs. gray matter in preliminary data. Thus, the proposed studies will yield essentially the first comprehensive test of the hypothesis that chronic stress accelerates transcriptional brain aging and will illuminate sex differences in stress responsiveness and the potential roles of GC, P4, and Sgk1 in gray and white matter. Even if all of our working hypotheses are rejected by the results, the proposed studies should have translational value for geriatric medicine.