Expression alteration of microRNAs in Nucleus Accumbens is associated with chronic stress and antidepressant treatment in rats

Weichen Song,Ran Zhang,Shunying Yu,Sufang Peng,Xia Li,Ailing Ning,Huafang Li,Yanhua Zhang,Yifeng Shen,Guan Ning Lin

doi:10.1186/s12911-019-0964-z

Abstract

BackgroundNucleus 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.MethodsWe 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.ResultA 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.ConclusionEscitalopram 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.

Highlights

Nucleus Accumbens (NAc) is a vital brain region for the process of reward and stress, whereas microRNA plays a crucial role in depression pathology
Escitalopram treatment can significantly reverse NAc miRNA abnormality induced by chronic stress
The novel miRNA alteration that is absent in stress pathology emerges, which means that antidepressant treatment is unlikely to bring miRNA expression back to the same level as the controls

Summary

Introduction

Nucleus Accumbens (NAc) is a vital brain region for the process of reward and stress, whereas microRNA plays a crucial role in depression pathology. The abnormality of NAc miRNA expression during the stress-induced depression and antidepressant treatment, as well as its biological significance, are still unknown. It has been discovered that chronic stress is associated with a disturbance in cognition, and daily function of MDD patients, and plays a vital role in the pathology of depression [4]. Research suggests that the miRNA expression pattern may serve as a biomarker for diagnosis of depression [9] or response of antidepressant [10, 11]. To achieve these goals, a comprehensive understanding of the impacts of depression/antidepressant on miRNA expression is required

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Conclusion