Tachykinins in Reproductive Aging

描述（由申请人提供）：越来越多的证据表明，中枢神经系统在女性向生殖衰老的过渡中起着关键作用。虽然导致生殖周期丧失的神经事件尚不完全清楚，但一种合理的解释是下丘脑的关键神经递质/神经肽的活性及其对雌激素反馈的反应随着年龄的变化而变化。我研究的长期目标是了解雌激素驱动循环GnRH神经元活动导致黄体生成素（LH）激增的机制，以及这些机制如何随着年龄的增长而变化。这一提议将验证一个工作假设，即速动素家族的神经肽在调节循环GnRH神经元活动中起着关键作用，雌性大鼠生殖周期的丧失部分是由于速动素表达模式或相对水平的变化。我将解决以下具体目标：(1)我将检查特异性神经激肽受体拮抗剂对雌性大鼠黄体生成素分泌的影响，以及对快速激肽的反应是否随着年龄的变化而变化。(2)我将确定速激素是否直接与GnRH神经元交流，以及这种情况随着年龄的变化在多大程度上发生变化。(3)我将评估脑关键区域的促黄体生成素(PPT)-A和PPT- b mRNA和蛋白表达模式是否随着类固醇诱导的LH激增而改变，以及年龄和/或生殖状态如何影响这种表达模式。本科生参与这些实验将为他们提供一个学习生殖神经内分泌学和细胞生物学基础技术的独特机会，这些经验将为他们将来的研究生学习提供良好的服务。

DESCRIPTION (provided by applicant): A growing body of evidence suggests that the central nervous system plays a critical role in the transition to reproductive senescence in the female. Although the neural events leading to loss of reproductive cyclicity are not completely understood, one plausible explanation is that the activity of key neurotransmitters/neuropeptides of the hypothalamus and their responsiveness to estrogen feedback changes with age. The long-term objectives of my research are to understand the mechanisms by which estrogen acts to drive cyclic GnRH neuronal activity leading to the generation of luteinizing hormone (LH) surges and how these mechanisms change with age. This proposal will test the working hypothesis that the tachykinin family of neuropeptides plays a critical role in regulating cyclic GnRH neuronal activity and a loss of reproductive cyclicity in the female rat is due, in part, to changes in the pattern or relative levels of the expression of the tachykinins. I will address the following specific aims: (1) i will examine the effects of specific neurokinin receptor antagonists on LH secretion in the female rat and whether the responsiveness to tachykinins changes with age. (2) I will determine whether the tachykinins communicate directly with GnRH neurons and to what extent this changes with age. (3) I will assess whether the patterns of preprotachykinin (PPT)-A and PPT-B mRNA and protein expression in key brain regions change with the occurrence of the steroid-induced LH surge and how age and/or reproductive status influences this pattern of expression. Participation by undergraduate students in the outlined experiments will provide a unique opportunity for them to learn fundamental techniques in reproductive neuroendocrinology and cellular biology, experiences that will serve them well as they pursue graduate studies in the future.