Deficiency of microglia and TNFα in the mPFC-mediated cognitive inflexibility induced by social stress during adolescence.

The crucial roles played by the microglia and their release of cytokines in the regulation of brain maturation are increasingly being recognized. Adolescence is a unique period characterized by continued brain maturation, especially in the area of the prefrontal cortex. Our previous studies showed that adolescent social stress (ASS) induced impairment of extradimensional set-shifting (EDS), a core component of cognitive flexibility mediated by the medial prefrontal cortex (mPFC) in adult mice. The present study further determined the role of the microglia and the inflammatory cytokine tumor necrosis factor alpha (TNFα) in cognitive dysfunction. Accompanied by a deficit in EDS in adulthood, ASS mice showed significant reductions in the expression of microglial molecular biomarker Iba1, cell numbers, and the levels of TNFα mRNA and protein in the mPFC. Pharmacological inhibition of TNFα signaling by direct injection of a neutralizer into the mPFC also specifically impaired the EDS performance. Moreover, these cognitive and immune alterations in previously stressed adult mice were ameliorated by both acute LPS and chronic antidepressant treatment. Together, our data suggest that the microglia and TNFα play roles in cognitive flexibility and can act as a potential therapeutic target for the treatment of cognitive deficits in psychiatric disorders.