NEUROENDOCRINE MECHANISMS OF REPRODUCTIVE AGING

生殖衰老的神经内分泌机制

• 批准号: 6186772
• 负责人: LOTHAR H JENNES
• 金额: $ 20.44万
• 依托单位: UNIVERSITY OF KENTUCKY
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-06-01 至 2004-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6186772
• 关键词: age difference; aging; estradiol; estrogen receptors; estrus; female; glutamates; gonadotropin releasing factor; hormone regulation /control mechanism; laboratory rat; mature animal; neuroendocrine system; neurotransmitter transport; norepinephrine; ovulation; pituitary gonadal axis; protein localization

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.

描述（根据申请人的摘要进行了改编）：拟议研究的总体目标是确定生殖衰老期间大脑中发生的变化，并揭示导致疏远周期规则性逐渐下降的潜在机制，随后是中等年龄女性循环性的完全戒烟。要测试的中心假设是，虽然中年动物中循环雌二醇水平正常或略有升高，但类固醇信号未达到GNRH神经元，该神经元导致较低的卵石前LH激增和发情循环的不规则长度。本提案的重点是谷氨酸能和去甲肾上腺素能神经递质系统，它们共同刺激了gnRH释放，至少部分受雌二醇调节，其活性或有效性在中间大鼠中降低。此外，将研究雌二醇在与生殖衰老相关的神经内分泌变化产生中的作用。特别是提出的：目标1：检验以下假设：在生殖衰老过程中，谷氨酸释放和/或对谷氨酸能刺激的反应降低；目的2：检验以下假设：GNRH神经元对去甲肾上腺素能刺激的反应性降低了生殖衰老期间；目的3：检验以下假设：终身暴露于雌二醇的生理水平会导致GNRH神经元的谷氨酸能和去甲肾上腺素能调节的故障，这些调节在生殖衰老过程中变得显而易见。拟议的研究将提供有关在生殖衰老期间对GNRH神经元的调节输入中发生的变化的全面信息，并确定雌二醇是否引起这些变化。对这些事件的详细知识将有助于确定一些基本的基本机制，这些机制是大脑与卵巢之间不适当相互作用的基础，并可能为治疗疾病的治疗提供了线索，这些疾病是由于中心无法维持足够的GNRH释放而引起的。