ESTROGEN AND COGNITION OVER THE LIFESPAN

这项研究的长期目标是了解衰老过程中大脑依赖性记忆功能下降的机制。 阿尔茨海默病的发病率预计在未来50年内将增加近四倍，其中女性发病率最高。 重要的是，雌激素治疗可以延缓与衰老和阿尔茨海默病相关的记忆丧失的进展。 然而，关于雌激素对大脑功能的许多相关影响中哪一个对记忆力很重要，人们知之甚少。 在海马体中发现几种不同的雌激素受体（Ers）使这一挑战更加艰巨。 最近的研究表明，与年龄相关的记忆障碍是由于突触修饰阈值的变化，突触修饰被认为是记忆储存过程的基础。 反过来，阈值变化与衰老过程中Ca2+稳态的改变有关。 有趣的是，雌二醇（E2）对Ca2+稳态的影响与在老年记忆受损动物中观察到的变化完全相反。 拟议的研究测试的假设，E2对记忆的影响是由于改变的Ca2+稳态过程的结果，在突触修饰的易感性的变化。 该提案有三个具体目标。 首先，我们将描述E2替代的影响，在生理相关剂量，对任务是敏感的依赖于记忆的功能。 此外，这些研究将采用雌性Eralpha敲除小鼠来确定Eralpha激活是否参与E2介导的记忆效应。 其次，我们将测试的假设，E2对记忆的影响是由突触可塑性阈值的变化介导的。 据预测，突触可塑性的频率响应函数是由E2替代转换，由于在突触修饰的阈值的移动，和记忆功能将与突触可塑性。 第三，我们将测试的假设，E2介导的突触修饰的变化是由于非基因组机制，快速调节Ca 2+稳态和细胞兴奋性。 在这些研究中，将在海马切片中检查E2对Ca2+依赖性过程（包括突触可塑性）的影响。 我们相信，我们的实验结果将显着增加我们的知识有关突触功能的调节在整个生命周期，并提供了一个基础，了解雌激素的记忆效应的机制。

The long-term goals of this research are to understand the mechanisms for the decline in hippocampal-dependent memory function during aging. The incidence of Alzheimer s disease is projected to nearly quadruple in the next 50 years with the greatest prevalence in women. Importantly, estrogen treatment can delaying the progression of memory loss associated with aging and Alzheimer s disease. However, little is known concerning which of the many estrogen associated effects on brain function are important for memory. The discovery of several different estrogen receptors (Ers) within the hippocampus makes this challenge more formidable. Recent studies suggest that age- related memory impairment is due to changes in the threshold for synaptic modification thought to underlie memory storage processes. In turn, threshold changes are linked to altered Ca2+ homeostasis during aging. Interestingly, the influence of estradiol (E2) on Ca2+ homeostasis is diametrically opposed to the changes observed in aged memory impaired animals. The proposed studies test the hypothesis that E2 effects on memory are due to changes in the susceptibility to synaptic modification as a result of altered Ca2+ homeostasis processes. The proposal has three specific aims. First we will characterize the effects of E2 replacement, at physiologically relevant doses, on tasks that are sensitive to hippocampal-dependent memory function. In addition, these studies will employ female Eralpha knockout mice to determine whether Eralpha activation is involved in E2 mediated effects on memory. Second, we will test the hypothesis that E2 effects on memory are mediated by changes in the thresholds for synaptic plasticity. It is predicted that the frequency-response function for synaptic plasticity is transformed by E2 replacement due to a shift in the threshold for synaptic modification, and memory function will correlate with synaptic plasticity. Thirdly, we will test the hypothesis that E2 mediated changes in synaptic modification are due to nongenomic mechanisms that rapidly regulate Ca2+ homeostasis and cell excitability. For these studies, the effect of E2 on the Ca2+-dependent processes including synaptic plasticity will be examined in the hippocampal slice. We believe that the results of our experiments will add significantly to our knowledge concerning the regulation of synaptic function across the life span and provide a basis for understanding the mechanism for estrogen s effects of memory.