Table_1_miR-30 Family miRNAs Mediate the Effect of Chronic Social Defeat Stress on Hippocampal Neurogenesis in Mouse Depression Model.pdf

Depression is a debilitating psychiatric disorder with a high rate of relapse and a low rate of response to antidepressant treatment. There is a dearth of new antidepressants due to an incomplete understanding of the molecular mechanisms involved in its etiopathology. Chronic stress appears to be one of the foremost underlying causes of depression. Studies in animal models in the past decade have implicated epigenetic mechanisms in mediating the negative effects of chronic stressful events on the progression/manifestation of depression and other co-morbid neuropsychiatric disorders. However, non-coding RNAs, another layer of epigenetic regulation is relatively less studied in depression. Here, using the chronic social defeat stress (CSDS)-induced depression model, we hypothesized dysregulation in miRNA-mRNA networks in the neurogenic dentate gyrus (DG) region of male C57BL/6 mice. Among several dysregulated miRNAs identified via miRNA arrays, the most striking finding was the downregulation of miRNAs of the miR-30 family in stressed/defeated mice. To investigate miRNAs in the DG-resident neural stem/progenitor cells (NSCs/NPCs), we used the in vitro neurosphere culture, where proliferating NSCs/NPCs were subjected to differentiation. Among several differentially expressed miRNAs, we observed an upregulation of miR-30 family miRNAs upon differentiation. To search for the gene targets of these miRNAs, we performed gene arrays followed by bioinformatics analysis, miRNA manipulations and luciferase assays. Our results suggest that miR-30 family miRNAs mediate chronic stress-induced depression-like phenotype by altering hippocampal neurogenesis and neuroplasticity via controlling the epigenetic and transcription regulators such as Mll3 and Runx1; and cell signaling regulators like Socs3, Ppp3r1, Gpr125, and Nrp1.

抑郁症是一种致残性精神疾病，具有较高的复发率，且对抗抑郁药物的响应率较低。由于对其病因病理学相关分子机制的认识尚不充分，新型抗抑郁药物的研发存在严重匮乏。慢性应激被认为是抑郁症最重要的潜在诱因之一。过去十年间的动物模型研究表明，表观遗传机制介导了慢性应激事件对抑郁症及其他共病神经精神疾病的发生发展与症状表现的负面影响。然而，作为表观遗传调控的另一重要层面，非编码RNA在抑郁症中的相关研究仍相对匮乏。本研究采用慢性社交挫败应激（chronic social defeat stress, CSDS）诱导的抑郁症模型，针对雄性C57BL/6小鼠的神经发生性齿状回（dentate gyrus, DG）区域，提出miRNA-mRNA网络失调的假说。通过miRNA芯片筛选鉴定出多个差异表达miRNA后，最显著的发现是：应激/挫败小鼠体内miR-30家族miRNA的表达显著下调。为探究齿状回驻留神经干细胞/祖细胞（neural stem/progenitor cells, NSCs/NPCs）中的miRNA表达情况，本研究采用体外神经球培养体系，对增殖状态的NSCs/NPCs进行分化诱导。在多个差异表达的miRNA中，我们观察到分化诱导后miR-30家族miRNA的表达显著上调。为探寻这些miRNA的靶基因，本研究开展了基因芯片检测，并辅以生物信息学分析、miRNA操控实验以及荧光素酶报告基因实验。本研究结果表明，miR-30家族miRNA可通过调控表观遗传及转录调控因子（如Mll3、Runx1）与细胞信号通路调控因子（如Socs3、Ppp3r1、Gpr125及Nrp1），进而改变海马神经发生与神经可塑性，最终介导慢性应激诱导的抑郁样表型。