海马miR-98-5p通过调节脑源性神经营养因子参与抑郁症的病理机制研究

陈燕; 居新梅; 曹飞飞; 林小云; 管伟

doi:10.3969/j.issn.2096-3882.2023.12.003

海马miR-98-5p通过调节脑源性神经营养因子参与抑郁症的病理机制研究

MiR-98-5p participates in the pathogenesis of depression through regulating the expression of BDNF in the hippocampus of mice

摘要

摘要: 目的探讨海马miR-98-5p对慢性社交挫败应激（CSDS）小鼠抑郁行为的作用及可能的病理机制。方法 8周龄雄性C57BL/6J小鼠40只，分为对照组、CSDS组、CSDS+mimic NC组（阴性对照组）以及CSDS+miR-98-5p mimic组。除对照组外，其余3组小鼠先构建CSDS抑郁模型，在CSDS前1周阴性对照组小鼠海马立体定位注射mimic NC，CSDS+miR-98-5p mimic组小鼠海马注射miR-98-5p mimic，对照组和CSDS组小鼠均给予生理盐水。随后行为学实验（糖水偏好测试、悬尾测试、强迫游泳测试以及社会接触测试）检测小鼠抑郁样行为；ELISA法检测不同组小鼠海马炎症相关细胞因子的表达水平，包括肿瘤坏死因子-α（TNF-α）、白细胞介素-1β（IL-1β）和白细胞介素-6（IL-6）；Western blot法检测小鼠海马脑源性神经营养因子（BDNF）、磷酸化环磷腺苷效应元件结合蛋白（p-CREB）和CREB表达；免疫荧光法检测小鼠海马区双皮质素（DCX）和神经核蛋白（NeuN）表达。结果行为学测试结果显示，与对照组小鼠相比，CSDS组小鼠糖水消耗量和社会互动时间明显降低（P<0.01），不动性时间显著增加（P<0.01）；与CSDS组相比，CSDS+miR-98-5p mimic组小鼠不动性时间明显减少（P<0.01），社会互动时间和糖水消耗量明显增加（P<0.01）。ELISA检测结果显示，miR-98-5p mimic显著降低CSDS小鼠TNF-α、IL-1β和IL-6水平（P<0.01）。miR-98-5p mimic通过激活海马BDNF-CREB信号通路抑制CSDS对小鼠海马神经发生的损伤。结论 miR-98-5p mimic可以通过靶向BDNF改善CSDS诱导的小鼠抑郁样行为，表明其在抑郁症中具有保护作用。

Abstract: Objective To explore the role and mechanism of hippocampal microRNA (miR)-98-5p in a chronic social defeat stress (CSDS)-induced mouse model of depression.Methods A total of 40 male C57BL/6J mice, aging 8 weeks, were selected and divided into four groups:a control group, a CSDS group, a CSDS + mimic control treatment group and a CSDS + miR-98-5p mimic treatment group. Except for the control group, mice in the remaining three groups were subjected to CSDS. One week before CSDS, a CSDS + mimic control treatment group and a CSDS + miR-98-5p mimic treatment group were stereotactically injected with mimic-NC or miR-98-5p mimic, respectively, while those in the control group and the CSDS group were given the same amount of normal saline. A series of behavioral tests were conducted to evaluate the depression-like behaviors of mice, including sucrose preference test, tail suspension test, forced swimming test and social interaction test. The expression of inflammatory factors in the hippocampus of each group was examined by ELISA, including tumor necrosis factor (TNF)-α, interleukin (IL)-1β and IL-6. The levels of brain-derived neurotrophic factor (BDNF), phosphorylated-cAMP responsive element-binding protein (p-CREB) and CREB in the hippocampus were measured by Western blot. The expression of dicorticocortin (DCX) and neuronal nuclear protein (NeuN) in the hippocampus was quantified by immunohistochemistry.Results According to behavioral test, compared with the control group, the CSDS group showed significant decreases in sucrose consumption and social interaction time (P<0.01) and increases in immobility time (P<0.01). Furthermore, compared with the CSDS group, the CSDS+miR-98-5p mimic group presented significantly reduced immobility time, as well as increased sucrose consumption and social interaction time (P<0.01). Treatment with miR-98-5p mimic remarkably improved the levels of TNF-α, IL-1β and IL-6 in CSDS-induced mice (P<0.01). Furthermore, miR-98-5p mimic attenuated the neurogenesis in the hippocampus of CSDS-induced mice through activating the BDNF-CREB signal pathway.Conclusions MiR-98-5p mimic can improve CSDS-induced depression-like behavior in mice through targeting BDNF, indicating its protective role in depression.

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