Stress is caused by various adverse environments, and often causes emotional changes including depression and elevated anxiety. Using social defeat stress in mice, we previously reported that repeated social defeat stress activates microglia in the medial prefrontal cortex (mPFC), then decreases dendritic arborization of mPFC pyramidal neurons and leads to social avoidance. Recently, we found that microglial activation in the mPFC occurs more rapidly and strongly with repetition of social defeat stress. This finding led us to speculate that repetition of social defeat stress induced persistent epigenomic changes of microglia in the mPFC. However, due to the limited sensitivity of chromatin immune precipitation sequencing (ChIP-seq), a brain region- and cell type-specific epigenomic analysis has been challenging. Here we optimized the protocol of ChIP-seq for epigenomic analyses of mPFC microglia isolated by fluorescence-activated cell sorting. This protocol allows us to detect enrichment of active histone marks near microglia-specific genes in mPFC microglia. We are currently investigating repeated social defeat stress-induced epigenomic changes of mPFC microglia associated with emotional changes.