Microglial activation is crucial for stress pathology in mental illness. However, how stress alters microglia remains elusive. Here we found that microglia show brain region-specific (local) and non-specific (global) transcriptional responses to chronic social stress in mice. Local super-enhancer responses specific to the medial prefrontal cortex (mPFC) emerged after acute stress leading to adjacent gene expressions after chronic stress. Global super-enhancer responses that occurred in both the mPFC and nucleus accumbens emerged along with adjacent gene expressions after acute and chronic stress. We are investigating transcription factors involved in the local and global responses. These findings pave the way for elucidating a transcriptional program of microglia for integrating brain and peripheral signals under stress. In this symposium, I will introduce these recent findings and discuss their implications in the glial role for brain-peripheral interactions.