Neuropsychiatric Disease and Treatment (Mar 2019)
Identification of key genes, pathways and miRNA/mRNA regulatory networks of CUMS-induced depression in nucleus accumbens by integrated bioinformatics analysis
Abstract
Ke Ma,1 Hongxiu Zhang,2 Guohui Wei,1 Zhenfei Dong,1 Haijun Zhao,1 Xiaochun Han,1 Xiaobin Song,1 Huiling Zhang,1 Xin Zong,1 Zulqarnain Baloch,3 Shijun Wang1 1Shandong Co-Innovation Center of Classic TCM formula, Shandong University of Traditional Chinese Medicine, Jinan, Shandong 250355, People’s Republic of China; 2Institute of Virology, Jinan Center for Disease Control and Prevention, Jinan 250021, People’s Republic of China; 3College of Veterinary Medicine, South China Agricultural University, Guangzhou 510642, People’s Republic of China Introduction: Major depressive disorder (MDD) is a recurrent, devastating mental disorder, which affects >350 million people worldwide, and exerts substantial public health and financial costs to society. Thus, there is a significant need to discover innovative therapeutics to treat depression efficiently. Stress-induced dysfunction in the subtype of neuronal cells and the change of synaptic plasticity and structural plasticity of nucleus accumbens (NAc) are implicated in depression symptomology. However, the molecular and epigenetic mechanisms and stresses to the NAc pathological changes in depression remain elusive. Materials and methods: In this study, treatment group mice were treated continually with the chronic unpredictable mild stress (CUMS) until expression of depression-like behaviors were found. Depression was confirmed with sucrose preference, novelty-suppressed feeding, forced swimming, and tail suspension tests. We applied high-throughput RNA sequencing to assess microRNA expression and transcriptional profiles in the NAc tissue from depression-like behaviors mice and control mice. The regulatory network of miRNAs/mRNAs was constructed based on the high-throughput RNA sequence and bioinformatics software predictions. Results: A total of 17 miRNAs and 10 mRNAs were significantly upregulated in the NAc of CUMS-induced mice with depression-like behaviors, and 12 miRNAs and 29 mRNAs were downregulated. A series of bioinformatics analyses showed that these altered miRNAs predicted target mRNA and differentially expressed mRNAs were significantly enriched in the MAPK signaling pathway, GABAergic synapse, dopaminergic synapse, cytokine–cytokine receptor interaction, axon guidance, regulation of autophagy, and so on. Furthermore, dual luciferase report assay and qRT-PCR results validated the miRNA/mRNA regulatory network. Conclusion: The deteriorations of GABAergic synapses, dopaminergic synapses, neurotransmitter synthesis, as well as autophagy-associated apoptotic pathway are associated with the molecular pathological mechanism of CUMS-induced depression. Keywords: stress, depression, nucleus accumbens, miRNA, mRNA
