GLUCOCORTICOIDS, STRESS, AND HIPPOCAMPAL AGING

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Prolonged exposure to increased plasma glucocorticoid levels in later life promotes the loss of hippocampal neurons, disrupts hippocampal electrophysiology, and contributes to cognitive deficits. In the aged rat (and probably in humans) chronically elevated glucocorticoid levels derive from dysfunction within the hypothalamic-pituitary-adrenal (HPA) axis, notably from inefficient corticosteroid negative feedback regulation. This condition results in increased corticotropin-releasing hormone (CRH) synthesis in the hypothalamic neurons which regulate pituitary ASH release. In aged rats increased HPA activity selectively associated with hippocampal pathology, and neither are an inevitable consequence of aging. In the first part of this proposal were are examining the neurobiological mechanisms for such individual differences in HPA activity in later life. Our focus is on 1) hypothalamic CRH gene expression and 2) glucocorticoid negative feedback sensitivity in aged- impaired vs. aged-unimpaired rats. In the second part of the proposal we are examining the effects of various antidepressant drugs treatments on HPA function in aged rats. These studies derive from earlier research in young animals and our initial studies where we showed that HPA dysfunction in the aged, cognitive-impaired rat is reversed with chronic desipramine treatment. We propose to test the idea that longterm antidepressant drug treatment might serve to 1) increase corticosteroid negative-feedback efficiency by increasing corticosteroid receptor biosynthesis in certain critical brain regions known to regulate HPA activity, 2) to reduce hypothalamic CRH synthesis and release, 3) thus to reduce HPA hyperactivity in aged rats, and 4) to attenuate hippocampal pathology in later life. The studies in this section will examine the effects of antidepressant drug treatment on hypothalamic CRH mRNA expression, corticosteroid receptor mRNA and binding levels in various brain regions and pituitary, and glucocorticoid feedback sensitivity. Further studies are designed to examine both the short term and long-term consequences for hippocampal function of reducing HPA activity in aging animals, including a populations of animals that can be considered at "high risk" for the development of age-related hippocampal pathology. It is becoming increasingly apparent that age-related forms of neuropathology emerge in response to a number of events, some unquestionably associated with the genome, others epigenetic in origin. Whether such epigenetic factors, such as endocrine responses to stress contribute to the development of Alzheimer's disease (or other forms of clinical dementia) remains to be determined. However, from what we know of the disease process and the brain structures most affected (e.g., hippocampus), it seems infinitely reasonable that chronic exposure to "stress hormones" such as the glucocorticoids can influence the seventy of symptoms and the progression of the disorder. On the basis of our recent findings, we feel that 1) we have a very relevant target for therapeutic intervention (the neural glucocorticoid receptor system and feedback sensitivity) and 2) a potentially very useful tool (antidepressant drugs) with which to study potentially effective interventions (be they some form of antidepressant or other treatments). Although the focus here is on neurological aging, chronically increased glucocorticoid levels can also contribute to the onset of diabetes and hypertension, both prevalent amongst the elderly. Thus the saliency of this research extends beyond that of brain aging.