MicroRNA And MRNA Profiles In Nucleus Accumbens Underlying Depression Versus Resilience In Response To Chronic Stress

Background: Major depression in negative mood is presumably induced by chronic stress with lack of reward.Yet,numerous individuals who are subjected to chronic stress demonstrate resilience.Molecular mechanisms underlying stress-induced depression versus resilience remain unknown,which are investigated in brain reward circuits.This topic is to explore the changes in the mRNA and miRNA expression profiles of depression-like and resilience mice in the specific brain area of the nucleus accumbens,and then construct the miRNA/mRNA regulatory network.By regulatory network to analyze the epigenetic mechanism under neuronal cell structure and functional pathological changes.Methods: First,mice were treated by chronic unpredictable mild stress(CUMS)for four weeks.The tests of sucrose preference,Y-maze and forced swimming were applied to identify depression-like emotional behavior or resilience.Second,RNA purification and RNA sequencing from the nucleus accumbens in groups of CUMS-depression,CUMS-resilience and control.Third,high-throughput sequencing was used to analyze mRNA and miRNA quantity in the nucleus accumbens(NAc)harvested from control,CUMS-induced depression(CUMS-depression)and CUMS-resistance mice to identify molecular profiles of CUMS-depression versus CUMS-resilience.Fourth,The differentially expressed genes(DEGs)were screened based on NOIseq package method that affected DEGs between two groups with the biological replicates,such as control versus CUMS-induced major depressive disorder(CUMS-depression),control versus CUMS-resilience,the threshold used to identify DEGs was fold-change larger than 1.5.Fifth,from the Kyoto Encyclopedia of Genes and the Genomes(KEGG)database were used in these enrichment analyses in DEGs association with physiological or biochemical processes were conducted.Sixth,then their predicted target mRNAs match the measures by miRNA sequencing based on the databases(RNAhybrid,Targetscan and miRanda)about complex interactions between miRNAs and mRNAs.Finally,qRT-PCR and dual luciferase reporter assay were used to validate the results of the high-throughput sequencing.Results: The downregulation of serotonergic/dopaminergic synapses,MAPK/calcium signalingpathways and morphine addiction as well as the upregulation of cAMP/PI3K-Akt signaling pathways and amino acid metabolism are associated with CUMS-depression.The downregulation of chemokine signaling pathway,synaptic vesicle cycle and nicotine addiction as well as the upregulation of calcium signaling pathway and tyrosine metabolism are associated with CUMS-resilience.It is noteworthy that some of the differentially expressed miRNA only exist in the CUMS-depression group,such as miR142a-3p,mmu-miR-98-3p,miR-935,miR873-5p and so on.Certain mi RNAs reversely express in CUMS-depression mice versus CUMS-resilience mice,such as let-7c-2-3p,miR-199a-3p,miR-199b-3p,miR-202-5p,miR-224-5p,miR-3074-5p,miR-3105-5p,miR-34b-3p,miR-34b-5p,miR-669c-5p,miR-7019-3p,mi R-466c-3p and miR-551b-3p.Conclusions: Impairments of serotonergic/dopaminergic synapses and PI3K-Akt/MAPK signaling pathways in the NAc are associated to depression.The upregulation of these entities is associated with resilience.miRNA analysis shows that some of the differentially expressed mi RNAs may influence mice in the CUMS to be either depression or resilience.Finally,Consistent results from analyzing mRNA/miRNA and using different methods validate our finding and conclusion.