The role of stress exposure on estradiol-induced changes in neuroinflammation and cognition

压力暴露对雌二醇引起的神经炎症和认知变化的作用

• 批准号: 10686940
• 负责人: MARIA C ALVARADO
• 金额: $ 74.44万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-01 至 2027-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10686940
• 关键词: Acetamides; Address; Adverse event; Aftercare; Age; Age-associated memory impairment; Aging; Animal Model; Attenuated; Behavior; Behavioral; Behavioral inhibition; Brain; Brain region; C-reactive protein; Cerebrospinal Fluid; Chronic; Chronic stress; Clinical Data; Cognition; Cognitive; Cognitive aging; Cognitive deficits; Data; Estradiol; Experimental Models; Exposure to; Female; Fluorine; Future; Gene Expression Regulation; Hippocampus; Human; Immune; Impaired cognition; Individual; Inflammation; Inflammatory; Interleukin-6; Intervention; Knowledge; Label; Longevity; Macaca mulatta; Measures; Memory; Microglia; Modeling; Monkeys; Neurobiology; Outcome; Peripheral; Peripheral Blood Mononuclear Cell; Persons; Physiological; Positioning Attribute; Positron-Emission Tomography; Prefrontal Cortex; Prevention; Process; Psychosocial Stress; Risk; Role; Scanning; Signal Transduction; Site; Social Environment; Social status; Stress; Testing; Treatment/Psychosocial Effects; Woman; Work; aged; behavioral outcome; executive function; experimental group; falls; flexibility; glial activation; health disparity; improved; inflammatory marker; insight; men; neurobehavioral; neuroimaging; neuroinflammation; neurotransmitter release; nonhuman primate; novel; pre-clinical; reproductive; social; social adversity; social group; spatial memory; stressor; tool; translational model

Abstract The number of people suffering from age-related cognitive decline is growing at an unprecedented rate as the human lifespan increases. In addition, exposure to social adversity and other stressors increases risk for cognitive deficits which may be exacerbated in aging. Because women are at greater risk for developing cognitive impairment compared to men, a potential role for estradiol is implicated. However, findings from studies assessing the effects of estradiol on cognition are equivocal. Consequently, there is a need to understand whether adverse experiential factors may impact estradiol efficacy that would account for the variance in the effects of estradiol on cognitive aging in females. One mechanism by which stress exposure and estradiol both impact cognition and memory is modulation of neuro-inflammatory processes that alter neurotransmitter release and synthesis and are associated with unhealthy aging. Despite observations that chronic stress exposure increases vulnerability to cognitive decline, it is not clear whether stress induced alterations in estradiol’s efficacy in modulating neuroinflammation and cognitive behavior. To fill this gap in knowledge, the proposed studies will leverage a well characterized non-human primate model of psychosocial stress to test the overarching hypothesis that low social status produces cognitive deficits in female rhesus monkeys and neuroinflammation in the brain that are exacerbated by estradiol. Using social group rearrangements and estradiol manipulations, we will test the effects of social status and age on neuroinflammation by using PET neuroimaging to site-specifically quantify microglial activation in the brain, as well as measure concentrations of pro-inflammatory signals in cerebral spinal fluid. We will also determine the effects of chronic social status and age on cognitive flexibility and memory capacity, and determine the extent to which neuroinflammation account for variance in executive function assessed. Finally, we will determine the causal effects of social status on estradiol’s ability to modulate neuroinflammation and cognition. At its conclusion, the proposed studies will extend upon our previous work by following the same individuals across experimentally determined changes in their social status to generate insight into both the causal effects of social status on estradiol’s ability to influence cognitive behavior and brain region-specific markers of neuroinflammation and their plasticity with changes in the social environment. By assessing and integrating the physiological, neurobiological, and behavioral data collected as part of the proposed studies, we will be able to identify a novel mechanism underlying risk for aging-related health disparities in the female brain.

抽象的 与年龄有关的认知下降遭受的人数正在以前所未有的速度增长 人类的寿命增加。此外，接触社交广告和其他压力源会增加 认知定义可能会在衰老中加剧。因为妇女的发展风险更大 与男性相比，认知障碍涉及雌二醇的潜在作用。但是，来自 评估雌二醇对认知作用的研究是同等的。因此，有必要 了解不利的经历因素是否会影响雌二醇效率 雌二醇对女性认知衰老的影响的差异。压力暴露的一种机制 雌二醇影响认知和记忆是对改变的神经炎症过程的调节 神经递质释放和合成，并与不健康的衰老有关。尽管有观察 慢性压力暴露增加了认知能力下降的脆弱性，尚不清楚压力是否引起 雌二醇在调节神经炎症和认知行为方面的效率的改变。填补这个空白 知识，拟议的研究将利用一个特征良好的非人类心理私人模型 强调要检验总体假设，即低社会地位会导致女性恒河所的认知缺陷 雌二醇加剧的大脑中的猴子和神经炎症。使用社会群体 重排和雌二醇操纵，我们将测试社会地位和年龄的影响 通过使用PET神经成像来特异性地定量大脑中的小胶质细胞激活，AS神经炎症 以及脑脊髓液中促炎信号的测量浓度。我们还将确定 慢性社会地位和年龄对认知灵活性和记忆能力的影响，并确定程度 神经炎症对所评估的执行功能的差异说明了这一点。最后，我们将确定 社会地位对雌二醇调节神经炎症和认知能力的因果影响。在它的 结论，拟议的研究将通过跟随相同的个人在整个过程中扩展我们以前的工作 实验确定其社会地位的变化，以洞悉 雌二醇影响认知行为和大脑区域特异性标记的社会地位 神经炎症及其可塑性随社会环境的变化而变化。通过评估和整合 作为拟议研究的一部分收集的物理，神经生物学和行为数据，我们将能够 确定女性大脑中与衰老相关的健康差异的新型机制。