PROGESTERONE/ANDROGEN FEEDBACK CONTROL OF GNRH NEURONS

GNRH 神经元的黄体酮/雄激素反馈控制

• 批准号: 6744673
• 负责人: Suzanne M MOENTER
• 金额: $ 12.24万
• 依托单位: UNIVERSITY OF VIRGINIA
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-04-23 至 2008-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6744673
• 关键词: androgens; calcium; cooperative study; disease /disorder etiology; electrophysiology; endogenous opioid; gamma aminobutyrate; genetically modified animals; gonadotropin releasing factor; green fluorescent proteins; hormone regulation /control mechanism; ion transport; laboratory mouse; neural transmission; neuroendocrine system; neurons; polycystic ovary syndrome; potassium; progesterone

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.

促性腺激素释放激素（GnRH）神经元形成调节生殖的最终共同途径。 GnRH的脉冲式释放刺激垂体促性腺激素分泌促黄体生成素（LH）和促卵泡激素（FSH），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驱动LH或FSH的优先释放，为卵泡成熟创造适当的激素环境。GnRH脉冲模式在很大程度上受来自卵巢类固醇孕酮和雌二醇的负反馈调节。虽然这种反馈在体内得到了很好的表征，但其潜在的细胞机制和神经通路尚未阐明。 这妨碍了对下丘脑性不孕症常见形式的神经成分的理解，如多囊卵巢综合征（PCOS），其中循环雄激素水平升高伴随着持续高频率的LH（可能还有GnRH）释放。后者似乎部分是由于雄激素干扰孕酮反馈的功效。大量证据表明，类固醇激素反馈调节GnRH释放的机制之一是跨突触的。特别是，解剖和生理数据支持γ-氨基丁酸（GABA）和阿片肽产生神经元在这种通信中的作用。提出了四个具体的目标，以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功效。主 方法将是急性脑切片中绿色荧光蛋白鉴定的GnRH神经元的电生理记录。目的1研究激素和神经递质环境对GnRH神经元放电特性和放电模式的影响。目的2将研究类固醇和神经递质如何改变GABA能驱动GnRH神经元。目标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，因为这些在设置神经元的放电特性以及它们对突触输入的响应能力中起主要作用。这些研究将帮助我们了解健康和疾病状态下的GnRH神经元生理学，这些知识对于改善下丘脑生育障碍的治疗，开发新的避孕方法，确保有效的生殖， 濒危和粮食生产物种，并了解其他类似的神经系统。