ESTROGEN AND COGNITION OVER THE LIFESPAN

本研究的长期目标是了解海马依赖记忆功能在衰老过程中衰退的机制。阿尔茨海默病的发病率预计在未来50年内将增加近4倍，其中以女性发病率最高。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影响中哪一个对记忆很重要，我们知之甚少。海马体中几种不同雌激素受体（er）的发现使这一挑战更加艰巨。最近的研究表明，与年龄相关的记忆损伤是由于突触修饰阈值的变化，突触修饰被认为是记忆存储过程的基础。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截然相反。提出的研究验证了E2对记忆的影响是由于Ca2+稳态过程改变导致突触修饰易感性的变化。该提案有三个具体目标。首先，我们将描述E2替代在生理相关剂量下对海马体依赖性记忆功能敏感的任务的影响。此外，这些研究将使用雌性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，我们将验证E2对记忆的影响是由突触可塑性阈值的变化介导的假设。预测E2替代导致突触修饰阈值移位，从而改变突触可塑性的频响函数，记忆功能将与突触可塑性相关。第三，我们将验证E2介导的突触修饰变化是由于非基因组机制快速调节Ca2+稳态和细胞兴奋性的假设。对于这些研究，E2对包括突触可塑性在内的Ca2+依赖性过程的影响将在海马切片中进行检查。我们相信我们的实验结果将大大增加我们对突触功能在整个生命周期中的调节的认识，并为理解雌激素对记忆的影响机制提供基础。

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.