NEUROENDOCRINE MECHANISMS OF REPRODUCTIVE AGING

描述（改编自申请人摘要）：拟议研究的总体目标是确定生殖衰老期间大脑发生的变化，并揭示导致中年雌性大鼠发情周期规律逐渐下降并随后完全停止周期的潜在机制。要测试的中心假设是，当中年动物的循环雌二醇水平正常或略有升高时，类固醇信号不会到达GnRH神经元，从而导致排卵前的低LH激增和发情周期的不规则长度。目前的建议侧重于谷氨酸能和去甲肾上腺素能神经递质系统，它们的共同点是它们刺激GnRH的释放，它们至少部分受到雌二醇的调节，它们的活性或有效性在中年大鼠中下降。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将被检查。具体提出：目的1：验证生殖衰老过程中谷氨酸释放和/或对谷氨酸刺激的反应性降低的假设；目的2：验证GnRH神经元对去甲肾上腺素能刺激的反应性在生殖衰老过程中降低的假设；目的3：验证终身暴露于生理水平的雌二醇导致GnRH神经元的谷氨酸能和去甲肾上腺素能调节功能障碍的假设，这种功能在生殖衰老期间变得明显。拟议的研究将提供关于生殖衰老过程中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，并可能为治疗由中枢故障引起的疾病提供线索，以维持足够的GnRH释放。

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.