Reproductive Aging and the Human Hypothalamus

生殖衰老和人类下丘脑

• 批准号: 7255900
• 负责人: NAOMI E RANCE
• 金额: $ 36.48万
• 依托单位: UNIVERSITY OF ARIZONA
• 依托单位国家: 美国
• 财政年份: 1991
• 资助国家: 美国
• 起止时间: 1991-06-01 至 2010-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7255900
• 关键词: Ablation; Address; Aging; Agonist; Anatomy; Behavioral; Biological; Body Temperature; Cell Size; Cutaneous; Disease; Dynorphins; Employee Strikes; Estrogen Receptors; Estrogens; Event; Flushing; Functional disorder; Funding; Gene Expression; Generations; Goals; Heating; Hot flushes; Human; Hypertrophy; Hypothalamic structure; Indium; Injection of therapeutic agent; Macaca fascicularis; Menopause; Messenger RNA; Microinjections; Modeling; Neuraxis; Neurokinin B; Neuromedin K Receptor; Neurons; Ovarian; Ovariectomy; Peptides; Physiologic Thermoregulation; Physiological; Physiology; Pilot Projects; Play; Postmenopause; Rattus; Regulation; Reproduction; Role; Structure of nucleus infundibularis hypothalami; Sweat; Sweating; Symptoms; Tail; Testing; Vasodilation; Vasodilation disorder; Withdrawal; Woman; Work; base; preoptic nucleus; receptor; reproductive; reproductive axis; response; tool

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.

描述（由申请人提供）：我们的总体目标是描述和了解更年期后人类中枢神经系统中发生的事件。我们已经发现，人类绝经与下丘脑漏斗（弓状）核的显著肥大和神经激肽B（NKB）基因表达增加有关。在上一个资助期间，我们发现NKB基因表达和细胞大小的变化可以通过切除年轻食蟹猴的卵巢复制，并提供了强有力的证据，表明弓状NKB神经元参与下丘脑生殖调节。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障碍，其特征在于激活生理机制以散热（皮肤血管舒张、出汗和行为变化）。下丘脑生殖和体温调节控制中心的整合似乎是潮红机制的关键因素。我们推测弓形NKB神经元参与雌激素对体温和LH分泌的调节，因此可能参与潮红的产生。为了支持这一假设，我们在大鼠中的初步研究表明，尾血管扩张响应于中央注射的NK3受体激动剂和定位的NK3受体在正中视前核，一个主要的整合中心的温度调节血管舒张。具体目标1将在大鼠模型中使用药理学工具来检验NKB神经元参与体温调节和生殖调节的假设。具体目标2将描述弓形NKB神经元和体温调节轴之间的解剖关系。具体目标3将测试我们的假设，即在弓状核的NKB神经元或在正中视前核的NK3R表达神经元发挥重要作用，通过确定这些神经元的选择性消融对体温调节轴的影响，在体温调节血管舒张。具体目标4将探索人类下丘脑中NKB、kisspeptin和强啡肽mRNA之间的形态学关系，并确定这些肽的受体mRNA是否由GnRH神经元表达。我们的研究提供了一个特殊的机会，以解决基本的生物学问题直接相关的绝经后妇女的生理。