Background Depression is a neuropsychiatric disease with high disability rate and mainly caused by the chronic stresses or genetic factors. There is increasing evidences that miRNAs play a critical role in the pathogenesis of depression. However, the underlying molecular mechanism for the pathophysiology of depression of miRNA remains entirely unclear so far. Methods We first established a Chronic Social Defeat Stress (CSDS) mice model of depression, and depression-like behaviors of mice were evaluated by a series of behavioral tests. Next, we detected several abundantly expressive miRNAs that had been suggested to be involved in depression in previous reports and found miR-182-5p was selected as a candidate for analysis in the hippocampus, then western blotting and immunofluorescence were used together to examine whether AAV-siR-182-5p treatment alleviated chronic stress-induced decrease in hippocampal Akt/GSK3β/CREB signaling pathway and increase in neurogenesis impairment and neuroinflammation. Furthermore, cAMP-response element binding protein (CREB) inhibitor was adopted to examine if blockade of Akt/GSK3β/CREB signaling pathway abolished the antidepressant actions of AAV-siR-182-5p in mice. Results Knock-down of miR-182-5p alleviated depression-like behaviors and impaired neurogenesis of CSDS-induced mice. Intriguingly, the usage of agomiR-182-5p, produced significant increases in immobility times and aggravated neuronal neurogenesis damage of mice. More importantly, it suggested that the 666-15 blocked the reversal effects of AAV-siR-182-5p on the CSDS-induced depressive-like behaviors in the behavioral testing and the neuronal neurogenesis within hippocampus of mice. Conclusions These findings indicated that hippocampal miR-182-5p/Akt/GSK3β/CREB signaling pathway participated in the pathogenesis of depression, itmight be given more opportunities for new drug developments based on the miRNA target in the clinic.

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MiR-182-5p：治疗 CSDS 诱导小鼠抑郁症的新型生物标志物

研究背景抑郁症是一种致残率较高的神经精神疾病，主要由慢性应激或遗传因素引起。越来越多的证据表明 miRNA 在抑郁症的发病机制中发挥着关键作用。然而，迄今为止，miRNA 抑制的病理生理学的潜在分子机制仍完全不清楚。方法首先建立慢性社会失败应激（CSDS）小鼠抑郁模型，通过一系列行为测试评估小鼠的抑郁样行为。接下来，我们检测到了之前报道中被认为与抑郁症有关的几个表达丰富的 miRNA，并发现 miR-182-5p 被选为海马中的候选分析，然后结合使用蛋白质印迹和免疫荧光来检查 AAV 是否​​存在。 -siR-182-5p治疗缓解了慢性应激引起的海马Akt/GSK3β/CREB信号通路的减少以及神经发生损伤和神经炎症的增加。此外，采用cAMP反应元件结合蛋白（CREB）抑制剂来检查阻断Akt/GSK3β/CREB信号通路是否会消除AAV-siR-182-5p对小鼠的抗抑郁作用。结果 miR-182-5p 的敲低可减轻 CSDS 诱导小鼠的抑郁样行为并损害神经发生。有趣的是，使用 agomiR-182-5p 会导致小鼠的不动时间显着增加，并加剧神经元神经发生损伤。更重要的是，它表明666-15阻断了AAV-siR-182-5p对行为测试中CSDS诱导的抑郁样行为和小鼠海马内神经元神经发生的逆转作用。结论海马miR-182-5p/Akt/GSK3β/CREB信号通路参与抑郁症的发病机制，可能为临床基于miRNA靶点的新药开发提供更多机会。