Neuroendocrine Mechanisms of Reproductive Aging

The overall goals of the proposed research are to determine the changes that occur in the brain during reproductive aging and to reveal the underlying mechanisms that cause a gradual decline in the regularity of the estrous cycle which is followed by a complete cessation of cyclicity in the middle-aged female mouse. The central hypothesis to be tested is that while circulating estradiol levels are normal or slightly elevated in the middle-aged mouse, the steroid signal does not reach the GnRH neurons which leads to a low preovulatory LH surge and to an irregular length of the estrous cycle. The present proposal focuses on the glutamatergic neurotransmitter system because it stimulates GnRH release,it is, at least in part regulated by estradiol and its activity or effectiveness is decreased in the middle-aged animal. In addition, changes in gene expression in GnRH neurons will be determined during reproductive aging. Specifically, Aim 1: will test the hypothesis that the glutamatergic system does not respond to gonadal steroids during reproductive senescence; Aim 2: will test the hypothesis that the glutamatergic innervation of GnRH neurons is altered or ineffective during reproductive senescence which leads to a reduced activation of the GnRH neurons during the steroid-induced surge; Aim 3: will identify changes in gene expression of GnRH neurons changes during reproductive aging. The proposed studies will provide comprehensive information on the changes that occur in the regulatory input to the GnRH neurons during reproductive aging and will determine which estradiol receptor mediates these changes. A detailed knowledge of these events will help to identify some of the basic mechanisms which underlie the inappropriate interactions between the brain and the ovaries and may provide clues for treatment of disorders that are caused by a central failure to maintain adequate GnRH release.