The role of innate immune pathway in repeated social defeat stress-induced behavioral changes in mice

[Speaker] Shiho Kitaoka:1,2
[Co-author] Xiang Nie:1,2, Kohei Tanaka:3, Atsubumi Ogawa:3, Fumitake Nakano:1, Yuki Imoto:4, Eri Segi-Nishida:5, Shuh Narumiya:2, Tomoyuki Furuyashiki:1,2
1:Pharmacology, Kobe University Graduate School of Medicine, Japan, 2:AMED-CREST, Japan, 3:Kyoto University Graduate School of Medicine, Japan, 4:Kyoto University Graduate School of Pharmaceutical Sciences, Japan, 5:Tokyo University of Science, Japan

Stress is a risk factor for psychiatric disorder, and induces behavioral changes and cognitive dysfunction. Recently, it has been shown that repeated stress activates microglia. However, we still do not know how stress activates microglia and whether this microglial activation is essential for stress-induced behavioral changes. Originally, Toll-like receptors (TLRs) recognize exogenous ligands derived from bacteria. Recently, it has been reported that endogenous ligands can activate TLR. Therefore, we examined the role of TLRs in stress-induced microglial and behavioral changes. TLR deficiency impaired repeated social defeat stress-induced social avoidance and elevated anxiety. Repeated stress activated microglia in medial prefrontal cortex (mPFC), not in nucleus accumbense (NAc), in a TLR-dependent manner. Furthermore, repeated stress-induced attenuation of stress-induced c-Fos response was suppressed in mPFC of TLR-deficient mice. TLR knockdown in mPFC microglia blocked repeated stress-induced social avoidance. Transcriptome analysis of microglia from mPFC and NAc revealed that repeated stress induced inflammatory cytokines specifically in mPFC microglia in a TLR-dependent manner. Neutralizing antibodies to these cytokines into mPFC suppressed repeated stress-induced social avoidance. These results suggest that TLR is critical for microglial activation in mPFC, thereby leading to neuronal and behavioral changes through inflammatory cytokines.
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