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

  • Mol Psychiatry. 2026 Mar;31(3):1455-1474. doi: 10.1038/s41380-025-03260-1.
Jiabei Wang  #  1  2 ,  Jianhao Wang  #  1  2 ,  Hongyu Chen  #  1  2 ,  Feng Gao  #  1  2 ,  Ruifeng Xu  1  2  3 ,  Yida Lv  1  2 ,  Shuai Ding  1  2 ,  Fang Li  1  2 ,  Xiang Li  1  2 ,  Yuke Shi  1  2 ,  Hangyu Wei  4 ,  Xinzhuo Chen  5 ,  Junqin Zhao  1  2 ,  Jing Xiong  1  2 ,  Xuejie Li  1  2  6 ,  Liang Zhao  3 ,  Qing-Tao Meng  7 ,  Xuan Xiao  8 ,  Zhi-Hao Wang  9  10
Affiliations
  • 1. Department of Neurology, Renmin Hospital of Wuhan University, Wuhan, 430060, China.
  • 2. Center for Neurodegenerative Disease Research, Renmin Hospital of Wuhan University, Wuhan, 430060, China.
  • 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.
  • 4. Department of Anesthesiology, Renmin Hospital of Wuhan University, Wuhan, China.
  • 5. Department of Hematology, the Second Affiliated Hospital of Anhui Medical University, Hefei, China.
  • 6. Department of Ophthalmology, Renmin Hospital of Wuhan University, Wuhan, China.
  • 7. Department of Anesthesiology, Renmin Hospital of Wuhan University, Wuhan, China. [email protected].
  • 8. Department of Ophthalmology, Renmin Hospital of Wuhan University, Wuhan, China. [email protected].
  • 9. Department of Neurology, Renmin Hospital of Wuhan University, Wuhan, 430060, China. [email protected].
  • 10. Center for Neurodegenerative Disease Research, Renmin Hospital of Wuhan University, Wuhan, 430060, China. [email protected].
  • # Contributed equally.
PMID: 40954280 DOI: 10.1038/s41380-025-03260-1
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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