Effects of estrogen on working memory during stress

描述（由申请人提供）：压力往往对记忆和认知产生不利影响，这些影响对老年人来说尤其具有挑战性，因为他们要在现有的与年龄相关的衰退基础上维持下去。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降低了应激反应的幅度并有助于认知。此外，体外和体内动物研究表明，E2保护大脑免受应激激素的负面影响。总之，这种结果模式表明，E2可以在压力期间保护老年女性的神经和认知完整性。本申请通过检查短期E2治疗对受应激影响的各种系统的影响以及测试E2保护的作用机制来测试该假设。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能力的损害，以及大脑激活的相关变化。我们实验室的工作表明，由于服用E2补充剂而导致唾液E2水平高的绝经后妇女释放的应激激素皮质醇比唾液E2水平低的妇女更少。我们还发现，高E2女性的工作记忆表现不受压力的影响，而低E2女性在压力下的表现明显不如在控制条件下。作为E2相关的应激激素释放减少的结果，我们期望发现E2将与1）在应激和控制条件下抑制应激诱导的海马脑血流量变化和静息时的双侧连接，2）较小的应激诱导的心率变异性降低，以及3）玩工作记忆游戏时海马和前额叶皮层活动有关。第二，我们将测试雌二醇对压力的保护作用的潜在机制。我们假设E2限制了海马体对压力影响的脆弱性，使海马体能够有效地关闭压力反应，从而减少了可用皮质醇的水平和皮质醇作用于神经组织的时间。测试 我们将比较雌二醇组和安慰剂组在静息、应激和对照条件下对海马脑血流和双侧功能连接的影响。这些措施将 与所有雌二醇水平、皮质醇反应、心率变异性和与工作记忆相关的大脑活动和表现相关。这项研究的目的是揭示E2是否真的可以减少压力对绝经后女性记忆的负面影响，以及参与这种压力保护的大脑机制。这项研究将进一步为医学领域提供关于E2对压力和记忆的影响的信息，这可能会为更年期期间或之后寻求E2治疗信息的患者提供更好的指导和建议。

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.