Reproductive Aging and the Human Hypothalamus

描述(由申请人提供)：我们的总体目标是描述和理解发生在人类中枢神经系统中的事件对更年期的反应。我们发现，人类更年期与下丘脑漏斗状核(弓状核)神经激肽B(NKB)基因表达显著肥大和增加有关。在上一次资助期间，我们发现幼年食蟹猴卵巢切除可以复制NKB基因表达和细胞大小的变化，为弓状NKB神经元参与下丘脑的生殖调控提供了强有力的证据。在这次更新中，我们将开始将下丘脑NKB基因表达的变化与绝经后妇女最突出的症状之一-潮热联系起来。潮热是一种中枢体温调节的紊乱，其特征是激活了散热的生理机制(皮肤血管扩张、出汗和行为变化)。整合下丘脑的生殖控制中心和体温调节似乎是潮红机制中的一个关键因素。我们假设弓状NKB神经元参与雌激素对体温和黄体生成素分泌的调节，因此可能参与潮红的发生。为了支持这一假说，我们在大鼠身上的初步研究表明，中枢注射NK3受体激动剂后，尾部血管扩张，以及NK3受体在正中视前核的定位，视前核是温度调节血管扩张的主要整合中心。特定目标1将在大鼠模型中使用药理学工具来测试NKB神经元参与体温调节和生殖调节的假设。具体目标2将描述弓状NKB神经元和体温调节轴之间的解剖关系。具体目标3将通过确定选择性消融这些神经元对温度调节轴的影响来检验我们的假设，即弓状核中的NKB神经元或正中核视前核中NK3R表达的神经元在温度调节性血管扩张中发挥重要作用。特异靶4将探索人类下丘脑中NKB、Kispeptin和强啡肽mRNAs之间的形态关系，并确定这些多肽的受体mRNAs是否由GnRH神经元表达。我们的研究提供了一个特殊的机会来解决与绝经后妇女的生理直接相关的基本生物学问题。

DESCRIPTION (provided by applicant): Our overall goal is to characterize and understand the events that occur in the human central nervous system in response to menopause. We have found that human menopause is associated with a striking hypertrophy and increase in neurokinin B (NKB) gene expression in the hypothalamic infundibular (arcuate) nucleus. During the last funding period, we showed that the changes in NKB gene expression and cell size could by duplicated by ovariectomy of young cynomolgus monkeys and provided strong evidence that arcuate NKB neurons participate in the hypothalamic regulation of reproduction. In this renewal, we will begin to relate the changes in hypothalamic NKB gene expression to one of the most prominent symptoms in postmenopausal women, the hot flush. Hot flushes, a disorder of central thermoregulation, are characterized by activation of the physiologic mechanisms to dissipate heat (cutaneous vasodilatation, sweating and behavioral changes). Integration of the hypothalamic control centers for reproduction and thermoregulation appears to be a key element in the mechanism of flushes. We hypothesize that arcuate NKB neurons participate in the estrogen modulation of body temperature and LH secretion and therefore could be involved in the generation of flushes. In support of this hypothesis, our pilot studies in the rat demonstrate tail vasodilatation in response to central injection of an NK3 receptor agonist and localization of NK3 receptors in the median preoptic nucleus, a major integrating center for thermoregulatory vasodilation. Specific aim 1 will use pharmacological tools in a rat model to test the hypothesis that NKB neurons participate in the regulation of thermoregulation and reproduction. Specific aim 2 will characterize the anatomic relationship between arcuate NKB neurons and the thermoregulatory axis. Specific aim 3 will test our hypothesis that NKB neurons in the arcuate nucleus or NK3R-expressing neurons in the median preoptic nucleus play an important role in thermoregulatory vasodilation by determining the effects of selective ablation of these neurons on the thermoregulatory axis. Specific aim 4 will explore the morphologic relationship between NKB, kisspeptin and dynorphin mRNAs in the human hypothalamus and determine if the receptor mRNAs for these peptides are expressed by GnRH neurons. Our studies provide an exceptional opportunity to address basic biological issues directly relevant to the physiology of postmenopausal women.