Genome-Wide miRNA Expression Alterations in Nucleus Accumbens Provide Insights into Chronic Stress and Treatment in Depression

Nucleus Accumbens (NAc) is a key area for reward and response to stress, and microRNA plays a critical role in depression. However, the miRNA expression alteration in NAc during the stress-induced depression and antidepressant treatment, as well as its biological significance, remains mostly unexplored. We randomly selected 24 rats to control, chronic unpredictable mild stress (CUMS) and CUMS+Escitalopram treatment group (8 each). Nucleus Accumbens of rats from 3 groups were microRNA-sequenced. We applied differential expression analysis and co-expression analyses on expression data. After target gene prediction by Targetscan, network and pathway analysis were also performed. 18/8 differential expressing (DE) miRNA (FDR <0.05, log2FC >1 or <−1) are observed in control VS case/ case VS treatment comparison,2 of them are overlapping. We observed a negative correlation between log2FC(control vs. case) and log2FC (case vs. treatment). Weighted co-expression analysis discovered a module (M1) with a strong positive correlation with stress (R=0.96, P=0.003), and another module(M7) with a positive correlation with anhedonia (R=0.89, P=0.02). In miRNA-mRNA networks of M1, TFRC had most neighbors. Strikingly, pathway analysis of Kyoto encyclopedia of genes and genomes (KEGG) reveals enrichment in Ras signaling pathway of predicted target genes of miRNAs associated with both depression, treatment and anhedonia. indicating its potential involvement in depression. Conclusion: Escitalopram treatment can significantly reverse both behavioral and NAc miRNA abnormality caused by chronic stress. TFRC were strongly regulated in stress and/or antidepressant treatment. The Ras-signaling pathway may influence both onset, symptom and treatment response of stress-induced depression.