Single Cell RNAseq of the hippocampus after RSD following microglia depletion

Chronic stress is associated with anxiety and cognitive impairment. Repeated social defeat (RSD) in mice induces anxiety-like behavior driven by microglia and the recruitment of inflammatory monocytes to the brain. Nonetheless, it is unclear how microglia communicate with other cells to modulate the physiological and behavioral responses to stress. Using single-cell (sc)RNAseq, novel stress-associated microglia were identified in the hippocampus and defined by RNA profiles of cytokine/chemokine signaling, cellular stress, and phagocytosis. Microglia depletion with a CSF1R antagonist (PLX5622) attenuated the stress-associated profile of leukocytes, endothelia, and astrocytes. Furthermore, RSD-induced social withdrawal and cognitive impairment were microglia dependent, but social avoidance was microglia independent. Furthermore, single-nuclei (sn)RNAseq showed robust responses to RSD in hippocampal neurons that were both microglia dependent and independent. Notably, stress-induced CREB, oxytocin, and glutamatergic signaling in neurons were microglia dependent. Collectively, these stress-associated microglia influenced transcriptional profiles in the hippocampus linked to social and cognitive deficits.