Consequences of Estrogen Deficiency on Neuroinflammation and Cognitive Impairments

项目总结 认知障碍和痴呆症是残疾、依赖和死亡的重要原因， 据估计，目前全球有5000万人患有痴呆症。雌激素丢失后，如天然 或手术引起的更年期，与认知能力下降的易感性增加有关。此外，女性 早年雌激素缺乏的人患认知障碍的风险更高； 然而，调节雌激素丢失和认知功能障碍之间联系的机制并不是 完全理解。雌激素可以与大脑中普遍表达的受体相互作用，发挥抗 炎性物质。此外，它们可能通过与小胶质细胞相互作用来调节神经免疫系统， 大脑的主要先天免疫细胞。小胶质细胞的激活和随后炎症的释放 分子可以驱动一系列的生理和行为改变，从而使认知能力恶化 结果。此外，一种新兴的文献表明，为了应对先前的状况(例如， 衰老、压力、昼夜节律紊乱)，小胶质细胞可能会被激活。小胶质细胞启动是一个用来描述 向基线致敏炎症表型的转变，其特征是对 炎症性刺激。在这里，我们提出雌激素丢失可以作为启动的前置条件 小胶质细胞对衰老相关的神经免疫变化，导致促炎反应加剧 这可能会导致认知能力下降。目前还缺乏对小胶质细胞特异性的理解。 雌激素减轻神经炎症和认知功能衰退的机制。因此，总体来说， 这项建议的目的是(I)确定卵巢切除和雌激素丢失的时机是否会导致升高 导致行为缺陷的神经炎症，(Ii)评估小胶质细胞是否因 卵巢切除，以及(Iii)确定小胶质细胞是否对产生认知障碍至关重要 卵巢切除和衰老。核心假设是卵巢切除，特别是在生命早期，会增加易感性。 通过启动引起夸大的神经免疫反应来引起不良认知变化(即， 对衰老敏感的)小胶质细胞。为了检验这一假说，本文提出了两个具体目标。概述了这些实验 在目标1中，将调查卵巢切除和早期雌激素丢失是否刺激神经免疫系统， 情感和认知行为的缺陷。在目标2中，小胶质细胞将在体内被消融，以确定 神经炎症和行为缺陷在没有小胶质细胞的情况下会减少。这些发现将确立 如果小胶质细胞是负责雌激素丢失引起的神经免疫和行为变化的细胞类型。 总体而言，这项建议将有助于促进对绝经后女性认知障碍的理解 并可能导致针对与衰老相关的认知能力下降的新疗法。

PROJECT SUMMARY Cognitive impairment and dementia are significant causes of disability, dependency, and death, with an estimated 50 million individuals currently dealing with dementia worldwide. Estrogen loss, such as after natural or surgically induced menopause, is linked to a heightened susceptibility to cognitive decline. Moreover, women who become estrogen-deficient earlier in life have an even higher risk of developing cognitive impairments; however, the mechanisms mediating the association between estrogen loss and cognitive dysfunction are not fully understood. Estrogens can interact with receptors ubiquitously expressed in the brain to exert anti- inflammatory properties. In addition, they may regulate the neuroimmune system by interacting with microglia, the primary innate immune cell of the brain. Microglial activation and the subsequent release of inflammatory molecules can drive a suite of physiological and behavioral alterations that can worsen cognitive outcomes. Furthermore, an emerging body of literature suggests that in response to a previous condition (e.g., aging, stress, circadian disruption), microglia can become primed. Microglial priming is a term used to describe the shift towards a baseline sensitized inflammatory phenotype characterized by an amplified response to an inflammatory stimulus. Here, we propose that estrogen loss can act as an antecedent condition that primes microglia to the neuroimmune changes associated with aging, causing exacerbated pro-inflammatory responses that may contribute to cognitive decline. There is currently a lack of understanding behind the microglia-specific mechanisms through which estrogens mitigate neuroinflammation and cognitive decline. Therefore, the overall objectives of this proposal are to (i) establish whether ovariectomy and timing of estrogen loss lead to elevated neuroinflammation that contributes to behavioral deficits, (ii) assess if microglia become primed in response to ovariectomy, and (iii) determine whether microglia are critical for generating cognitive impairments with ovariectomy and aging. The central hypothesis is that ovariectomy, particularly earlier in life, raises vulnerability to adverse cognitive changes by eliciting an exaggerated neuroimmune response through priming (i.e., sensitizing) microglia to aging. Two specific aims are proposed to test this hypothesis. The experiments outlined in Aim 1 will investigate whether ovariectomy and earlier estrogen loss prime the neuroimmune system, leading to deficits in affective and cognitive behaviors. In Aim 2, microglia will be ablated in vivo to determine whether neuroinflammation and behavioral deficits are curtailed in the absence of microglia. These findings will establish if microglia are the cell type responsible for the neuroimmune and behavioral changes induced by estrogen loss. Overall, this proposal will help advance the understanding of cognitive impairments in post-menopausal women and may lead to novel therapies for targeting the cognitive decline associated with aging.