Friday, April 26, 2024
4/26/2024
Project Summary Excess alcohol use in adolescence is associated with negative health consequences including corticolimbic damage and cognitive deficits. However, the mechanisms underlying these negative sequelae are not well understood. Microglia, macrophages that reside within the brain, are activated in both humans and animals exposed to alcohol. Activation of microglia to a proinflammatory phenotype can lead to tissue damage and is thus considered a possible cause of adolescent corticolimbic damage following ethanol exposure. Interestingly, we do not see evidence of a proinflammatory microglial phenotype concomitant with corticolimbic pathology in binge ethanol exposed rats. Given that microglial function is more complex than previously appreciated, we consider instead that microglia may serve a neuroprotective role following exposure to ethanol. To test this hypothesis in Aim 1 adolescent rats will be exposed to 2 days of binge ethanol following by microglial morphological and transcriptomic analysis to characterize activation state. Microglia will then be depleted prior to, throughout, and following ethanol exposure using a CSF1R antagonist to determine the effects on markers of neurodegeneration and cognitive function. Interestingly, microglia are known to exhibit a form of immune memory by which prior exposure results in altered responsivity to future activation. We hypothesize that persistent changes to the microglial set-point underlie exacerbation of corticolimbic pathology with repeat exposure to ethanol. In Aim 2 adolescent rats will undergo 2 days of binge ethanol exposure followed by microglia depletion and repopulation before another 2 days of binge ethanol exposure. This replacement of the microglia population may serve to reset these cells to a baseline phenotype. We expect (1) that rats exposed to both ethanol binges will show greater microglial activation, corticolimbic neurodegeneration and cognitive deficits relative to a single 2-day binge ethanol exposure, and (2) that forced microglia turnover will ameliorate these effects. In combination, these aims will significantly enhance our understanding of role that microglial activation and memory play in corticolimbic neurodegeneration following exposure to ethanol.
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