Neuroendocrine mechanisms of reproductive aging

描述(申请人提供)：拟议研究的总体目标是确定大脑在生殖衰老过程中发生的变化，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小鼠的周期性。需要检验的中心假设是，虽然中年小鼠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。目前的建议集中在谷氨酸能神经递质系统，因为它刺激GnRH的释放，它至少部分受雌二醇调节，在中年动物中其活性或有效性降低。此外，GnRH神经元中基因表达的变化将在生殖衰老过程中确定。具体来说， 目的1：验证谷氨酸能系统在生殖衰老过程中对性腺激素无反应的假说； 目的2：验证GnRH神经元的谷氨酸能神经支配在生殖衰老过程中改变或无效，从而导致GnRH神经元在类固醇诱导的峰时激活减少的假说； 目的3：研究生殖衰老过程中促性腺激素释放激素神经元基因表达的变化。 这项拟议的研究将提供有关GnRH神经元在生殖衰老过程中调节性输入的变化的全面信息，并将确定哪些雌激素受体介导这些变化。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 (provided by applicant): 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.