Maresin-1改善青少年期抑郁小鼠的抑郁样行为和神经炎症

Improvement of depression-like behaviors and neuroinflammation in adolescent depressed mice using Maresin-1

摘要:

目的 阐明Maresin-1（MaR1）对慢性社交挫败（chronic social defeated stress，CSDS）诱导青少年期（5~8周）小鼠抑郁样行为的影响，验证其在CSDS诱导的神经炎症中的作用，为理解抑郁症的分子机制和探索生物标志物提供参考。方法 利用多种方法来检测CSDS诱导10 d后C57BL/6J小鼠的抑郁样行为和神经炎症。并每2 d注射1次MaR1（5 μg/kg）治疗小鼠，以观察其对CSDS诱导的抑郁样行为和神经炎症的影响。行为学实验后进行PET-CT扫描并对PET图像进行定量分析；收集小鼠脑组织样本进行免疫荧光染色，采用Image J对海马区域Iba-1细胞、 TSPO免疫荧光强度进行统计；将小鼠海马体在冰上分离，并立即在液氮中快速冷冻，然后储存在-80 ℃下进行随后的RNA提取，试剂盒检测肿瘤坏死因子-α（tumor necrosis factor-α，TNF-α）、白细胞介素1β（interleukin-1 beta，IL-1β）和IL-4含量。结果 与对照组相比，CSDS应激后，小鼠表现出低糖水偏好比（P=0.003）低社会交互比（P=0.000）、更长的不动时间（P=0.002），在海马区域，小胶质细胞活化，表现为SUV值升高（P=0.020），Iba-1和TSPO的免疫荧光强度增强（P=0.000）和促炎细胞因子IL-1β和TNF-α升高（P=0.016、0.036）。而MaR1改善了上述CSDS诱导的抑郁样行为，抑制小胶质细胞的激活和减少促炎因子的表达。结论 MaR1能够缓解CSDS诱导的青少年期小鼠抑郁样行为，抑制小胶质细胞的活化。神经炎症是青少年抑郁症的潜在致病因素，具有抗炎特性的药物如MaR1有潜力作为临床相关的抗抑郁药，需要进一步地研究。

Abstract:

Objective To elucidate the effect of Maresin-1（MaR1） on chronic social defeated stress（CSDS）-induced depression-like behaviors in adolescent mice（5-8 weeks old），validate its role in CSDS-induced neuroinflammation，and provide a reference for understanding the molecular mechanisms of depression and exploring biomarkers.Methods Multiple methods were used to measure depression-like behaviors and neuroinflammation in C57BL/6J mice ten days after CSDS induction. The mice were treated with MaR1（5 μg/kg） intravenously every two days to observe its effect on CSDS-induced depression-like behaviors and neuroinflammation. Behavioral experiments were followed by positron emission tomography-computerized tomography（PET-CT） scanning and quantitative analysis of PET images. The mouse brain tissue samples were collected for immunofluorescence staining，and the immunofluorescence intensities of Iba-1 cells in the hippocampal region and translocator protein（TSPO） were calculated using Image J. The mouse hippocampus was dissected on ice，immediately frozen in liquid nitrogen，and stored at -80°C for subsequent RNA extraction. A kit was used to measure the levels of tumor necrosis factor-α（TNF-α），interleukin-1 beta（IL-1β），and IL-4.Results Compared to the control group，mice subjected to CSDS stress showed a lower sucrose preference ratio（P=0.003），lower social interaction ratio（P=0.000），longer immobility time（P=0.002），and microglial cell activation in the hippocampal region evidenced by increased standardized uptake values（P=0.020），enhanced immunofluorescence intensity of Iba-1 and TSPO（P=0.000），and increased proinflammatory cytokines IL-1β and TNF-α（P=0.016，0.036）. In contrast，MaR1 improved CSDS-induced depression-like behaviors，inhibited microglia activation，and reduced the expression of proinflammatory factors.Conclusion MaR1 can alleviate CSDS-induced depression-like behaviors in adolescent mice and inhibit the activation of microglia. Neuroinflammation is a potential pathogenic factor for depression in adolescents，and drugs with anti-inflammatory properties such as MaR1 hold promise for use as a clinically relevant antidepressant，which needs further investigation.