The overall goals of the proposed studies are to identify and characterize the changes which occur in the gonadotropin releasing hormone (GnRH)-neuropeptide and GnRH receptor systems in the brain of aging female rats. Reproductive senescence is accompanied by a gradual decline in the regularity and height of the proestrous LH surge which is caused, at least in part, by a reduced release of GnRH. The applicant proposes to test the main hypothesis that the expression of GnRH and hypothalamic GnRH receptors as well as the activation of second messenger systems are altered during aging which would result in inadequate feedback interactions with the ovaries. Specifically, he proposes to: 1. Characterize the changes in GnRH mRNA and peptide levels which occur during reproductive senescence under positive and negative estradiol feedback situations. 2. Characterize the changes in GnRH receptor mRNA and GnRH receptor protein which occur in the aging mediobasal hypothalamus. 3. Identify the mechanisms which underlie a reduced responsiveness of the GnRH target neurons in the aging mediobasal hypothalamus. He will focus on GnRH-stimulated G-protein coupling and inositol phosphate production. The applicant states that the proposed studies will provide comprehensive information on the changes which occur in the neuronal GnRH-synthesizing system, in the GnRH receptor system and in the efficacy of the GnRH-activated signal transduction cascade in the brain of the aging female rat. A detailed knowledge of these events will help to identify some of the basic mechanisms which underlie the reproductive aging process and may provide some clues for treatment of disorders caused by a premature central failure to maintain an adequate GnRH release.
