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

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， 人的寿命会增加此外，暴露于社会逆境和其他压力因素会增加患上抑郁症的风险。 认知缺陷可能会在衰老中加剧。因为女性更容易患上 与男性相比，认知障碍涉及雌二醇的潜在作用。然而，来自 评估雌二醇对认知影响的研究结果是模棱两可的。因此，有必要 了解不良经验因素是否可能影响雌二醇的疗效， 雌二醇对女性认知老化影响的差异。压力暴露的一种机制是 和雌二醇都影响认知和记忆是调节神经炎症过程， 神经递质的释放和合成，并与不健康的衰老有关。尽管观察到， 慢性压力暴露会增加认知能力下降的脆弱性，目前尚不清楚压力是否会诱导 雌二醇调节神经炎症和认知行为的功效改变。为了填补这一空白， 知识，拟议的研究将利用一个充分表征的非人类灵长类动物的心理社会模型， 压力，以检验总体假设，即低社会地位会导致雌性恒河猴的认知缺陷 猴子和大脑中的神经炎症，这是由雌二醇加剧。使用社会团体 重排和雌二醇操作，我们将测试社会地位和年龄对 通过使用PET神经成像对大脑中的小胶质细胞活化进行位点特异性定量， 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，并决定其程度 其中神经炎症解释了所评估的执行功能的差异。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。第 结论，拟议的研究将扩展我们以前的工作，通过跟踪相同的个人， 通过实验确定了他们社会地位的变化，以深入了解 社会地位对雌二醇影响认知行为和脑区特异性标记物的能力 神经炎症及其可塑性与社会环境的变化。通过评估和整合 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风险的新机制。

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.