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.