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

Abstract

Running title: IL4-driven microglia modulate neurogenesis and stress resilience In Brief:Zhang et al. show that IL4-induced Arg1 + microglia restore hippocampal neurogenesis and promote resilience against stress in mice by increasing BDNF levels. Targeting microglia with immunomodulatory factors may be a strategy for treating mood disorders.2 Highlights:1. Vulnerability to stress in mice is associated with reduced IL4 signaling in the hippocampus 2. Brain-derived IL4 promotes adult hippocampal neurogenesis and stress resistance by driving Arg1 + microglia 3. IL4-driven Arg1 + microglia enhance hippocampal neurogenesis via a BDNF-dependent pathway 3 Abstract Adult neurogenesis in the dentate gyrus of the hippocampus is regulated by specific groups of microglia and is functionally implicated in behavioral responses to stress. However, the role of microglia in modulating hippocampal neurogenesis in stress responses remains poorly understood. Here we investigated the effects of IL4-driven Arg1 + microglia in the restoration of hippocampal neurogenesis and conferment of stress resilience. We found that low IL4 levels in the hippocampus of mice was associated with greater stress vulnerability and, conversely, overexpression of IL4 in the hippocampus induced a large number of Arg1 + microglia and ameliorated stress-induced depressive-like behaviors. Knockdown of microglial IL4 receptors in the hippocampus of mice exacerbated the stress-induced inflammatory response and abolished the antidepressant effects of IL4 overexpression. Enhancement or inhibition of IL4 signaling in hippocampal microglia modulated neurogenesis, and blockade of neurogenesis abolished the resilience to stress-induced depression. We further show that IL4-activated microglia is associated with upregulation of BDNF levels and neurogenesis. Taken together, our findings suggest that IL4-driven microglia in the hippocampus trigger BDNF-dependent neurogenesis in response 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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