Effects of estrogen on working memory during stress

雌激素对压力期间工作记忆的影响

• 批准号: 8996102
• 负责人: MARA MATHER
• 金额: $ 20.63万
• 依托单位: UNIVERSITY OF SOUTHERN CALIFORNIA
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-02-01 至 2018-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8996102
• 关键词: Accounting; Affect; Affective; Aftercare; Aging; Animal Experimentation; Animals; Attenuated; Behavioral; Bilateral; Brain; Cerebrovascular Circulation; Cognition; Cognitive; Data; Elderly; Estradiol; Estrogens; Exhibits; Feedback; Health; Hippocampus (Brain); Hormones; Human; Hydrocortisone; Impairment; In Vitro; Intervention; Investigation; Laboratories; Lead; Learning; Left; Measures; Medical; Memory; Menopause; Menstrual cycle; Patients; Pattern; Performance; Phase; Physiological; Placebos; Play; Postmenopause; Prefrontal Cortex; Psychophysiology; Regulation; Research; Rest; Salivary; Sampling; Sex Characteristics; Short-Term Memory; Stress; Structure; System; Testing; Time; Tissues; Woman; Work; age related; aged; biological adaptation to stress; experience; heart rate variability; human female; in vivo; male; memory process; neuroimaging; protective effect; relating to nervous system; response; sex; stressor; young adult; young man; young woman

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.

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，对于老年人来说，在现有的与年龄相关的衰退的基础上维持这种影响尤其具有挑战性。在这个项目中，我们研究雌二醇 (E2) 是否可以防止此类影响。对于人类来说，E2 可以降低应激反应的强度并帮助认知。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，这种结果模式表明 E2 可以在压力时期保护老年女性的神经和认知完整性。当前的应用程序通过检查短期 E2 治疗对受压力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这一假设。首先，我们将检查短期 E2 干预减少压力的生理影响、压力引起的工作记忆性能损伤以及大脑激活的相关变化的能力。我们实验室的工作表明，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在应对压力源时释放的应激激素皮质醇较少。我们还发现，高 E2 女性的工作记忆表现不受压力影响，而低 E2 女性在压力下的表现明显低于对照条件下的表现。由于 E2 相关的应激激素释放减少，我们期望发现 E2 与 1) 抑制压力和控制条件下静息时海马脑血流量和双侧连接性的压力诱发变化有关，2) 较小压力引起的心率变异性降低，以及 3）玩工作记忆游戏时海马和前额叶皮层的活动。其次，我们将测试雌二醇对抗压力的潜在作用机制。我们假设 E2 限制了海马体对压力影响的脆弱性，使海马体能够有效地关闭压力反应，从而减少可用的皮质醇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、压力和控制条件下海马脑血流量和双侧功能连接的情况。这些措施将 与所有雌二醇水平、皮质醇反应、HRV 以及与工作记忆相关的大脑活动和表现相关。拟议的研究旨在揭示 E2 是否确实可以减少压力对绝经后人类女性记忆力的负面影响，以及参与这种抵御压力的大脑机制。这项研究将进一步向医学界通报 E2 对压力和记忆力的影响，这可能会为绝经期间或绝经后寻求 E2 治疗信息的患者提供更好的指导和建议。