4.8 Article

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

Journal

SCIENCE ADVANCES
Volume 7, Issue 12, Pages -

Publisher

AMER ASSOC ADVANCEMENT SCIENCE
DOI: 10.1126/sciadv.abb9888

Keywords

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Funding

  1. National Natural Science Foundation of China [81571174, 81701308, U1808204]
  2. 863 project [2015AA020505]
  3. Sichuan Science and Technology Program [2020YJ0225]

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IL4-driven microglia expressing Arg1 in the hippocampus play a crucial role in maintaining neurogenesis and enhancing stress resilience. Modulating the expression of these microglia through IL4 signaling can restore neurogenesis and resilience. Additionally, BDNF is necessary for the proneurogenesis effects of these microglia.
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.

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