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

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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.