Very little is known about the molecular impact of immune and psychological stresses on the brain in the elderly and even less is known about the role of their in the pathogenesis of late life depression. Were this information known, the potential applications toward improving the diagnoses and treatment of late depression would be profound. There are, however, very few investigators who are able to integrate molecular and clinical approaches with studies involving elderly human populations. The research and educational components of this K01 application will provide the necessary training for the applicant to become such an investigator; this will involve close contact with basic research and clinical mentors. The research plan is basic science oriented and is based on the premise that stress neuropeptide systems in the hypothalamus and amygdala are overactivated with aging. Peptidergic overactivation is thought to reflect an overall decrease in functional CNS reserve and thus plays a role in the pathogenesis of late life depression. The hypotheses to be tested include: 1) Interleukin-1 administration to aged rats leads to a greater activation in hypothalamic neuropeptide stress systems; 2) this is associated with decreases in hippocampal corticosteroid receptors; 3) Restraint stress in aged rats leads to a greater activation in amygdalar CRF systems; and, 4) this is associated with overactivation of amygdalar phospho CREB. To test these hypotheses, the following specific measures will be made in old age rats and compared with rats of middle age and young adulthood: CRF and vasopressin gene and peptide expression will be measured in the hypothalamus and pituitary following central interleukin-1 (IL1) challenge. Hippocampal corticosteroid binding will also be measured following central IL1. An additional set of animals will be administered restraint stress; behavioral and molecular measurements of amygdalar CRF systems will be made along with amygdalar phosphoCERB levels. The development of mouse models will also be initiated given that this species is amenable to transgenic manipulation. While carrying out the basic research, the clinical mentors will oversee the research program and also provide the applicant with tutorials in clinical psychoneuroimmunology and late life depression. In addition, they will provide the applicant with guidance, to apply the molecular findings of the research to human populations. Completion of the 5-year program aims to make the applicant an independent investigator who can integrate molecular neuroendocrinology physiology research with clinical geropsychiatry research.
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