NEUROENDOCRINE MECHANISMS OF REPRODUCTIVE AGING

描述（改编自申请人的摘要）：所提出的研究的总体目标是确定在生殖衰老期间大脑中发生的变化，并揭示导致中年雌性大鼠发情周期规律性逐渐下降的潜在机制，随后是周期性的完全停止。待检验的中心假设是，虽然中年动物的循环雌二醇水平正常或略有升高，但类固醇信号不能到达GnRH神经元，导致排卵前LH峰低和发情周期长度不规则。目前的建议集中在催乳素能和去甲肾上腺素能神经递质系统，它们的共同点是刺激GnRH释放，它们至少部分受雌二醇调节，并且它们的活性或有效性在中年大鼠中降低。此外，雌二醇在与生殖衰老相关的神经内分泌变化的产生中的作用也将被研究。具体而言，建议：目标1：目的2：检验生殖衰老期间GnRH神经元对去甲肾上腺素能刺激的反应性降低的假设;目的3：来验证生命的假设长期暴露于生理水平的雌二醇会导致GnRH神经元的多巴胺能和去甲肾上腺素能调节功能障碍，在生殖衰老期很明显拟议的研究将提供有关生殖衰老期间GnRH神经元调节输入发生变化的全面信息，并将确定雌二醇是否引起这些变化。对这些事件的详细了解将有助于确定大脑和卵巢之间不适当相互作用的一些基本机制，并可能为治疗由中枢未能维持足够的GnRH释放引起的疾病提供线索。

DESCRIPTION (Adapted From The Applicant's Abstract): 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 rat. The central hypothesis to be tested is that while circulating estradiol levels are normal or slightly elevated in the middle-aged animals, 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 and noradrenergic neurotransmitter systems which have in common that they stimulate GnRH release, they are, at least in part regulated by estradiol and their activity or effectiveness are decreased in the middle-aged rat. In addition, the role of estradiol in the generation of the neuroendocrine changes associated with reproductive aging will be examined. Specifically it is proposed: Aim 1: to test the hypothesis that glutamate release and/or responsiveness to glutamatergic stimulation decreases during reproductive senescence; Aim 2: to test the hypothesis that the responsiveness of GnRH neurons to noradrenergic stimulation decreases during reproductive senescence; Aim 3: to test the hypothesis that life-long exposure to physiological levels of estradiol causes the malfunction in the glutamatergic and noradrenergic regulation of GnRH neurons that become apparent during reproductive senescence. 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 if estradiol causes 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.