Psychosocial stress interactions with electrophysiology and brain aging

描述（由申请人提供）：本申请提出解决社会心理应激和脑老化领域中的基本未解决的问题，即社会心理应激通过其促进不健康的脑老化（乌巴）的神经生物学途径的性质。这些研究的重点将是在不健康大脑老化与健康大脑老化的分歧年龄附近发展的大脑老化标记，因为这些标记似乎特别容易受到压力的影响。这个项目也将测试中年大脑对压力反应的变化促进乌巴出现的假设。这一观点源于我们最近的电生理学和微阵列技术研究，这些研究表明，大鼠在中年左右出现了对压力敏感的大脑衰老标记，而在中年左右，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，在一个既定的大鼠模型老化的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，免疫组化与电池的染色，单独的微阵列分析个别大鼠大脑，脑电图监测睡眠模式，和行为测试。将在每只动物中应用多种技术。这些研究将追求在相同动物中将不健康大脑老化的电生理学和基因组标记物相关联的目的，并将暴露于心理社会应激与乌巴的发展作为年龄的函数以及在急性与慢性条件下相关联。重要的是，行为和药理干预，以减少压力和保护睡眠模式将被用来测试是否可以改变乌巴的过程中，在长期研究。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对接受心理社会压力减轻和睡眠促进干预的老年动物进行评价，以测试这些干预可能减少/逆转乌巴症状的转换的命题，如果是这样，则确定这是通过哪些脑通路发生的。总的来说，这些研究应该充分阐明心理社会压力影响大脑衰老标志物的神经生物学途径，并且应该重要地确定年龄在调节压力影响中的作用。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：这项拟议的研究将在一个已建立的衰老大鼠模型中调查急性和慢性心理社会应激对大脑功能的影响。这些研究将阐明影响健康和不健康大脑衰老差异的神经生物学标志物和过程，重点关注中年前后开始的变化，还将评估减轻压力和促进睡眠的干预措施对抗心理压力影响的能力。因此，拟议的研究应该在确定人脑老化过程中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.