Excessive alcohol use damages the brain, especially corticolimbic regions such as the hippocampus and rhinal cortices, leading to learning and memory problems. While neuroimmune reactivity is hypothesized to underly alcohol-induced damage, direct evidence of the causal role of microglia, brain-resident immune cells, in this process is lacking. Here, we depleted microglia using PLX5622 (PLX), a CSF1R inhibitor commonly used in mice, but rarely in rats, and assessed cell death following binge-like alcohol exposure in male rats. Eleven days of PLX treatment depleted microglia >
90%. Further, PLX treatment prevented alcohol-induced neuronal death in the hippocampus and rhinal cortices, as the number of FluoroJade-B-positive cells (dying neurons) was reduced to control diet levels. This study provides direct evidence that alcohol-induced microglial reactivity is neurotoxic in male rats. Improved understanding of alcohol-microglia interactions is essential for developing therapeutics that suppress pro-cytotoxic and/or amplify protective microglia activity to relieve alcohol-related damage.