Estrogen and the Aging Brain

描述(由申请者提供)：本项目的主要目标是研究大脑老化和女性生殖衰老之间的相互作用。早期对年轻雌性大鼠的研究清楚地表明，循环雌激素(E)水平的变化影响下丘脑回路和海马体的细胞和分子属性，暗示E参与调节生殖神经内分泌回路和认知。然而，我们现在知道，衰老的大脑对E的反应不同于年轻的大脑，我们也知道雌激素/衰老的相互作用在啮齿动物和非人类灵长类动物之间有重要的不同。未来五年的关键是最大限度地利用这两种动物模型，为围绕更年期和绝经后认知障碍的神经生物学复杂的临床问题提供神经生物学框架。我们将对关键问题进行全面的分析；从雌激素的信号机制到深入的结构和功能评估，以了解雌激素对调节生殖功能(下丘脑)和认知(海马体和前额叶皮质)的回路的影响。我们将继续揭示循环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分子和突触基础。啮齿动物的研究在分子机制方面特别有用，他们揭示了下丘脑、海马体和前额叶皮质中E信号的几个新的研究靶点。非人灵长类动物的研究揭示了E诱导老年猴子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质和相关认知功能作为E靶标的重要性。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对认知和神经生物学的影响。拟议的研究将调查“机会之窗”假说和停止治疗后有益效果的持续时间。这些结果将提供关于大脑老化的至关重要的信息，并将有助于设计为绝经后女性提供最大神经益处的激素治疗方法。

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.