Altered regulation of the hypothalamic-pituitary-adrenalcortical axis (HPAA), including hippocampal function, has been identified for both endocrine and neurotransmitter systems with age. Corticosteroids are among the hormonal factors identified to modulate the HPAA with aging, including an age-dependent decline in corticosteroid binding sites in the hippocampus. Similarly, alterations in neurotransmitter function in the HPAA with age include the decline of hippocampal serotonin (5- hydroxytryptamine; 5-HT) neuronal systems. Recent investigations of possible 5-HT/corticosteroid interactions in the mammalian central nervous system have identified the ability of this neurotransmitter afferent input to modulate the expression of corticosteroid receptor function in the hippocampus. However, the physiological and pharmacological consequences of this interaction on aging of the HPAA remain to be addressed. A series of experiments will address the hypothesis that age-related alterations in serotonergic function modulate the corticosteroid-induced decline of hippocampal cell function. The cellular and molecular alterations in 5-HT and corticosteroid function, including mineralocorticoid receptor (MR) and glucocorticoid receptor (GR), will be investigated by a multidisciplinary analysis of CAI and CA3 hippocampal fields in 3,12, 18 and 24 month old female Fischer 344 rats. The regulation of 5-HT and corticosteroid function will be addressed using in vivo and in vitro cellular electrophysiological recording techniques, neurochemical radioligand binding techniques as well as application of Northern blot and in situ hybridization techniques. Particular emphasis will be placed on assessment of changes for multiple 5-HT (5-HT1A, 5-HT2, 5-HT3) and corticosteroid (MR and GR) receptors by evaluation age-related changes in RNA species and levels for these receptors. In addition, studies of the depletion of 5-HT on age-related changes in corticosteroid hippocampal responses will provide new insights into the nervous/endocrine system interactions that underlie both normal aging and pathological changes found in Alzheimer' disease.
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