Defining the neurophysiologic mechanisms engaged by estradiol feedback in regulating reproductive neuroendocrine function

项目摘要 15%-20%的美国夫妇正在与不孕不育问题作斗争。女性不孕不育的最常见原因 是无排卵的，因此了解排卵是如何控制的对于帮助形成和生长至关重要。 家庭的健康，改善我国的生殖健康，增加我们对 繁殖。促黄体生成素(黄体生成素)分泌模式的转换刺激排卵 间歇性到持续性释放(黄体生成素激增)。在低生理浓度下，雌二醇调节发作 分泌(负反馈)。卵泡期末期(发情前期)雌二醇持续升高 (啮齿动物)刺激黄体生成素高峰的开始(正反馈)。在大多数哺乳动物中，促黄体生成素激增是由 通过雌激素诱导的促性腺激素释放激素(GnRH)分泌激增和伴随的 脑下垂体对这种荷尔蒙的反应增强。尽管不需要改变GnRH输入模式来 在人类中诱导促黄体生成素激增，在恒河猴中观察到排卵前和雌二醇诱导的促黄体生成素激增 这表明GnRH的激增可能在灵长类动物的典型生殖功能中也起到了作用。这个 这项提议的目标是增加我们对驱动过渡的中枢神经机制的了解 在周期中从负反馈到正反馈，并确定这些机制是否是雌二醇- 很敏感。促性腺激素释放激素神经元本身不表达可检测到的雌激素受体α(ERα)，因此 在这个过程中需要雌激素敏感的传入神经，前腹侧脑室周围核(AVPV)是 被认为是雌激素正反馈的关键部位，因为它含有共同表达这两种激素的神经元 促性腺激素释放激素释放激素激活剂Kispeptin和ERα、AVPV kispeptin神经元表达更多的Kispeptin 在正反馈期间，雌激素依赖的方式更活跃，这表明 来自这些细胞的信号有助于推动积极的反馈。在我们的理解上仍然存在差距 雌二醇激活动静脉窦房结蛋白神经元并调节其传递Kispeptin和快速突触 传递给GnRH神经元的信号。我们假设雌二醇调节钾电流和突触特性。 AVPV神经元在正反馈过程中增加其活动和随后的兴奋性传递 传递给GnRH神经元的信号。在两个目标中，我们将测量钾电流，功能性突触连接 和可塑性，以及AVPV kisspeptin神经元释放kisspeptin来确定这些参数是否 在周期中，通过比较发情周期和发情周期从负反馈到正反馈的转变来修正 发情的老鼠。为了研究哪些机制受到雌激素的特定调控，我们将利用一只小鼠 雌二醇诱导的黄体生成素峰模型。这些研究将有助于提供机械性的见解，有助于在 我们对雌激素调节生殖的神经生理机制的理解 神经内分泌输出。这种知识可以为新的生育治疗以及针对以下目标的治疗提供信息 其他雌激素调节的中枢过程，如焦虑、神经保护和对压力的反应。

Project Summary 15-20% of American couples struggle with infertility problems. The most common cause of infertility in women is anovulation, thus understanding how ovulation is controlled is critical for assisting the formation and growth of families, improving the reproductive health of our country, and increasing our fundamental knowledge of reproduction. Ovulation is stimulated by a switch in the pattern of luteinizing hormone (LH) secretion from episodic to continuous release (LH surge). At low physiological concentrations, estradiol regulates episodic secretion (negative feedback). Sustained elevation of estradiol at the end of the follicular phase (proestrus in rodents) stimulates the onset of the LH surge (positive feedback). In most mammals, the LH surge is triggered by an estradiol-induced surge in gonadotropin-releasing hormone (GnRH) secretion and an accompanying increase in pituitary response to this hormone. Although a shift in the pattern of GnRH input is not needed to induce an LH surge in humans, both pre-ovulatory and estradiol-induced surges have been observed in rhesus macaques, suggesting a GnRH surge likely plays a role in typical reproductive function in primates as well. The goals of this proposal are to increase our knowledge of the central neuronal mechanisms driving the transition from negative to positive feedback during the cycle, and to determine if these mechanisms are estradiol- sensitive. GnRH neurons themselves do not express detectable levels of estrogen receptor α (ERα), thus estradiol-sensitive afferents are needed in this process The anteroventral-periventricular nucleus (AVPV) is postulated to be a critical site for estradiol positive feedback as it contains neurons that co-express both kisspeptin, a potent activator of GnRH secretion, and ERα, AVPV kisspeptin neurons express more kisspeptin and are more active in an estradiol-dependent manner during positive feedback, suggesting increased signaling from these cells helps drive positive feedback. There are still gaps in our understanding of how estradiol activates AVPV kisspeptin neurons and modulates their transmission of kisspeptin and fast synaptic signals to GnRH neurons. We hypothesize estradiol modulates potassium currents and synaptic properties of AVPV neurons during positive feedback to increase their activity and subsequent transmission of excitatory signals to GnRH neurons. In two Aims, we will measure potassium currents, functional synaptic connectivity and plasticity, and kisspeptin release by AVPV kisspeptin neurons to determine if these parameters are modified by the transition from negative to positive feedback during the cycle by comparing diestrous and proestrous mice. To examine which mechanisms are specifically regulated by estradiol, we will utilize a murine estradiol-induced LH surge model. These studies will help provide mechanistic insights that will help build on our understanding of the neurophysiological mechanisms by which estradiol regulates reproductive neuroendocrine output. This knowledge can inform new fertility treatments as well as treatments targeted at other estradiol-modulated central processes, such as anxiety, neuroprotection, and response to stress.