ESTROGEN INFLUENCES ON NEUROENDOCRINE AGING

这些研究的目的是确定卵巢类固醇激素、衰老及其相互作用对促性腺激素释放激素神经元的功能、神经解剖学和神经药理学的影响，以及NMDAR对它们的调节。GnRH神经元是调节生殖的关键细胞，在NMDAR的介导下，谷氨酸向GnRH心包和神经末梢的传入对GnRH的合成和分泌起着重要的调节作用。这些过程被与年龄相关的循环性腺类固醇激素的变化所改变，而性腺类固醇激素反过来又对神经内分泌大脑区域产生深远影响。拟议的研究将利用去卵巢的雌性大鼠(年轻、中年和老年)和猴子(年轻和老年)，给予激素(雌激素+/-黄体酮)或车辆替代品。所有人的生殖状况 动物在卵巢切除前的特征，和循环雌二醇和孕酮浓度将监测期间(猴子)或在终止(大鼠)每个实验。我们将测试GnRH神经元表达NMDAR亚单位，这种表达被激素和/或衰老改变，以及这具有功能后果的假设。目的1利用光学显微镜观察激素和衰老对大鼠和猴下丘脑视前区NMDAR亚单位与GnRH包膜解剖关系的影响。在目标2中，我们将用光镜和电子显微镜观察激素和衰老对大鼠和猴子正中隆起GnRH神经末梢及其NMDAR亚单位表达的影响。AIMS 1和AIMS 2的数据将提供对GnRH神经元和NMDAR相互作用的全面了解，以及它们的激素和 年龄规定，在GnRH Pedkarya和终端。在目标3中，我们将利用神经药理学的方法来检测NMDAR的激活或拮抗对GnRH神经末梢超微结构的影响，以及对GnRH基因表达的影响。总体而言，这三个特定的目标将为激素、衰老及其相互作用对GnRH神经元的影响提供新的信息。实验设计将有助于比较雌性大鼠和猴子。这些研究的结果将对了解妇女绝经的原因和后果以及为未来关于绝经后激素替代疗法的研究提供信息具有相当大的相关性。

The goal of the proposed studies is to determine effects of ovarian steroid hormones, aging, and their interactions on the function, neuroanatomy, and neuropharmacology of GnRH neurons, and their regulation by NMDA receptors (NMDAR). GnRH neurons are the key cells regulating reproduction, and inputs from glutamate to GnRH perikarya and neuroterminals, mediated by the NMDAR, play important regulatory roles in GnRH synthesis and secretion. These processes are altered by age-related changes in circulating gonadal steroid hormones, which in turn have profound effects on neuroendocrine brain regions. The proposed studies will utilize ovariectomized female rats (young, middle-aged and old) and monkeys (young and old), given hormone (estrogen +/- progesterone) or vehicle replacement. The reproductive status of all animals is characterized prior to ovariectomy, and circulating estradiol and progesterone concentrations will be monitored during (in monkeys) or at the termination (rats) of each experiment. We will test the hypotheses that GnRH neurons express NMDAR subunits, that this expression is altered by hormones and/or aging, and that this has functional consequences. Aim 1 will utilize light microscopy to examine effects of hormones and aging on the anatomical relationships between NMDAR subunits and GnRH perikarya in rat and monkey hypothalamus preoptic area. In Aim 2, we will examine effects of hormones and aging on GnRH neuroterminats and their expression of NMDAR subunits in the median eminence of rats and monkeys, using light and electron microscopy. Data from Aims 1 and 2 will provide a comprehensive understanding of the interactions of GnRH neurons and NMDAR, and their hormonal and age regulation, at both GnRH pedkarya and terminals. In Aim 3 we will utilize a neuropharmacological approach to examine effects of NMDAR activation or antagonism on the ultrastructure of GnRH neuroterminals, and on GnRH gene expression. As a whole, these three Specific Aims will provide novel information on effects of hormones, aging, and their interactions on GnRH neurons. The experimental design will facilitate comparisons between female rats and monkeys. The outcomes of these studies will have considerable relevance to understanding the causes and consequences of menopause in women and in informing future studies on postmenopausal hormone replacement therapy.