Consequences of Estrogen Deficiency on Neuroinflammation and Cognitive Impairments

项目摘要 认知障碍和痴呆是残疾、依赖和死亡的重要原因， 据估计，目前全世界有5000万人患有痴呆症。雌激素的损失，如后自然 或手术导致的更年期，与认知能力下降的易感性增加有关。此外，妇女 在生命早期缺乏雌激素的人患认知障碍的风险更高; 然而，调节雌激素损失和认知功能障碍之间联系的机制并不清楚， 完全理解。雌激素可以与大脑中普遍表达的受体相互作用，从而产生抗雌激素的作用。 炎症特性。此外，它们可以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。小胶质细胞活化和随后的炎症释放 分子可以驱动一系列生理和行为改变， 结果。此外，新出现的大量文献表明，为了响应先前的条件（例如， 老化、压力、昼夜节律紊乱），小胶质细胞可以变得启动。小胶质细胞启动是一个用来描述 向基线致敏炎性表型的转变，其特征在于对 炎症刺激在这里，我们提出，雌激素的损失可以作为一个先决条件， 小胶质细胞的神经免疫变化与衰老有关，引起促炎反应加剧 这可能会导致认知能力下降。目前缺乏对小胶质细胞特异性 雌激素缓解神经炎症和认知能力下降的机制。因此整体 该提案的目标是（i）确定卵巢切除术和雌激素丢失的时间是否会导致雌激素水平升高 （ii）评估小胶质细胞是否响应于神经炎症而被致敏， 卵巢切除术，和（iii）确定小胶质细胞是否是产生认知障碍的关键， 卵巢切除术和衰老核心假设是卵巢切除术，特别是在生命早期， 通过引发引起过度的神经免疫应答而导致不利的认知变化（即， 使）小胶质细胞对老化敏感。提出了两个具体目标来检验这一假设。概述的实验 目的1将研究卵巢切除术和早期雌激素丢失是否会引发神经免疫系统， 情感和认知行为的缺陷。在目标2中，将在体内消融小胶质细胞以确定是否 神经炎症和行为缺陷在小胶质细胞不存在的情况下被减少。这些发现将建立 如果小胶质细胞是负责由雌激素损失引起的神经免疫和行为变化的细胞类型。 总的来说，这一建议将有助于促进对绝经后妇女认知障碍的理解 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.