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 neuroinflammationin adolescent depressed mice using Maresin-1

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(5μg/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。

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 under-standing 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(5µg/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 hippo-campus 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),lon-ger 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-1βand 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.