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

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.

The miRNome of Depression

“…In rodents, acute stress induced an increased expression of miR-34c-5p in the amygdala [ 59 ]. Chronic stress, in turn, was associated with the upregulation of miR-34c-5p in the nucleus accumbens [ 60 ] and the amygdala [ 59 ], while experiencing early life stress caused the aforementioned changes in the hippocampus, prefrontal cortex, and amygdala [ 61 ]. It has been observed that blood-derived exosomes collected from MDD patients had the potential to evoke depressive-like symptoms in mice [ 62 ].…”

Chronic Stress-Induced Gene Changes In Vitro and In Vivo: Potential Biomarkers Associated With Depression and Cancer Based on circRNA- and lncRNA-Associated ceRNA Networks

“…GO and KEGG pathway analyses of the DEGs in ceRNA network also involved in several pathways associated with cancer, such as RAS, Wnt, MAPK, and PI3K-AKT signaling pathways. Some of these pathways are playing important roles in both depression and cancer, such as RAS signaling pathway ( 31 , 37 ) and IL-17 signaling pathway ( 32 , 38 ). So, we performed stress-induced cancer progression in vivo and in vitro experiments to investigate the mRNA expression involved in the pathways.…”

“…KEGG enrichment revealed that the important signaling pathways such as hippo, MAPK, Wnt, PI3K/Akt, cGMP-PKG, RAS, and IL-17. All of these pathways are involved in the regulation of hippocampal function or pathological processes associated with depression (27)(28)(29)(30)(31)(32), indicating the pivotal roles of DE RNAs in depression pathogenesis. Further studies are needed to demonstrate the intricate functions of these DE RNAs.…”

Early-life stress induces genome-wide sex-dependent miRNA expression and correlation across limbic brain areas in rats

“…Other reports of these miRNAs in stress and antidepressant treatment further corroborate our findings. Fang et al found decreased miR-200b-5p and miR-34c-3p expression in stressed animals treated with fluoxetine, and Song et al found increased nucleus accumbens miR-34c-5p in stressed rats compared with controls [ 48 , 49 ]. Additionally, we found that miR-20b-5p, miR-34, miR-200b-3p and miR-203a-3p acted as hub miRNAs and shared the gene target, VEGFA .…”