Psychosocial stress interactions with electrophysiology and brain aging

描述（由申请人提供）：本申请旨在解决社会心理压力和大脑衰老领域的一个基本未解决的问题，即社会心理压力促进不健康大脑衰老（UBA）的神经生物学途径的本质。这些研究的重点将放在接近不健康和健康大脑衰老分化年龄的大脑衰老标志物上，因为这些标志物似乎特别容易受到压力的影响。该项目还将测试一个假设，即中年时大脑对压力的反应变化会促进UBA的出现。这一观点来源于我们最近使用电生理和微阵列技术的研究，表明应激激素敏感的大脑衰老标记在大鼠中年左右出现，而在同一年龄段，不健康的认知衰老开始出现。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，受社会心理压力影响的神经生物学途径。它将涉及最先进的脑切片细胞内电生理学、免疫组织化学染色、单个大鼠脑的单独微阵列分析、睡眠模式的脑电图监测和行为测试。每只动物将采用多种技术。这些研究的目的是在相同的动物中，将不健康脑衰老的电生理和基因组标记联系起来，并将暴露于社会心理压力与UBA的发展作为年龄的函数以及急性和慢性疾病的关系联系起来。重要的是，减少压力和保护睡眠模式的行为和药理学干预将用于测试是否可以在长期研究中改变UBA的过程。接受心理社会压力减轻和睡眠促进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，以检验这些干预措施的转换可能会减少/逆转UBA症状的观点，如果是这样，则确定这种情况是通过哪些脑通路发生的。总的来说，这些研究应该从本质上阐明社会心理压力影响大脑衰老标志物的神经生物学途径，并应该重要地确定年龄在调节压力影响中的作用。此外，建议的干预研究应具有直接的翻译相关性。

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.