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.