Estrogens, Ovarian Aging and Calcium Channel Modulation

雌激素在衰老过程中对神经元生理起着基础性作用，而雌激素在衰老过程中 更年期会增加中风、认知障碍和炎症的发生率。在雌激素治疗期间 (ET)对年轻女性或手术绝经后有益，对老年人有害， 绝经后的女性。我们认为，老龄化和与之相关的恐怖分子的失调 环境通过突触前后的改变控制这种二分性S运用其 通过基因组和基因转录机制的生物学作用。雌激素的基因组作用 已经被研究了几十年，但快速的、非基因组的行为直到最近才被证明控制了 通过G蛋白偶联的神经元兴奋性、细胞内钙信号和激酶/磷酸酶活性 感受器。目标：本提案的目的是使用。一种卵巢衰老和更年期的大鼠模型 ET背景下控制Ga2+和突触功能的非基因组雌激素机制 与个体认知评估：VYE假设，在卵巢老化期间，非基因组(膜限制) 基底前脑胆碱能区突触前和突触后部位雌激素信号减弱 神经元以及这种缺陷在突触前和突触后部位被ET不平等地挽救。 衰老的受试者。突触前和突触后快速雌激素信号的不平等恢复可能有助于 认知功能障碍。我们将使用Functibhal(钳夹记录、荧光成像)、行为(水 以及分子方法(Western blotting、RT-PCR、microRNA分析)来验证这一假说 雌性F344大鼠：成年多胎(MA，5-6个月)和生殖衰老(RS，14-17个月) 研究对象。MA和RS将细分为卵巢切除对照组(DVX)和OVX+雌激素(OVX+E) 组。BF胆碱能神经元将成为目标，因为它们对ET有反应，并且在 与年龄相关的认知衰退。我们的实验将定义雌激素的非基因组作用以及如何 这些作用受卵巢老化和ET的调节，识别异常的雌激素信号将 为确定未来药物治疗的潜在目标提供了重要的第一步。

Estrogen plays a fundamental role in neuronal physiology during aging, and declining estrogens at menopause increase the incidence of stroke, cognitive impairment and inflamhiation. While estrogen therapy (ET) is beneficial in young females or following surgical menopause, ET is detrimental in older, postmenopausal females. We believe that aging and the associated dysregulation of the horriional environment controls this dichotomy by alteration of pre-and postsynaptic s exerts its biological actions through both genomic and hoh-genorriicrriechanisms. the genomid actions of estrogens have been studied for decades, but rapid, non-genomic actions only recently haye been shown to control neuronal excitability, intracellular Ca2+ signaling, and kinase/phosphatase activity through G-protein coupled receptors. The goal: of the present proposal is to use. a rat model of ovarian aging and menopause to test the non-genomic estrogenic mechanisms that control Ga2+ and synaptic function against a background of ET with individual cognitive assessrnent:Vye hypothesize that, during ovarian aging, non-genomic (membranedelimited) estrogen signaling declines at pre- and postsynaptic sites in basal forebrain (BF) cholinergic neurons and that this deficit is inequitably rescued at pre- and postsynaptic sites by ET in reproductively senescent subjects. Unequal restoration of pre- and postsynaptic rapid estrogen signaling could contribute to cognitive dysfunction. We will use functibhal (jaatch clamp recording, fluorescent imaging), behavioral (water maze), and molecular approaches (Western blotting, Rt-PCR, microRNA analyses) to test this hypothesis in female F344 rats: mature multigravid adults (MA, 5-6 mo) and reproductively senescent (RS, 14-17 mo) subjects. MA and RS will be subdivided into^ovanectomized control:(dVX) and OVX +estrogen (OVX+E) groups. BF cholinergic neurons will be targeted because they; are responsive to ET and are important in age-related cognitive decline. Our experiments will define the non-genomic actions of estrogens and how these actions are modulated by ovarian aging and ET, Identification of aberrant estrogen signaling will provide an important first step in ideritifying potential targets for future drug therapies..