Wang Hanxiao, Peng Jie, Zhu Haojie, Sun Micona, Fang Yunli, Chen Zhuo, Hu Wenfeng, Tong Lijuan, Ren Jie, Huang Chao, Lu Xu
Department of Pharmacology, School of Pharmacy, Nantong University, #19 Qixiu Road, Nantong 226001, Jiangsu Province, China.
Invasive Technology Department, Nantong First People's Hospital, The Second Affiliated Hospital of Nantong University, #6 North Road Hai'er Xiang, Nantong 226001, Jiangsu Province, China.
Physiol Behav. 2025 Mar 15;291:114782. doi: 10.1016/j.physbeh.2024.114782. Epub 2024 Dec 12.
Depression triggered by harmful stress in adolescents is a common phenomenon that can lead to serious social problems. Its treatment is still frustrating in the clinic. We reported the phenomenon that a 12-day chronic unpredictable stress (CUS), starting on postnatal day 28, led to a significant decrease in the number of microglia in the dentate gyrus of the hippocampus in adult mice. Reversing this decline with a single injection of low-dose lipopolysaccharide (LPS), a classical immunostimulant, could rapidly reverse the depression-like behavior induced by 12 days of CUS stimulation during adolescence. In the dose-dependent experiment, a single injection of LPS at doses of 75 and 100 μg/kg, but not at doses of 25 and 50 μg/kg, produced an antidepressant effect in mice exposed to 12-day CUS during adolescence. The time-dependent experiment showed that the antidepressant effect of the single injection of LPS (100 μg/kg) occurred at time points 5 and 8 h, but not 3 h after LPS injection. The antidepressant effect of the single LPS injection (100 μg/kg) lasted for at least 7 days, and 14 days after the single LPS injection, a repeated injection could still induce the stressed mice to develop an antidepressant phenotype. Furthermore, inhibition of microglia by minocycline or depletion of microglia by PLX3397 was found to prevent the antidepressant effect of the single LPS injection. These results suggest that reversing the decline of microglia in the dentate gyrus may be a potential strategy for the treatment of depression induced by harmful stress in adolescents.
青少年中由有害应激引发的抑郁症是一种常见现象，可导致严重的社会问题。其治疗在临床上仍然令人沮丧。我们报道了这样一种现象：从出生后第28天开始的为期12天的慢性不可预测应激（CUS），导致成年小鼠海马齿状回中微胶质细胞数量显著减少。用单次注射低剂量脂多糖（LPS）（一种经典的免疫刺激剂）来逆转这种减少，可迅速逆转青春期12天CUS刺激所诱导的抑郁样行为。在剂量依赖性实验中，单次注射75和100μg/kg剂量的LPS可使青春期暴露于12天CUS的小鼠产生抗抑郁作用，而25和50μg/kg剂量则无此作用。时间依赖性实验表明，单次注射LPS（100μg/kg）的抗抑郁作用在注射后5和8小时出现，而不是3小时。单次注射LPS（100μg/kg）的抗抑郁作用持续至少7天，单次注射LPS 14天后，重复注射仍可诱导应激小鼠产生抗抑郁表型。此外，发现用米诺环素抑制微胶质细胞或用PLX3397清除微胶质细胞可阻止单次注射LPS的抗抑郁作用。这些结果表明，逆转齿状回中微胶质细胞的减少可能是治疗青少年有害应激所致抑郁症的一种潜在策略。
