期刊
NEURON
卷 99, 期 3, 页码 464-+出版社
CELL PRESS
DOI: 10.1016/j.neuron.2018.06.035
关键词
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资金
- CREST grant from JST [JP15gm0410006]
- CREST grant from AMED [JP17gm0910012]
- Japan Society for the Promotion of Science [15J07561, 17J09360]
- Ministry of Education, Culture, Sports, Science and Technology in Japan [25116517, 25116715, 15H01289, 17H06057, 17H05572]
- Uehara Memorial Foundation
- Sumitomo Foundation
- Naito Foundation
- Astellas Foundation for Research on Metabolic Disorders
- Takeda Science Foundation
- [24689015]
- [16H05132]
- [17K19457]
- [17K08593]
- Grants-in-Aid for Scientific Research [15J07561, 17H06057, 17J09360, 17H05572, 25116715, 25116517, 15H01289] Funding Source: KAKEN
Repeated environmental stress has been proposed to induce neural inflammation together with depression and anxiety. Innate immune receptors, such as Toll-like receptors (TLRs), are activated by exogenous or endogenous ligands to evoke inflammation. Here we show that the loss of TLR2 and TLR4 (TLR2/4) abolished repeated social defeat stress (R-SDS)-induced social avoidance and anxiety in mice. TLR2/4 deficiency mitigated R-SDS-induced neuronal response attenuation, dendritic atrophy, and microglial activation in the medial prefrontal cortex (mPFC). Furthermore, mPFC microglia-specific TLR2/4 knockdown blocked social avoidance. Transcriptome analyses revealed that R-SDS induced IL-1 alpha and TNF-alpha in mPFC microglia in a TLR2/4-dependent manner, and antibody blockade of these cytokines in the mPFC suppressed R-SDS-induced social avoidance. These results identify TLR2/4 as crucial mediators of R-SDS-induced microglial activation in the mPFC, which leads to neuronal and behavioral changes through inflammation-related cytokines, highlighting unexpected pivotal roles of innate immunity in the mPFC in repeated environmental stress-induced behavioral changes.
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