Cellular and molecular bases for rhythmic GnRH release

描述（由申请方提供）：促性腺激素释放激素（GnRH）的间歇性释放形成生殖中枢调节的最终共同途径。因此，了解这种释放的机制对人类健康有直接的好处，为人类和重要的食物和纤维生产物种的生育和避孕提供了新的策略。目前的电生理学方法将被用来调查的内在和网络特性，在四个特定的目标，情节性GnRH释放的基础。目的1将检查单个GnRH神经元内在的离子电导，这是动作电位产生启动的基础。这些电导如何随着时间的推移在单个神经元中被修改，以及它们如何在生殖状态之间变化，将被确定。目的2将研究GnRH神经元动作电位放电引起的电压和钙激活电导。将确定动作电位尖峰之间的这些电导的差异，并在爆发中的最终动作电位之后，以解决电导如何改变以停止这些细胞的放电的问题。目标3将测试GnRH神经元如何相互通信。以前的工作表明，这些神经元可以使用GnRH和谷氨酸作为递质。对GnRH的反应是剂量依赖性的，低剂量抑制和高剂量刺激GnRH神经元活性。这些差异反应背后的信号通路将用通过特定GnRH受体-G蛋白组合发出信号的配体进行检测。GnRH神经元之间的化学突触和电偶联将通过双重记录进行检查，并探索协调部位。第四个目标将探索GnRH神经元与它们所在的局部网络之间的相互作用。最近的研究表明，GnRH神经元不仅释放激素控制下游垂体前叶，而且还在局部调节其GABA能传入。我们将探讨其他的本地网络与GABA和谷氨酸神经元，并与星形胶质细胞的鞘GnRH神经元的相互作用。星形胶质细胞在协调GnRH神经元活动的可能作用将得到解决。总之，这些研究将提供深入了解的内在和网络特性，导致发作性GnRH释放。

DESCRIPTION (provided by applicant): Episodic release of gonadotropin-releasing hormone (GnRH) forms the final common pathway for the central regulation of reproduction. As such, understanding the mechanisms underlying this release has direct benefits to human health by providing new strategies for fertility and contraception in humans and in important food and fiber producing species. State-of-the-are electrophysiological approaches will be used to investigate the intrinsic and network properties that underlie episodic GnRH release in four specific aims. Aim 1 will examine the ionic conductances intrinsic to individual GnRH neurons that underlie initiation of action potential generation. How these conductances are modified over time in an individual neuron and how they change between reproductive state will be determined. Aim 2 will examine the voltage- and calcium-activated conductances induced by action potential firing in GnRH neurons. Differences in these conductances between action potential spikes and following the final action potential in a burst will be determined to address the question of how conductances change to stop firing of these cells. Aim 3 will test how GnRH neurons communicate with one another. Previous work shows that these neurons can use GnRH and glutamate as transmitters. The response to GnRH is dose-dependent with low doses inhibiting and high doses stimulating GnRH neuron activity. The signaling pathways underlying these differential responses will be tested with ligands that signal through specific GnRH receptor-Gprotein combinations. Chemical synaptic and electortonic coupling between GnRH neurons will be examined with dual recordings and the site of coordination explored. The fourth aim will explore interactions between GnRH neurons the local network in which they reside. Recent data indicate GnRH neurons not only release hormone to contol the downstream anterior pituitary, but also locally to regulate their GABAergic afferents. We wll explore other local network interactions with GABA and glutamate neurons, and with the astrocytes that ensheath GnRH neurons. A possible role for astrocytes in coordinating GnRH neuron activity will be addressed. Together these studies will provide insight into both the intrinsic and network properties leading to episodic GnRH release.