PROGESTERONE/ANDROGEN FEEDBACK CONTROL OF GNRH NEURONS

促性腺激素释放激素(GnRH)神经元形成了调节生殖的最终共同途径。促性腺激素释放激素(GnRH)脉冲式释放能刺激垂体促性腺激素黄体生成素(LH)和卵泡刺激素(FSH)的分泌，是生育所必需的。在雌性哺乳动物中，GnRH脉冲频率的变化有助于在周期的特定时间优先释放黄体生成素或卵泡刺激素，为卵巢卵泡成熟创造合适的激素环境。促性腺激素释放激素的脉冲模式在很大程度上受到卵巢类固醇、孕酮和雌二醇负反馈的调节。虽然这种反馈在体内已经很好地描述了，但是潜在的细胞机制和神经通路还没有被阐明。 这阻碍了对常见形式的下丘脑不孕症的神经成分的了解，如多囊卵巢综合征(PCOS)，在这种情况下，循环雄激素水平升高伴随着持续的高频率的促黄体生成素(LH)(可能还有促性腺激素释放激素)的释放。后者似乎部分是由于雄激素干扰了黄体酮反馈的效果。大量证据表明，激素反馈调节GnRH释放的一种机制是跨突触的。特别是，解剖学和生理学数据支持伽马氨基丁酸(GABA)和阿片肽产生神经元在这种交流中的作用。提出了四个特定的目标来研究孕酮反馈的细胞机制，以及雄激素如何改变孕酮反馈的效果。初级阶段 方法将是对急性脑片中绿色荧光蛋白识别的GnRH神经元的电生理记录。目的1研究类固醇和神经递质环境对促性腺激素释放激素(GnRH)神经元放电特性和放电模式的影响。目标2将研究类固醇和神经递质如何改变GnRH神经元的GABA能驱动。AIMS 3和4将分别研究类固醇和神经递质对钾电流和钙电流的影响，因为这些电流在设定神经元的放电特性以及它们对突触输入的反应能力方面发挥着重要作用。这些研究将有助于我们了解GnRH神经元在健康和疾病状态下的生理学，有助于改善下丘脑生育障碍的治疗，开发新的避孕方法，确保 濒危和食物生产物种，以及了解其他类似的神经系统。

Gonadotropin-releasing hormone (GnRH) neurons form the final common pathway regulating reproduction. Pulsatile release of GnRH stimulates secretion of luteinizing hormone (LH) and follicle-stimulating hormone (FSH) from pituitary gonadotropes and is absolutely required for fertility. In female mammals, shifts in GnRH pulse frequencies help drive the preferential release of LH or FSH at specific times of the cycle to create appropriate hormone milieux for ovarian follicle maturation. GnRH pulse patterns are largely regulated by negative feedback from the ovarian steroids progesterone and estradiol. Although this feedback is well characterized in vivo, the underlying cellular mechanisms and neural pathways have yet to be elucidated. This has precluded understanding the neural components of common forms of hypothalamic infertility, such as polycystic ovarian syndrome (PCOS), in which elevated circulating androgen levels are accompanied by a persistent high frequency of LH (and presumably GnRH) release. The latter appears to be due in part to androgens interfering with the efficacy of progesterone feedback. Considerable evidence suggests one mechanism of steroid feedback regulation of GnRH release is transsynaptic. In particular, anatomical and physiological data support a role for gamma-aminobutyric acid (GABA)- and opiate peptide-producing neurons in this communication. Four Specific Aims are proposed to investigate the cellular mechanisms of progesterone feedback, and how androgens might alter the efficacy of progesterone feedback. The primary methodology will be electrophysiological recordings of green-fluorescent protein-identified GnRH neurons in acute brain slices. Aim 1 will investigate the effects of steroid and neurotransmitter milieux on the firing properties and firing patterns of GnRH neurons. Aim 2 will examine how steroids and neurotransmitters alter GABAergic drive to GnRH neurons. Aims 3 and 4 will study the effects of steroids and neurotransmitters on potassium and calcium currents, respectively, as these play major roles in setting firing properties of neurons as well as their ability to respond to synaptic input. These studies will help us understand GnRH neuron physiology in both healthy and diseased states, knowledge paramount for improving treatments for hypothalamic fertility disorders, developing novel contraceptive methods, ensuring effective reproduction in endangered and food-producing species, and understanding other similar neuronal systems.