BACKGROUND Nucleus Accumbens (NAc) is a vital brain region for the process of reward and stress, whereas microRNA plays a crucial role in depression pathology. However, the abnormality of NAc miRNA expression during the stress-induced depression and antidepressant treatment, as well as its biological significance, are still unknown. METHODS We performed the small RNA-sequencing in NAc of rats from three groups: control, chronic unpredictable mild stress (CUMS), and CUMS with an antidepressant, Escitalopram. We applied an integrative pipeline for analyzing the miRNA expression alternation in different model groups, including differential expression analysis, co-expression analysis, as well as a subsequent pathway/network analysis to discover both miRNA alteration pattern and its biological significance. RESULT A total of 423 miRNAs were included in analysis.18/8 differential expressing (DE) miRNA (adjusted p < 0.05, |log2FC| > 1) were observed in controls Vs. depression/depression Vs. treatment, 2 of which are overlapping. 78% (14/18) of these miRNAs showed opposite trends of alteration in stress and treatment. Two micro RNA, miR-10b-5p and miR-214-3p, appeared to be hubs in the regulation networks and also among the top findings in both differential analyses. Using co-expression analysis, we found a functional module that strongly correlated with stress (R = 0.96, P = 0.003), and another functional module with a moderate correlation with anhedonia (R = 0.89, P = 0.02). We also found that predicted targets of these miRNAs were significantly enriched in the Ras signaling pathway, which is associated with both depression, anhedonia, and antidepressant treatment. CONCLUSION Escitalopram treatment can significantly reverse NAc miRNA abnormality induced by chronic stress. However, the novel miRNA alteration that is absent in stress pathology also emerges, which means that antidepressant treatment is unlikely to bring miRNA expression back to the same level as the controls. Also, the Ras-signaling pathway may be involved in explaining the depression disease etiology, the clinical symptom, and treatment response of stress-induced depression.

中文翻译：

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伏隔核中microRNA的表达改变与大鼠慢性应激和抗抑郁药治疗有关。

背景技术伏隔核（NAc）是奖励和压力过程中至关重要的大脑区域，而微小RNA在抑郁症病理中起着至关重要的作用。然而，在应激诱导的抑郁和抗抑郁治疗过程中，NAc miRNA表达的异常及其生物学意义仍然未知。方法我们在三组大鼠的NAc中进行了小RNA测序：对照组，慢性不可预测的轻度应激（CUMS）和含抗抑郁药Escitalopram的CUMS。我们应用了整合的流水线来分析不同模型组中的miRNA表达变化，包括差异表达分析，共表达分析以及随后的途径/网络分析，以发现miRNA改变模式及其生物学意义。结果分析中总共包含423个miRNA。在对照Vs中观察到18/8差异表达（DE）miRNA（调整后的p <0.05，| log2FC |> 1）。沮丧/沮丧 治疗，其中2个是重叠的。这些miRNA中有78％（14/18）在压力和治疗方面显示出相反的变化趋势。两种微RNA，即miR-10b-5p和miR-214-3p，似乎是调控网络中的枢纽，也​​是两种差异分析中的主要发现之一。使用共表达分析，我们发现了一个与压力密切相关的功能模块（R = 0.96，P = 0.003），以及另一个与快感低下程度相关的功能模块（R = 0.89，P = 0.02）。我们还发现，这些miRNA的预测靶标在Ras信号通路中显着富集，这与抑郁症，快感缺乏症，和抗抑郁药治疗。结论艾司西酞普兰治疗可显着逆转慢性应激引起的NAc miRNA异常。但是，也出现了在压力病理学中不存在的新颖的miRNA改变，这意味着抗抑郁药治疗不太可能使miRNA的表达回到与对照相同的水平。同样，Ras信号通路可能与解释抑郁症的病因，临床症状以及应激性抑郁症的治疗反应有关。