Investigation of Anatomical and Functional Mechanisms Underlying the Suppression of Gonadotropin Secretion by Metabolic Stress

项目总结 压力是功能性下丘脑闭经和不孕症的主要原因。闭经与 心血管疾病、骨质疏松症和心理健康，因此阐明了 压力抑制促性腺激素的分泌可能会为预防慢性病提供新的途径。 新陈代谢应激在健康人和几种疾病状态下都会发生。胰岛素诱导的低血糖 (IIH)是一种可靠、可重复和可量化的急性代谢应激模型，可抑制脉搏 黄体生成素的分泌；然而，调节抑制黄体生成素的机制并不是 为人所知。这项提案将使用遗传学、药理学和分子方法来检验这一假设 室旁核(PVN)中的Urocortin 2细胞由脑干去甲肾上腺素神经元支配，并且 投射到弓状核并抑制Kispeptin神经元，抑制IIH中搏动性的促黄体生成素分泌。在……里面 目的1，我们将确定室旁核中的urocortin-2细胞是否接受脑干的解剖和功能输入。 IIH期间的去甲肾上腺素神经元。在目标2中，我们将确定Kispeptin细胞是否接受解剖学和 IIH期间下丘脑室旁核内urocortin-2神经元的功能输入。在目标3中，我们将描述 Urocortin 2对永生化下丘脑Kisspeptin表达细胞系ARC Kisspeptin神经元功能的影响。 本项目将研究脑干-下丘脑室旁核-弓状核神经回路的形式和功能 代谢应激时促黄体生成素的搏动性分泌。这些实验将检验一个创新的假设，包括 Urocortin 2信号将促进我们对综合应激反应的了解，调节 促性腺激素分泌，并为申请者提供必要的关键技能培训 学术研究事业成功。

PROJECT SUMMARY Stress is a leading cause of functional hypothalamic amenorrhea and infertility. Amenorrhea is associated with cardiovascular disease, osteoporosis, and mental health, therefore elucidation of the mechanisms by which stress suppresses gonadotropin secretion may provide new avenues to protect against chronic illnesses. Metabolic stress occurs in healthy people as well as in several disease states. Insulin-induced hypoglycemia (IIH) is a reliable, repeatable and quantifiable model of acute metabolic stress that suppresses pulsatile luteinizing hormone (LH) secretion; however, the mechanisms that mediate the suppression of LH are not known. This proposal will use genetic, pharmacologic and molecular approaches to test the hypothesis that urocortin 2 cells in the paraventricular nucleus (PVN) are innervated by brainstem norepinephrine neurons, and project onto and inhibit kisspeptin neurons in the arcuate nucleus to suppress pulsatile LH secretion in IIH. In Aim 1, we will determine if urocortin 2 cells in the PVN receive anatomical and functional input from brainstem norepinephrine neurons during IIH. In Aim 2, we will determine if kisspeptin cells receive anatomical and functional input from urocortin 2 neurons in the PVN during IIH. In Aim 3, we will characterize the effects of urocortin 2 on ARC kisspeptin neuron function in an immortalized hypothalamic kisspeptin-expressing cell line. This project will examine the form and function of a brainstem-PVN-arcuate nucleus neural circuit to inhibit pulsatile LH secretion during metabolic stress. These experiments will test an innovative hypothesis involving urocortin 2 signaling that will advance our knowledge of integrated stress responses, regulation of gonadotropin secretion, and provide the applicant training in critical skills that will be necessary for a successful career in academic research.