The long-term goal of this proposal is to elucidate the role of changing hypothalamic function in age-related reproductive dysfunction in females. In young rats, norepinephrine (NE) mediates the positive and negative feedback actions of estradiol that govern hypothalamic luteinizing hormone releasing hormone (LHRH), and thereby pituitary luteinizing hormone (LH) secretion. In those middle-aged rats that are still exhibiting regular estrous cycles, the responses to both the positive and negative feedback actions of estradiol are diminished, and circadian rhythms are disrupted, leading to changes in basal LH secretion and LH surges. It remains to be determined whether these age-related changes in LH secretion, that may be harbingers of reproductive dysfunction and senescence, are caused by alterations in NE release in the vicinity of the LHRH neurons. Therefore this proposal will focus on the role of NE in the age-related decrease in the negative and positive feedback actions of estradiol on LH secretion. The FIRST SPECIFIC AIM will test the hypothesis that the basal NE release in the diagonal band of estradiol-treated ovariectomized (OVX+E) rats increases with age and that the early and late increases in release associated with the LH surge in young rats are attenuated or abolished in middle-aged rats. The SECOND SPECIFIC AIM will test the hypothesis that replacement with a pattern of NE release typical of young rats into the diagonal band of middle-aged rats restores the timing and magnitude of the LH surge to those of young rats. The THIRD SPECIFIC AIM will test the hypothesis that the early increase in NE release in the diagonal band of young OVX+E rats is the priming and/or timing signal for the LH surge. The FOURTH SPECIFIC AIM will test the hypothesis that the late increase in NE release in the diagonal band of young OVX+E rats, which occurs at the peak of the LH surge, controls the magnitude of the LH surge. The proposed studies will determine NE release in the region of the LHRH cells bodies in conscious, freely-moving animals by in vivo microdialysis with high pressure liquid chromatography. These studies are critical to our understanding of central nervous system mechanisms that mediate reproductive senescence because they will determine the role of NE in the feedback actions of estradiol on LH secretion and will determine the role of these mechanisms in reproductive aging.
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