Effects of estrogen on working memory during stress

描述（由申请人提供）：压力通常会对记忆和认知产生不利影响，这种影响对老年人来说尤其具有挑战性，尤其是在现有的与年龄相关的衰退之上。在这个项目中，我们研究雌二醇（E2）是否可以防止这种影响。在人类中，E2降低了应激反应的强度，并有助于认知。此外，体外和体内动物研究表明，E2可以保护大脑免受应激激素的负面影响。总之，这种模式的结果表明E2可能在压力下保护老年妇女的神经和认知完整性。目前的应用通过检查短期E2治疗对受应激影响的各种系统的影响以及测试E2保护的作用机制来验证这一假设。首先，我们将研究短期E2干预的能力，以减少压力的生理影响，压力引起的工作记忆表现损伤，以及大脑激活的相关变化。我们实验室的研究表明，与唾液E2水平较低的女性相比，服用E2补充剂后唾液E2水平较高的绝经后女性释放的压力激素皮质醇较少，以应对压力源。我们还发现，e2水平高的女性的工作记忆表现不受压力的影响，而e2水平低的女性在压力下的表现明显不如对照组。由于E2相关的应激激素释放减少，我们期望发现E2将与以下因素有关：1)抑制应激和控制条件下休息时海马脑血流量和双侧连通性的应激引起的变化；2)较小的应激引起的心率变异性下降；3)在玩工作记忆游戏时海马和前额叶皮层的活动。其次，我们将测试雌二醇对应激保护的潜在作用机制。我们假设E2限制了海马体对压力影响的脆弱性，使海马体有效地关闭压力反应，从而减少了可用的皮质醇水平和皮质醇可用于神经组织的时间。测试

DESCRIPTION (provided by applicant): Stress often has detrimental effects on memory and cognition, effects that are especially challenging for older adults to sustain on top of existing age-related declines. In this project, we investigate whether estradiol (E2) protects against such effects. In humans E2 reduces the magnitude of the stress response and aids cognition. Further, in vitro and in vivo animal research shows that E2 protects the brain from the negative effects of stress hormones. Together, this pattern of results suggests the E2 may protect aging women's neural and cognitive integrity during times of stress. The current application tests this hypothesis by examining the effects of short-term E2 treatment on various systems affected by stress as well as testing a mechanism of action for E2 protection. First, we will examine the ability of a short-term E2 intervention to reduce physiological effects of stress, stress-induced impairments in working memory performance, and associated changes in brain activation. Work in our laboratory reveals that post-menopausal women with high salivary E2 levels as a result of taking E2 supplements release less of the stress hormone, cortisol, in response to a stressor than women with low salivary E2 levels. We also found that working memory performance in the high-E2 women was unhindered by stress, whereas low-E2 women performed significantly worse under stress than under control conditions. As a result of the E2-related reduction in stress hormone release we expect to find that E2 will be associated with 1) dampening the stress-induced changes in hippocampal cerebral blood flow and bilateral connectivity at rest during stress and control conditions, 2) smaller stress-induced decreases in heart-rate variability, and 3) hippocampal and prefrontal cortex activity while playing a working memory game. Second, we will test a potential mechanism of action for estradiol protection against stress. We hypothesize E2 limits vulnerability of the hippocampus to the effects of stress, allowing the hippocampus to effectively shut down the stress response, which curtails the levels of cortisol available and the amount of time cortisol is available to act on neural tissue. To test this we will compare estradiol and placebo groups on hippocampal cerebral blood flow and bilateral functional connectivity at rest, under stress and control conditions. These measures will be correlated with all estradiol levels, cortisol response, HRV, and working- memory-related brain activity and performance. The proposed research aims to uncover whether E2 can in fact reduce the negative effect of stress on memory in post-menopausal human females, as well as the brain mechanisms involved in this protection against stress. This research will further inform the medical field on the effects of E2 on stress and memory, which could lead to better guidance and advice for patients seeking information on E2 treatment during or after menopause.