Estrogen and cognition over the lifespan

雌激素与整个生命周期的认知

• 批准号: 6819361
• 负责人: THOMAS C FOSTER
• 金额: $ 32.47万
• 依托单位: UNIVERSITY OF FLORIDA
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-12-15 至 2010-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6819361
• 关键词: G protein; aging; calcium flux; central neural pathway /tract; cognition; developmental neurobiology; estradiol; estrogen receptors; estrogens; gene targeting; genetic regulation; genetic transcription; genetically modified animals; hippocampus; hormone regulation /control mechanism; in situ hybridization; laboratory mouse; memory; memory disorders; microarray technology; mitogen activated protein kinase; neural degeneration; neural plasticity; neuroendocrine system; synapses

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.

描述（由申请人提供）：有证据表明雌激素对依赖于海马体的记忆过程具有积极影响，包括推迟与年龄相关的记忆障碍。然而，雌激素的影响是多种多样的，确定哪些生物机制对于雌二醇 (E2) 对认知的影响很重要仍然是一个挑战。几种不同的核雌激素受体（ER）的发现以及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变得更加艰巨。我们的长期目标是了解雌激素对海马体的作用机制，它会影响整个生命周期的记忆。 E2 以与衰老过程中观察到的相反的方式快速影响生理过程。然而，E2 反应性随着年龄的增长而降低，可能是由于 ERα 相关转录的丧失。目前的研究将确定哪些海马基因与 ERalpha 活性相关。据推测，ERα 相关基因调节快速 E2 效应的反应性，而活动的减少与功能性大脑衰老和记忆力下降有关。具体目标 1 将使用微阵列技术测试 E2 影响与大脑衰老相关的功能相关基因的转录的假设。具体目标 2 将使用 ER 敲除小鼠来测试 ERalpha 在调节与衰老和记忆功能相关的基因中发挥重要作用的假设。具体目标 3 将使用电生理学和第二信使测定来测试 ERalpha 有助于第二信使信号通路的 E2 反应性的假设，以比较野生型和基因敲除小鼠的反应。具体目标 4 将使用基于病毒载体的基因传递来恢复体内海马体的 ERalpha 功能。 ERalpha 可能是检查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，因此预计分娩会对记忆产生巨大的影响。