NEUROENDOCRINE MECHANISMS OF REPRODUCTIVE AGING

描述(改编自申请人的摘要)：拟议研究的总体目标是确定在生殖衰老过程中大脑发生的变化，并揭示导致发情周期规律性逐渐下降的潜在机制，随后完全停止中年雌性大鼠的周期性。需要检验的中心假设是，虽然中年动物的循环雌二醇水平正常或略有升高，但类固醇信号不会到达GnRH神经元，从而导致排卵前黄体生成素峰值较低，发情周期不规律。本研究主要针对谷氨酸能和去甲肾上腺素能神经递质系统，这两种神经递质系统的共同点是刺激GnRH的释放，它们至少部分受雌二醇的调节，在中年大鼠其活性或有效性降低。此外，还将研究雌二醇在与生殖衰老相关的神经内分泌变化中的作用。具体地说，目的1：检验生殖衰老过程中谷氨酸释放和/或对谷氨酸能刺激的反应性降低的假说；目的2：检验GnRH神经元在生殖衰老过程中对去甲肾上腺素能刺激的反应性降低的假说；目的3：检验终生暴露于生理水平的雌二醇导致GnRH神经元在生殖衰老过程中谷氨酸能和去甲肾上腺素能调节功能障碍的假说。这项拟议的研究将提供有关生殖衰老期间GnRH神经元调节性输入的变化的全面信息，并将确定雌激素是否会导致这些变化。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，并可能为中枢未能维持足够的GnRH释放而引起的疾病的治疗提供线索。

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.