Maternal behavior promotes resilience to adolescent stress in mice through a microglia-neuron axis

Hongyu Chen, Ruifeng Xu, Jianhao Wang, Feng Gao, Yida Lv, Xiang Li, Fang Li, Junqin Zhao, Xi Zhang, Jiabei Wang, Ruicheng Du, Yuke Shi, Hang Yu, Shuai Ding, Wenxin Li, Jing Xiong, Jie Zheng, Liang Zhao, Xin-Ya Gao and Zhi-Hao Wang ()
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Hongyu Chen: Renmin Hospital of Wuhan University
Ruifeng Xu: Renmin Hospital of Wuhan University
Jianhao Wang: Renmin Hospital of Wuhan University
Feng Gao: Renmin Hospital of Wuhan University
Yida Lv: Renmin Hospital of Wuhan University
Xiang Li: Renmin Hospital of Wuhan University
Fang Li: Renmin Hospital of Wuhan University
Junqin Zhao: Renmin Hospital of Wuhan University
Xi Zhang: Renmin Hospital of Wuhan University
Jiabei Wang: Renmin Hospital of Wuhan University
Ruicheng Du: Renmin Hospital of Wuhan University
Yuke Shi: Renmin Hospital of Wuhan University
Hang Yu: Renmin Hospital of Wuhan University
Shuai Ding: Renmin Hospital of Wuhan University
Wenxin Li: Renmin Hospital of Wuhan University
Jing Xiong: Renmin Hospital of Wuhan University
Jie Zheng: Peking University
Liang Zhao: Chinese Academy of Medical Sciences and Peking Union Medical College
Xin-Ya Gao: Henan Provincial People’s Hospital
Zhi-Hao Wang: Renmin Hospital of Wuhan University

Nature Communications, 2025, vol. 16, issue 1, 1-27

Abstract: Abstract Early life experience modulates resilience to stress in later life. Previous research implicated maternal care as a key mediator of behavioral responses to the adversity in adolescence, but details of molecular mechanisms remain elusive. Here, we show social stress activates transcription factor C/EBPβ in mPFC neurons of adolescent mice, which transcriptionally upregulates Dnm1l and promotes mitochondrial dysfunction, thereby conferring stress susceptibility in adolescent mice. Moreover, different maternal separation differentially regulates adolescent stress susceptibility. Mechanistically, this differential effect depends on maternal behavior-stimulated IGF-1, which inhibits neuronal C/EBPβ through mTORC1-induced C/EBPβ-LIP translation. Furthermore, we identify maternal behavior-stimulated IGF-1 is mainly released from mPFC microglia. Notably, increased maternal care under an environmental enrichment condition or maternal behavior impairment induced by repeated MPOAEsr1+ cells inhibition in dams prevents or promotes stress susceptibility via microglial-to-neuronal IGF-1-C/EBPβ-DRP1 signaling. In this work, these findings have unveiled molecular mechanisms by which maternal behavior promotes stress resilience in adolescents.

Date: 2025
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DOI: 10.1038/s41467-025-57810-w

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