Psychosocial stress interactions with electrophysiology and brain aging

描述(由申请人提供)：本申请旨在解决心理社会压力和脑老化领域中一个尚未解决的基本问题，即心理社会压力促进不健康脑老化(UBA)所通过的神经生物学途径的性质。研究的重点将是在不健康和健康大脑老化的背离年龄附近形成的大脑老化标志物，因为这些似乎特别容易受到压力的影响。该项目还将检验这样一个假设，即大脑对压力反应的中年变化促进了UBA的出现。这一观点源于我们最近对电生理和微阵列技术所做的工作，这些技术表明，大鼠大脑老化的应激激素敏感标记物在中年前后出现，而不健康的认知衰老开始出现的年龄范围也是相同的。拟议的研究将包括一个大型的多学科项目，旨在获得一个独特的综合视角，在一个已建立的大鼠衰老模型中，研究心理社会应激对神经生物学途径的影响。它将涉及最先进的脑切片细胞内电生理学、一组染色的免疫组织化学、单独的大鼠大脑微阵列分析、睡眠模式的脑电监测以及行为测试。将在每只动物身上应用多种技术。这些研究将致力于将同一动物中不健康的大脑老化的电生理和基因组标记联系起来，并将暴露于心理社会压力与UBA的发展作为年龄的函数以及急性与慢性条件下的UBA联系起来。重要的是，用于减轻压力和保护睡眠模式的行为和药物干预将被用来测试UBA的过程是否可以在长期研究中改变。接受心理社会压力减轻和促进睡眠干预的老年动物将通过一系列行为、电生理、睡眠监测、微阵列和免疫组织化学分析进行评估，以测试这些干预措施可能减少/逆转UBA症状的命题，如果是这样的话，确定这是通过哪些大脑途径发生的。总体而言，这些研究应该实质上阐明心理社会应激影响脑老化标记物的神经生物学途径，并重要地确定年龄在调节应激影响中的作用。此外，拟议的干预研究应具有直接的翻译相关性。 公共卫生相关性：这项拟议的研究将调查急性和慢性心理社会应激对已建立的衰老大鼠模型脑功能的影响。这些研究将阐明影响健康和不健康大脑老化差异的神经生物学标志和过程，重点关注中年前后开始的变化，并将评估减轻压力和促进睡眠的干预措施对抗心理社会压力影响的能力。因此，所提出的研究在确定人脑老化的过程中应该具有预测和治疗价值。

DESCRIPTION (provided by applicant): This application proposes to address a fundamental unresolved question in the field of psychosocial stress and brain aging, the nature of the neurobiological pathways through which psychosocial stress promotes unhealthy brain aging (UBA). The focus of the studies will be on brain aging markers developing near the age of divergence of unhealthy from healthy brain aging, as these seem particularly likely to be susceptible to stress. This project will also test the hypothesis that midlife changes in the brain's responses to stress promote the emergence of UBA. This view derives from our recent work with both electrophysiological and microarray techniques showing that stress hormone-sensitive markers of brain aging emerge around midlife in rats, the same age range in which unhealthy cognitive aging begins to appear. The proposed studies will comprise a large multidisciplinary project aimed at obtaining a unique integrated perspective on neurobiological pathways affected by psychosocial stress in an established rat model of aging. It will involve state-of-the-art intracellular electrophysiology in brain slices, immunohistochemistry with a battery of stains, separate microarray analysis of individual rat brains, EEG monitoring of sleep patterns, and behavioral testing. Multiple techniques will be applied in each animal. These studies will pursue the aims of correlating electrophysiological and genomic markers of unhealthy brain aging in the same animals and will relate exposure to psychosocial stress to the development of UBA as a function of age and under acute vs. chronic conditions. Importantly, behavioral and pharmacological interventions to reduce stress and protect sleep patterns will be used to test whether the course of UBA can be altered in long-term studies. Aged animals subjected to psychosocial stress-reducing and sleep-promoting interventions will be evaluated on a battery of behavioral, electrophysiological, sleep monitoring, microarray and immunohistochemical analyses, to test the proposition that conversion these interventions may reduce/reverse UBA symptoms, and, if so, to determine through which brain pathways this occurred. Overall, these studies should substantially elucidate neurobiological pathways through which psychosocial stress influences brain aging markers, and should importantly determine the role of age in modulating stress impact. Further, the proposed intervention studies should have direct translational relevance. PUBLIC HEALTH RELEVANCE: This proposed research will investigate the impact of acute and chronic psychosocial stress on brain function in an established rat model of aging. These studies will elucidate neurobiological markers of and processes influencing the divergence of healthy and unhealthy brain aging, focusing on changes beginning around midlife and will also evaluate stress reducing and sleep promoting interventions' ability to combat the effects of psychosocial stress. Therefore, the proposed studies should have both predictive and therapeutic value in determining the course of human brain aging.