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

项目摘要 压力是功能性下丘脑性闭经和不孕的主要原因。闭经与 心血管疾病、骨质疏松症和精神健康，因此阐明了 压力抑制促性腺激素分泌可能为预防慢性疾病提供新的途径。 代谢应激发生在健康人以及几种疾病状态中。胰岛素诱发的低血糖 (IIH)是一种可靠、可重复和可量化的急性代谢应激模型， 促黄体生成激素（LH）分泌;然而，介导LH抑制的机制不是 知道的该提案将使用遗传学、药理学和分子学方法来检验以下假设： 室旁核（PVN）中的urocortin 2细胞受脑干去甲肾上腺素神经元支配， 投射并抑制弓状核中的kisspeptin神经元，以抑制IIH中的脉冲式LH分泌。在 目的1，我们将确定PVN中的urocortin 2细胞是否接受来自脑干的解剖和功能输入 去甲肾上腺素神经元。在目标2中，我们将确定kisspeptin细胞是否接受解剖学和生物学上的刺激。 IIH期间来自PVN中的urocortin 2神经元的功能输入。在目标3中，我们将描述 在永生化的下丘脑kisspeptin表达细胞系中，urocortin 2对ARC kisspeptin神经元功能的影响。 本课题将研究脑干-PVN-弓状核神经回路的形式和功能， 代谢应激时LH的脉冲分泌。这些实验将测试一个创新的假设， 尿皮质素2信号，这将促进我们对综合应激反应， 促性腺激素分泌，并为申请人提供关键技能培训，这将是必要的 在学术研究中取得成功。

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.