Novel microglial transcriptional signatures promote social and cognitive deficits following repeated social defeat

Chronic stress is linked to anxiety and cognitive impairments. In mice, repeated social defeat (RSD) triggers anxiety-like behavior driven by microglia and the recruitment of inflammatory monocytes into the brain. However, the mechanisms through which microglia interact with other cells to regulate physiological and behavioral responses to stress remain unclear.

Using single-cell RNA sequencing (scRNA-seq), we identify a previously uncharacterized population of stress-associated microglia in the hippocampus, distinguished by RNA signatures related to cytokine/chemokine signaling, cellular stress, and phagocytosis. Depleting microglia with the CSF1R antagonist PLX5622 reduces the stress-related transcriptional changes observed in leukocytes, endothelial cells, and astrocytes.

Behaviorally, social withdrawal and cognitive impairment caused by RSD depend on microglia, but social avoidance does not. Additionally, single-nuclei RNA sequencing (snRNA-seq) reveals that RSD induces significant changes in hippocampal neurons, some of which are microglia-dependent and others microglia-independent. Notably, stress-induced activation of CREB, oxytocin, and glutamatergic signaling in neurons requires microglia. Together, these findings suggest that stress-associated microglia shape hippocampal gene expression patterns linked to social and cognitive deficits.