Estrogen and cognition over the lifespan

描述（由申请人提供）：有证据表明雌激素对依赖海马体的记忆过程有积极影响，包括延缓与年龄相关的记忆损伤。然而，雌激素的作用是多种多样的，确定哪些生物学机制对雌二醇（E2）对认知的影响是重要的，仍然是一个挑战。几种不同核雌激素受体（er）的发现以及对第二信使信号级联的快速非基因组影响的新证据使这一挑战更加艰巨。我们的长期目标是了解雌激素对海马体的作用机制，海马体在一生中影响记忆。E2以一种与衰老过程相反的方式迅速影响生理过程。然而，E2反应性随着年龄的增长而下降，这可能是由于erα相关转录的丢失。目前的研究将确定哪些海马基因与erα活性有关。据推测，与erα相关的基因调节快速E2效应的反应性，其活性降低与脑功能老化和记忆力下降有关。特异性目标1将使用微阵列技术测试E2影响与脑衰老相关的功能相关基因转录的假设。特异性目标2将使用ER敲除小鼠来验证erα在与衰老和记忆功能相关的基因调控中起重要作用的假设。特异性目标3将通过电生理学和第二信使试验来比较野生型和敲除小鼠的反应，验证ERalpha有助于E2对第二信使信号通路的反应性的假设。特异性靶4将使用基于病毒载体的基因递送来恢复体内海马中的erα功能。ERalpha可能是检验特定基因在记忆中的功能的一个很好的测试案例，因为ERalpha敲除小鼠在记忆功能中表现出基因剂量损伤，因此递送ERalpha预计会对记忆产生重大影响。

DESCRIPTION (provided by applicant): Evidence points to a positive influence of estrogen for memory processes that depend on the hippocampus, including postponement of age-related memory impairments. However, estrogen effects are diverse and the challenge remains to determine which biological mechanisms are important for estradiol (E2) effects on cognition. The discovery of several different nuclear estrogen receptors (ERs) and emerging evidence for rapid nongenomic influences on second messenger signaling cascades makes this challenge more formidable. Our long-term goal is to understand mechanisms of estrogen action on the hippocampus, which influence memory over the life span. E2 rapidly influences physiological processes in a manner opposite that observed during aging. However, E2 responsiveness decreases with advanced age possibly due to a loss of ERalpha associated transcription. The current study will determine which hippocampal genes are linked to ERalpha activity. It is hypothesized that ERalpha-linked genes regulate the responsiveness of rapid E2 effects and a decrease in activity is associated with functional brain aging and memory decline. Specific aim 1 will test the hypotheses that E2 influences transcription of functionally associated genes involved in brain aging using microarray technology. Specific aim 2 will employ ER knockout mice to test the hypothesis that ERalpha is important in the regulation of genes associated with aging and memory function. Specific aim 3 will test the hypothesis that ERalpha contributes to E2 responsiveness for second messenger signaling pathways using electrophysiology and second messenger assays to compare responses in wildtype and knockout mice. Specific aim 4 will use viral vector-based gene delivery to restore ERalpha function in the hippocampus in vivo. ERalpha may be a good test case for examining the function of a specific gene in memory since ERalpha knockout mice exhibit a gene dose impairment in memory function such that delivery would be expected to have a dramatic consequences on memory.