Abstract
Major depression is a prevalent affective disorder characterized by recurrent low mood. It presumably results from stress-induced deteriorations of molecular networks and synaptic functions in brain reward circuits of genetically-susceptible individuals through epigenetic processes. Epigenetic regulator microRNA-15b inhibits neuronal progenitor proliferation and is up-regulated in the medial prefrontal cortex of mice that demonstrate depression-like behavior, indicating the contribution of microRNA-15 to major depression. Using a mouse model of major depression induced by chronic unpredictable mild stress (CUMS), here we examined the effects of microRNA-15b on synapses and synaptic proteins in the nucleus accumbens of these mice. The application of a microRNA-15b antagomir into the nucleus accumbens significantly reduced the incidence of CUMS-induced depression and reversed the attenuations of excitatory synapse and syntaxin-binding protein 3 (STXBP3A)/vesicle-associated protein 1 (VAMP1) expression. In contrast, the injection of a microRNA-15b analog into the nucleus accumbens induced depression-like behavior as well as attenuated excitatory synapses and STXBP3A/VAMP1 expression similar to the down-regulation of these processes induced by the CUMS. We conclude that microRNA-15b-5p may play a critical role in chronic stress-induced depression by decreasing synaptic proteins, innervations, and activities in the nucleus accumbens. We propose that the treatment of anti-microRNA-15b-5p may convert stress-induced depression into resilience.
Highlights
Major depression is a prevalent affective disorder characterized by recurrent low mood
Their mood state was assessed by the sucrose preference test (SPT), Y-maze test (YMT), and forced swimming test (FST)
In terms of the initiative factor from the chronic unpredictable mild stress (CUMS) to these molecular and cellular changes in the nucleus accumbens, our study shows that the up-regulation of microRNA-15b-5p induces depression-like behavior, and the down-regulation of microRNA-15b-5p significantly rescues CUMS-induced depression by influencing these cellular and molecular changes in relevance to GABAergic neurons in the nucleus accumbens
Summary
After a week’s accommodation, two groups of mice were placed into the control house and the house with CUMS for 3 weeks, respectively. The expression of VAMP1 decreases from 100 Ϯ 8.22% in control mice (open symbols in Fig. 9D; n ϭ 6) to 28.65 Ϯ 5.73% in the CUMS-induced depression mice (red symbols, n ϭ 6), which is reversed to 63.43 Ϯ 8.48% in microRNA15b-5p antagomir-injection plus CUMS-treated mice (blue symbols; n ϭ 6, p Ͻ 0.05, one-way ANOVA). The expression of STXBP3A changes from 100.0 Ϯ 4.81% in control mice (open symbols in Fig. 9E; n ϭ 6) to 52.7 Ϯ 8% in the CUMS-induced depression mice (red symbols, n ϭ 6), which is reversed to 88.12 Ϯ 6.3% in microRNA-15b-5p antagomir-injection plus CUMS-treated mice (blue symbols; n ϭ 6, p Ͻ 0.05, one-way ANOVA). MicroRNA-15b-5p sufficiently suppresses the expression of genes and proteins (VAMP1 and STXBP3A) similar to that in the CUMS-induced depression
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