Intersectional Analysis Of Chronic Mild Stress-induced LncRNA-mRNA Interaction Networks In Rat Hippocampus Reveals Potential Anti-depression/anxiety Drug Targets

BackgroundChronic stress is considered to be an important risk factor of depression and anxiety,but the specific common and unique molecular mechanisms are still unclear.Previous studies have shown that long non-coding RNA(lncRNA)is closely associated with a variety of neuropsychiatric diseases at the epigenetic level,suggesting that lncRNA plays an important role in depression and anxiety disorders,and can be used as a potential drug target and provide new clues for drug research and development.Methods(1)Chronic mild stress(CMS)model was used to distinguish and obtain three groups: depression-susceptible,anxietysusceptible and insusceptible.(2)The expression profiles of lncRNA and messenger RNA(mRNA)in rat hippocampus were analyzed by microarray technique.(3)Gene differences and the expression changes of specific lncRNAs and mRNAs related to the behavioral phenotype of stressed rats.(4)The correlation between differentially expressed lncRNAs and mRNAs was analyzed using weighted correlation network analysis(WGCNA)and competing endogenous RNA(ceRNA)theory-based methods.(5)The biological function of dysregulated lncRNAs was predicted by analyzing the function of correlated mRNAs.(6)Some core lncRNAs were excavated to be used as potential targets of antidepression/anxiety drugs through intersectional analysis of phenotype-associated and drug-associated lncRNA-mRNA networks and subnetworks.Results(1)The results of microarray showed that 454 lncRNAs and 420 mRNAs were up-regulated,94 lncRNAs and 394 mRNAs were down-regulated in depression-susceptible group;1051 lncRNAs and 945 mRNAs were up-regulated,570 lncRNAs and 1463 mRNAs were down-regulated in anxiety-susceptible group;848 lncRNAs and 991 mRNAs were up-regulated,473 lncRNAs and 1304 mRNAs were down-regulated in insusceptible group.(2)The results of correlation analysis showed that 319 lncRNAs were highly correlated with 306 mRNAs in depression-susceptible group,791 lncRNAs were highly correlated with 1142 mRNAs in anxiety-susceptible group and 638 lncRNAs were highly correlated with 1069 mRNAs in insusceptible group.(3)The results of enrichment analysis based on gene ontology(GO)and Kyoto encyclopedia of genes and genomes(KEGG)showed that mRNAs correlated with differentially expressed lncRNAs were significantly enriched in metabolism dysfunctions in the depressionsusceptible group,signaling and secretion dysregulations in anxietysusceptible group,and signaling and synapse aberrations in insusceptible group.(4)The results of network analysis showed that 16 core lncRNAs related to both drug and behavior phenotype were obtained through integrated analysis of drug-associated and phenotype-associated lncRNA-mRNA networks and subnetworks.ConclusionIn summary,the current study lays a molecular foundation for understanding the potential pathophysiological mechanisms of stress-induced depression or anxiety and stress resilience,and reveals some important lncRNAs that may be new drug targets for depression and anxiety disorders.