Microglia contribute to social behavioral adaptation to chronic stress

Microglial activation has been regarded mainly as an exacerbator of stress response, a common symptom in psychiatric disorders. This study aimed to determine whether microglia contribute to adaptive response of the brain and behavior toward stress using a mild and adaptive stress model – chronic restraint stress (CRS) – with wild type (WT) and CX3CR1‐GFP (CX3CR1[G]) mice and human schizophrenia patients' data. Our results revealed that CRS did not exacerbate anxiety and depressive‐like behaviors, but instead strengthened social dominance and short‐term spatial learning in WT mice. Compared to WT and CX3CR1(+/G) heterozygous mice, CX3CR1(G/G) homozygotes were subordinate in social interaction before and after CRS. Microglia in WT mice underwent a series of region‐specific changes involving their phagocytosis of presynaptic vesicular glutamate transporter 2 protein, contacts with synaptic elements, CD206+microglial proportion, and gene expressions such as Cx3cr1. By contrast, CX3CR1‐deficient microglia showed decreased CD206+ while increased MHCII+ subpopulations and hypo‐ramification in the hippocampus, as well as sensitized polarization and morphological change in response to CRS. Furthermore, CD206+ microglial abundancy was positively correlated with social dominancy and microglial ramification in CX3CR1‐GFP mice. Moreover, CX3CR1 mRNA level was reduced in CRS‐treated mouse brains and showed a smaller interactome with other brain genes in the dorsal‐lateral prefrontal cortices of patients with schizophrenia. Our findings overall highlight microglia and its receptor CX3CR1 as key contributors in regulation of social behavioral adaptation to chronic stress. MAIN POINTS CRS primes C57BL6J mice in learning and social hierarchy. CRS modulates microglial presynaptic pruning, especially in CD206+ microglia. CX3CR1 regulates social submissiveness in mice and is associated with schizophrenia in humans.