Consequences of Estrogen Deficiency on Neuroinflammation and Cognitive Impairments

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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.