Reproductive Aging and the Human Hypothalamus

生殖衰老和人类下丘脑

• 批准号: 6725341
• 负责人: NAOMI E RANCE
• 金额: $ 25.19万
• 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 2006-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6725341
• 关键词: aging; antisense nucleic acid; chemical structure function; developmental genetics; estrogen receptors; female; female reproductive system; gene expression; hormone regulation /control mechanism; human tissue; hypertrophy; hypothalamus; immunocytochemistry; in situ hybridization; laboratory rat; luteinizing hormone; menopause; neurogenetics; neurons; neuropeptide receptor; neurophysiology; neuroregulation; ovariectomy; radioimmunoassay; tachykinin; women' s health

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 characterized by a striking hypertrophy of neurons within the hypothalamic infundibular nucleus. Postmenopausal neuronal hypertrophy occurs in a subpopulation of neurons containing estrogen receptor and neurokinin B (NKB) mRNA and is accompanied by a marked increase in tachykinin gene expression. GnRH gene expression also increases, but in a separate subpopulation of hypothalamic neurons. During our last funding period, we used animal models to provide strong evidence that the changes in NKB cell size and gene expression in postmenopausal women are due to removal of steroid negative feedback. In this renewal, we propose the first studies to elucidate the physiological relevance of the increase in NKB gene expression in postmenopausal women. In specific aim 1, we will test the hypothesis that NKB neurons participate in the hypothalamic circuitry regulating LH secretion in the rat using pharmacological tools and antisense oligodeoxynucleotide (ODN) knockdown techniques. In specific aim 2, we will characterize the anatomic relationship between arcuate NKB neurons and the reproductive axis. We will determine if arcuate NKB or NK3 receptor-immunoreactive neurons project to the preoptic-septal region (site of GnRH neurons) or the primary capillary plexus of the median eminence in the rat. We will also determine if GnRH neurons express NK3 receptor-immunoreactivity in the human or rat hypothalamus. In specific aim 3, we will attempt to gain a deeper understanding of the remarkable changes in the infundibular nucleus of postmenopausal women. We will determine if menopause is association with signs of cellular degeneration such as increased microglial cells or GFAP gene expression. We will also use the Golgi-method to determine if the neuronal hypertrophy is associated with expansion or regression of infundibular dendritic arbors. Our studies provide an exceptional opportunity to study human brain specimens and address basic biological, issues directly relevant to the physiology of postmenopausal women.

我们的总体目标是描述和了解更年期时人类中枢神经系统发生的事件。 我们发现人类更年期的特征是下丘脑漏斗核内神经元显著肥大。 绝经后神经元肥大发生在含有雌激素受体和神经激肽B（NKB）mRNA的神经元亚群中，并伴有速激肽基因表达的显著增加。 GnRH基因表达也增加，但在下丘脑神经元的一个单独的亚群。 在上一个资助期间，我们使用动物模型提供了强有力的证据，证明绝经后妇女NKB细胞大小和基因表达的变化是由于类固醇负反馈的消除。 在这次更新中，我们提出了第一个研究来阐明绝经后妇女NKB基因表达增加的生理相关性。 在具体目标1中，我们将使用药理学工具和反义寡脱氧核苷酸（ODN）敲低技术检验NKB神经元参与调节大鼠LH分泌的下丘脑回路的假设。 在具体目标2中，我们将描述弓状NKB神经元和生殖轴之间的解剖关系。 我们将确定是否弓状NKB或NK3受体免疫反应阳性神经元项目的视前区隔区（GnRH神经元的网站）或在大鼠正中隆起的初级毛细血管丛。 我们还将确定GnRH神经元是否表达人或大鼠下丘脑中的NK3受体免疫反应性。 在具体目标3中，我们将试图更深入地了解绝经后妇女漏斗核的显着变化。 我们将确定绝经是否与细胞变性的迹象有关，如小胶质细胞或GFAP基因表达增加。 我们也将使用高尔基方法来确定神经元肥大是否与漏斗树突的扩张或消退有关。 我们的研究提供了一个特殊的机会，研究人类大脑标本，并解决基本的生物学，直接相关的绝经后妇女的生理问题。