Estrogen and the Aging Brain

描述（由申请人提供）：本计划项目的主要目标是调查大脑老化和女性生殖衰老之间的相互作用。对年轻雌性大鼠的早期研究清楚地表明，循环雌激素（E）水平的变化影响下丘脑回路以及海马的细胞和分子属性，暗示E调节生殖神经内分泌回路和认知。然而，我们现在知道老年人的大脑对E的反应与年轻人的大脑不同，我们也知道啮齿动物和非人类灵长类动物之间的雌激素/衰老相互作用在重要方面有所不同。未来五年的关键是充分利用这两种动物模型，为围绕绝经和绝经后认知障碍的神经生物学的复杂临床问题提供神经生物学框架。我们将对关键问题进行全方位分析;从雌激素的信号传导机制到雌激素对调节生殖功能（下丘脑）和认知（海马和前额叶皮层）的电路的影响的深入结构和功能评估。我们将继续揭示由循环E激活的神经元信号通路，以及E诱导的突触可塑性与年龄相关的下降的分子和突触基础。啮齿类动物的研究是特别翔实的分子机制方面，他们已经发现了几个新的目标的调查E信号在下丘脑，海马和前额皮质。非人类灵长类动物的研究揭示了老年猴子中E诱导的认知增强的神经生物学基础，以及年轻雌性猴子在缺乏E的情况下认知弹性的突触基础。此外，非人灵长类动物的研究强调了前额叶皮层和相关认知功能作为E。目前在大鼠和非人灵长类动物模型中的研究正在调查不同激素治疗方案的认知和神经生物学效应。拟议的研究将调查“机会之窗”假设和停止治疗后有益效果的持续时间。这些结果将为大脑老化提供至关重要的信息，并将有助于设计激素治疗，为绝经后妇女提供最大的神经系统益处。

DESCRIPTION (provided by applicant): The primary goal of this Program Project is to investigate interactions between the aging brain and female reproductive senescence. Early studies in young female rats demonstrated clearly that changes in circulating estrogen (E) levels affect cellular and molecular attributes of hypothalamic circuits as well as hippocampus, implicating E in modulating both reproductive neuroendocrine circuits and cognition. However, we now know that the aged brain reacts to E differently than the young brain, and we also know that the estrogen/aging interactions differ in important ways between rodents and nonhuman primates. The key to the next five years is to use both animal models to their best advantage to provide a neurobiological framework for the complex clinical issues surrounding the neurobiology of menopause and post-menopausal cognitive impairment. We will pursue a full spectrum analysis of the key issues; from signaling mechanisms of estrogen to an in-depth structural and functional assessment of the effects of estrogen on the circuits regulating reproductive function (hypothalamus), and cognition (hippocampus and prefrontal cortex). We will continue to reveal the neuronal signaling pathways activated by circulating E, as well as the molecular and synaptic basis for age related decline in E-induced synaptic plasticity. The rodent studies are particularly informative with respect to molecular mechanisms, and they have revealed several new targets of investigation for E signaling in hypothalamus, hippocampus and prefrontal cortex. The nonhuman primate studies reveal the neurobiological underpinnings of E-induced cognitive enhancement in aged monkeys, as well as the synaptic basis of cognitive resilience in the absence of E in young female monkeys. In addition, the nonhuman primate studies have highlighted the importance of prefrontal cortex and related cognitive functions as a target for E. Current studies in both the rat and nonhuman primate models are investigating the cognitive and neurobiological effects of different hormone treatment regimens. Proposed studies will investigate the "window of opportunity" hypothesis and the duration of beneficial effects after cessation of treatment. These results will provide critically important information on brain aging and will aid in the design of hormone treatments that provide maximal neurological benefits for post-menopausal women.