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.

摘要 患有与年龄相关的认知能力下降的人数正在以前所未有的速度增长，因为 人类的寿命延长了。此外，暴露在社会逆境和其他压力源中会增加患癌症的风险 认知缺陷，可能会随着年龄的增长而加剧。因为女性患癌症的风险更大 认知障碍与男性相比，雌二醇的潜在作用是有牵连的。然而，来自 评估雌激素对认知的影响的研究是模棱两可的。因此，有必要 了解不利的经验因素是否可能影响雌二醇的疗效，这将解释 雌二醇对女性认知老化影响的差异。压力暴露的一种机制 雌二醇会影响认知和记忆，是神经炎症过程的调制，它会改变 神经递质的释放和合成与不健康的衰老有关。尽管观察到 长期的压力暴露会增加认知能力下降的风险，目前尚不清楚压力是否会导致 雌二醇在调节神经炎症和认知行为方面的有效性的改变。填补这一空白 知识，建议的研究将利用一个具有良好特征的非人类灵长类心理社会模型。 压力，以检验社会地位低会导致雌性恒河猴认知缺陷的首要假设 猴子和大脑中的神经炎症，这些炎症会因雌二醇而加剧。利用社交群组 重排和雌二醇的操纵，我们将测试社会地位和年龄对 神经炎症通过使用PET神经成像来定位量化大脑中的小胶质细胞激活，如 以及测量脑脊液中促炎信号的浓度。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及其程度 神经炎症可以解释执行功能评估的差异。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ITS 结论，拟议的研究将通过跟踪相同的个人来扩展我们之前的工作 通过实验确定他们的社会地位的变化，以洞察 社会地位对雌二醇影响认知行为和脑区特异性标志物能力的影响 随着社会环境的变化，神经炎症及其可塑性。通过评估和集成 作为拟议研究的一部分，我们将能够收集生理、神经生物学和行为数据 确定女性大脑中与衰老相关的健康差异的潜在风险的新机制。