Wang Jiabei, Wang Jianhao, Chen Hongyu, Gao Feng, Xu Ruifeng, Lv Yida, Ding Shuai, Li Fang, Li Xiang, Shi Yuke, Wei Hangyu, Chen Xinzhuo, Zhao Junqin, Xiong Jing, Li Xuejie, Zhao Liang, Meng Qing-Tao, Xiao Xuan, Wang Zhi-Hao
Department of Neurology, Renmin Hospital of Wuhan University, Wuhan, 430060, China.
Center for Neurodegenerative Disease Research, Renmin Hospital of Wuhan University, Wuhan, 430060, China.
Mol Psychiatry. 2025 Sep 16. doi: 10.1038/s41380-025-03260-1.
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.
越来越多的研究表明，生命早期的炎症与后期的行为障碍之间存在显著关联。然而，生命早期炎症对成年期攻击行为的影响仍知之甚少。在此，我们发现脂多糖（LPS）诱导的生命早期炎症会上调成年小鼠内侧前额叶皮质（mPFC）中的神经元动力蛋白相关蛋白1（DRP1）并损害线粒体功能，从而增加成年期的攻击行为。我们进一步确定CCAAT/增强子结合蛋白β（C/EBPβ）是Dnm1l的转录因子，其被生命早期炎症诱导的溶血磷脂酸（LPA）释放增加所激活。此外，LPA的过量产生是由于星形胶质细胞分泌的自分泌运动因子（ATX）特异性增加。特异性敲低星形胶质细胞的ATX可减少野生型小鼠中生命早期炎症诱导的攻击行为，但在Thy1-C/EBPβ转基因小鼠中则不然。值得注意的是，辅酶Q10可减少成年小鼠中生命早期炎症诱导的攻击行为。总之，这些发现为早期炎症促进成年期攻击行为的分子机制提供了新的见解。
