ABSTRACT Exposure to alcohol during development or adulthood may result in damage to the brain. Binge alcohol consumption is a growing problem in the US, particularly among adolescents and young adults whose brains are continuing to develop and are thus more susceptible to the harmful effects of binge drinking on brain function. Both clinical and preclinical evidence suggest that microglia –the brain’s resident immune cells– play a key role in modulating alcohol-induced neurotoxicity. Indeed, brain inflammation following alcohol binge can impair brain development and function. In addition, activation of microglia promotes drinking preference in mouse models of chronic alcohol exposure. However, the cellular or molecular mechanisms through which microglia could mediate neuronal damage and alter animal behavior in response to alcohol in the adult or the adolescent brain have not been identified. Moreover, the effects of alcohol on microglia-neuronal interactions at the structural or functional level have not been studied, mostly due to technological limitations. We previously performed in vivo imaging using two-photon microscopy and discovered the dynamic nature of microglia, providing the first real-time demonstration of their tissue surveillance function. We also revealed their previously unknown ability to rapidly respond to changes in their microenvironment. Following systemic inflammatory challenges microglia become activated, and increase their interactions with the surrounding brain tissue. Acute and chronic alcohol exposure increases pro-inflammatory cytokines systemically, which can in turn directly or indirectly affect blood-brain barrier (BBB) integrity, and promote neuro-inflammatory and neurotoxic effects in different brain regions. Our preliminary results in models of excessive ethanol exposure show microglial activation, BBB disruption, and neuronal loss in the prefrontal cortex (PFC) of mice, a brain region implicated in alcohol-induced impairments in humans. Also, monocyte-specific deletion of MyD88, a key adaptor protein downstream of Toll-like receptor 4, abrogated microglial activation, BBB damage, and neuronal loss following ethanol abuse, and prevented ethanol- induced impairments in mice. Based on these findings, our proposed studies will test the hypotheses that increasing ethanol exposure causes localized BBB damage and microglial activation, which is required for regional structural and functional disruption of neuronal networks, and for alcohol-induced behavioral impairments.