IL4-driven microglia modulate stress resilience through BDNF-dependent neurogenesis

Adult neurogenesis in the dentate gyrus of the hippocampus is regulated by specific microglia groups and functionally implicated in behavioral responses to stress. However, the role of microglia in hippocampal neurogenesis and stress resilience remains unclear. We identified interleukin 4 (IL4)-driv...

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Published in:Science advances 2021-03, Vol.7 (12)
Main Authors: Zhang, Jinqiang, Rong, Peijing, Zhang, Lijuan, He, Hui, Zhou, Tao, Fan, Yonghua, Mo, Li, Zhao, Qiuying, Han, Yue, Li, Shaoyuan, Wang, Yifei, Yan, Wan, Chen, Huafu, You, Zili
Format: Article
Language:English
Subjects:
Brain-Derived Neurotrophic Factor - genetics
Brain-Derived Neurotrophic Factor - metabolism
Cellular Neuroscience
Hippocampus - metabolism
Interleukin-4 - metabolism
Microglia - metabolism
Neurogenesis - genetics
Neuroscience
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Summary:Adult neurogenesis in the dentate gyrus of the hippocampus is regulated by specific microglia groups and functionally implicated in behavioral responses to stress. However, the role of microglia in hippocampal neurogenesis and stress resilience remains unclear. We identified interleukin 4 (IL4)-driven microglia characterized by high expression of Arg1, which is critical in maintaining hippocampal neurogenesis and stress resistance. Decreasing Arg1 microglia in the hippocampus by knocking down the microglial IL4R suppressed hippocampal neurogenesis and enhanced stress vulnerability. Increasing Arg1 microglia in the hippocampus by enhancing IL4 signaling restored hippocampal neurogenesis and the resilience to stress-induced depression. Brain-derived neurotrophic factor (BDNF) was found necessary for the proneurogenesis effects of IL4-driven microglia. Together, our findings suggest that IL4-driven microglia in the hippocampus trigger BDNF-dependent neurogenesis responding to chronic stress, helping protect against depressive-like symptoms. These findings identify the modulation of a specific microglial phenotype as a treatment strategy for mood disorders.
ISSN:2375-2548
2375-2548
DOI:10.1126/sciadv.abb9888