Reproductive Aging and the Human Hypothalamus

我们的总体目标是描述和理解人类中枢神经系统对更年期的反应。我们已经发现，人类更年期的特点是一个惊人的肥大的神经元在下丘脑漏斗核。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，但在单独的下丘脑神经元亚群中。在我们最后的资助期间，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去除。在这一更新中，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）敲除技术来验证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，我们将描述弓形NKB神经元与生殖轴之间的解剖关系。我们将确定弓形的NKB或NK3受体免疫反应神经元是否投射到大鼠视间隔前区（GnRH神经元的位置）或中央隆起的初级毛细血管丛。我们还将确定GnRH神经元是否在人类或大鼠下丘脑中表达NK3受体免疫反应性。在具体的目标3中，我们将试图对绝经后妇女的漏斗核的显著变化有更深入的了解。我们将确定更年期是否与细胞退化的迹象有关，如增加的小胶质细胞或GFAP基因表达。我们还将使用高尔基法来确定神经元肥大是否与基底树突状乔木的扩张或消退有关。我们的研究为研究人类大脑标本和解决与绝经后妇女生理学直接相关的基本生物学问题提供了一个特殊的机会。

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.