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Early-life inflammation increases aggressive behavior in adult male mice through an astrocyte-neuron signaling

Molecular Psychiatry (2025)Cite this article

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Abstract

Accumulating research has demonstrated a significant association between early-life inflammation and behavioral disorders later in life. However, the effects of early-life inflammation on aggressive behavior in adulthood remain poorly understood. Here, we show that early-life inflammation induced by lipopolysaccharide (LPS) upregulated neuronal dynamin-related protein 1 (DRP1) and impaired mitochondrial function in medial prefrontal cortex (mPFC) of adult mice, thereby increasing aggressive behavior in adulthood. We further identify that CCAAT/enhancer binding protein β (C/EBPβ) is the transcription factor of Dnm1l, which was activated by an increased release of lysophosphatidic acid (LPA) induced by early-life inflammation. Moreover, the overproduction of LPA was due to a specific increase in astrocyte-secreted autotaxin (ATX). Specific knockdown of astrocytic ATX reduced early-life inflammation-induced aggression in wild-type mice, but not in Thy1-C/EBPβ transgenic mice. Remarkably, coenzyme Q10 decreased early-life inflammation-induced aggressive behavior in adult mice. Altogether, these findings provide new insights into the molecular mechanisms by which early inflammation promotes aggressive behavior in adulthood.

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Fig. 1: Early-life inflammation exacerbates aggressive behavior by impairing mitochondrial function in adult mice.
Fig. 2: Early-life inflammation increases neuronal DRP1 expression in the mPFC of adult male mice.
Fig. 3: C/EBPβ transcriptionally activates DRP1 in mPFC neurons and mediates early-life inflammation-induced aggressive behavior in adult mice.
Fig. 4: Early-life inflammation increases LPA levels to activate C/EBPβ in the mPFC.
Fig. 5: Knockdown ATX in astrocytes decreases neuronal C/EBPβ-DRP1 axis activation.
Fig. 6: Aggression in LPS-treated Thy1-C/EBPβ transgenic mice is not affected by astrocytic ATX knockdown and coenzyme Q10 (CoQ10) decreases early-life inflammation-induced aggressive behavior in adult mice.

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Data availability

The data that support the findings of this study are available from the corresponding author upon reasonable request.

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Acknowledgements

We thank Dr. Keqiang Ye at Faculty of Life and Health Sciences, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences for generously providing Thy1-human C/EBPβ mice.

Funding

This work was supported by National Key Research Projects of China (No. 2021YFA1302400 to Z.-H.W), National Natural Science Foundation of China (No. 82371439 to Z.-H.W), Laboratory Animal Research Project of Hubei (No.2022DFE021 to Z.-H.W), Cross-Innovation Talent Project of Wuhan University People’s Hospital (JCRCZN-2022-002 to Z.-H.W), Wuhan University People’s Hospital Sixth Round of Young Key Talent Project (RMQNZD2024004 to Z.-H.W), Major Project of Science and Technology Innovation of Hubei Province (2024BCA003 to J.X and Z.-H.W), National Key R&D Program of China (2023YFC2308404 to X.X), Technology Innovation Team Project of Hubei Province (220171677 to X.X), National Natural Science Foundation of China (No. 82202410, and 82372201 to Q.M), Hubei Provincial Natural Science Foundation of China (No. 2022CFA022 to Q.M).

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Author notes

  1. These authors contributed equally: Jiabei Wang, Jianhao Wang, Hongyu Chen, Feng Gao.

Authors and Affiliations

  1. Department of Neurology, Renmin Hospital of Wuhan University, Wuhan, 430060, China

    Jiabei Wang, Jianhao Wang, Hongyu Chen, Feng Gao, Ruifeng Xu, Yida Lv, Shuai Ding, Fang Li, Xiang Li, Yuke Shi, Junqin Zhao, Jing Xiong, Xuejie Li & Zhi-Hao Wang

  2. Center for Neurodegenerative Disease Research, Renmin Hospital of Wuhan University, Wuhan, 430060, China

    Jiabei Wang, Jianhao Wang, Hongyu Chen, Feng Gao, Ruifeng Xu, Yida Lv, Shuai Ding, Fang Li, Xiang Li, Yuke Shi, Junqin Zhao, Jing Xiong, Xuejie Li & Zhi-Hao Wang

  3. Department of Thoracic Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China

    Ruifeng Xu & Liang Zhao

  4. Department of Anesthesiology, Renmin Hospital of Wuhan University, Wuhan, China

    Hangyu Wei & Qing-tao Meng

  5. Department of Hematology, the Second Affiliated Hospital of Anhui Medical University, Hefei, China

    Xinzhuo Chen

  6. Department of Ophthalmology, Renmin Hospital of Wuhan University, Wuhan, China

    Xuejie Li & Xuan Xiao

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  1. Jiabei Wang
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Contributions

JBW, JHW, HYC and FG contributed equally to this work. Z-HW conceptualized and designed all studies. JBW, JHW, HYC, FG, RFX, YDL, SD, FL, XL, YKS, XZC, and JQZ performed and analyzed the behavioral tests and molecular experiments, conducted animal treatment, virus injection and drug delivery. RFX and HYW conducted bioinformatic analysis and transcription factor prediction. JX, XJL, QM, and XX analyzed the data by double-blind method. JBW, JHW, HYC, FG, DS, and Z-HW wrote the manuscript.

Corresponding authors

Correspondence to Qing-tao Meng, Xuan Xiao or Zhi-Hao Wang.

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Competing interests

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Ethical approval

All animal experimental protocols were approved by the Laboratory Animal Welfare Ethical Committee of Renmin Hospital of Wuhan University (Approval No. WDRM 20250402A). Animal care and handling were conducted in accordance with the National Institutes of Health (NIH) animal care guidelines and the institutional guidelines of Wuhan University. Additionally, all procedures involving animals were reviewed and approved by the Institutional Animal Care and Use Committee of Renmin Hospital of Wuhan University.

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Wang, J., Wang, J., Chen, H. et al. Early-life inflammation increases aggressive behavior in adult male mice through an astrocyte-neuron signaling. Mol Psychiatry (2025). https://doi.org/10.1038/s41380-025-03260-1

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