Expression Profile Of Transcription And MicroRNA In Ventral Tegmental Area Of Chronic Stress Depression And Resilience Mice

Objective:Depression is one of the most common mental disorders in human beings,which is characterized by significant and persistent depression of mood.The main clinical manifestations were lack of pleasure,low mood and low self-evaluation and even suicide.Chronic stress with long-term lack of reward may deteriorate the reward circuit of the brain,resulting in depression;however,many individuals in chronic stress may not suffer from major depression,implying the presence of endogenous anti-depression in the brain.Therefore,we mainly study the molecular mechanism of microRNA(miRNA)and mRNA expression profile in ventral tegmental area(VTA)for stress-induced depression versus resilience.Methods: Mice were treated by chronic unpredictable mild stress(CUMS)for four weeks.Their mood states were tested by Y-maze,sucrose preference and forced swimming testes.MiRNA and microRNA profiles were quantified by high-throughput sequencing in the ventral tegmental area(VTA)harvested from mice of control and CUMS-induced depression(CUMS-Depression),control and CUMS resistance(CUMS-Resilience)to reveal comprehensive molecular profiles of major depression and resilience.Finally,quantitative RT-PCR and dual luciferase reporter assay were used to verify the sequencing results.Results: Major depression and resilience mice were produced by chronic unpredictable mild stress(CUMS)treatment;By comparing the sequencing data of the control,depression and resilience group,the mRNA and miRNA differentially expressed in the control and depression group,control and resilience group were screened by using the gene with the difference multiple of more than 1.5 times as a standard;The downregulation of neurotrophin,synaptic vesicle cycle,GABAergic synapse and morphine addiction as well as the upregulation of calcium signal,cAMP-dependent response element binding and transmitter release are associated to CUMS-Depression.The downregulation of tyrosine metabolism and protein process in endoplasmic reticulum as well as the upregulation of amino acid biosynthesis,neuroactive ligand-receptor interaction and dopaminergic synapse are associated with CUMS-Resilience.The miRNA/mRNA interaction regulation network map were drawn by Targetscan,RNA22,miRDB database in VTA of control and CUMS-Depression,control and CUMS-Resilience.A part of miRNA and mRNA differentially expression was selected for quantitative RT-PCR,which further proved the accuracy of the sequencing results(p<0.05),dual luciferase reporter assay suggest that Creb5 and Adrald mRNAs are the direct target of miR-574-3p.Conclusions: The downregulations of synaptic vesicle cycle and GABAergic synapses can impair synaptic transmission and neuronal synchronization in the VTA.Because the VTA is thought as an origin of dopamine,major neurotransmitter for positive emotion from reward,the impaired neuronal and synaptic activities in the VTA may lead to the negative mood of major depression.The upregulations of amino acid biosynthesis,dopaminergic synapse,neuroactive ligand-receptor interaction and renin-angiotensin system benefit the dopamine D3 receptor function for positive emotion,the transmitter synthesis and release to compensate a low synaptic vesicle cycling,and the ligand-receptor interaction to compensate synapse dysfunction,so that mice show resilience to the CUMS,instead of CUMS-induced depression.The impairment of neurons and GABA/dopaminergic synapses in the VTA is associated with major depression and the upregulation of these processes is associated with resilience.