Molecular Mechanism for Stress-Induced Depression Assessed by Sequencing miRNA and mRNA in Medial Prefrontal Cortex

Abstract

Background: Major depression is a prevalent mood disorder. Chronic stress is presumably main etiology that leads to the neuron and synapse atrophies in the limbic system. However, the intermediate molecules from stresses to neuronal atrophy remain elusive, which we have studied in the medial prefrontal cortices from depression mice.

Methods and results: The mice were treated by the chronic unpredictable mild stress (CUMS) until they expressed depression-like behaviors confirmed by the tests of sucrose preference, forced swimming and Y-maze. High-throughput sequencings of microRNA and mRNA in the medial prefrontal cortices were performed in CUMS-induced depression mice versus control mice to demonstrate the molecular profiles of major depression. In the medial prefrontal cortices of depression-like mice, the levels of mRNAs that translated the proteins for the GABAergic synapses, dopaminergic synapses, myelination, synaptic vesicle cycle and neuronal growth were downregulated. miRNAs of regulating these mRNAs are upregulated.

Conclusion: The deteriorations of GABAergic and dopaminergic synapses as well as axonal growth are associated with CUMS-induced depression.

Fig 1. Chronic unpredictable mild stress (CUMS) leads the mice to express depression-like behaviors.

Mice were subjected to the adaptation for a week, the CUMS for three weeks and the behavioral tests in three days. Behavior tests showed the significant decreases in sucrose preference (a) and the ratios of stay time in M-arm to stay time in three arms (b) as well as the increase in immobile time (c) from CUMS-induced depression mice (n = 10) and controls (n = 11). The results are expressed as mean ± SEM. *p<0.05, **p<0.01, ***p<0.001.

Fig 2. MicroRNA-mRNA network.

microRNA/mRNA networks were constructed between the fifteen upregulated miRNAs and 150 overlapped mRNAs with using transcriptome expression data and predicted target genes from Targetscan, PITA, RNA22 and miRDB databases. Blue symbols present the elevated expression of miRNA in CUMS-induced depression mice. Red symbols present the downregulated genes that are miRNA-predicted and -targeted in CUMS-induced depression mice. Gray symbols show mRNAs that are slightly downregulated. Their negative relationship was represented by the green bars.