Abstract
Deep brain stimulation (DBS) applied to the nucleus accumbens (NAc) alleviates the depressive symptoms of major depressive disorders. We investigated the mechanism of this effect by assessing gene expression and RNA methylation changes in the ventral tegmental area (VTA) following NAc-DBS in a chronic unpredictable mild stress (CUMS) mouse model of depression. Gene expression and N 6-methyladenosine (m6A) levels in the VTA were measured in mice subjected to CUMS and then DBS, and transcriptome-wide m6A changes were profiled using immunoprecipitated methylated RNAs with microarrays, prior to gene ontology analysis. The expression levels of genes linked to neurotransmitter receptors, transporters, transcription factors, neuronal activities, synaptic functions, and mitogen-activated protein kinase and dopamine signaling were upregulated in the VTA upon NAc-DBS. Furthermore, m6A modifications included both hypermethylation and hypomethylation, and changes were positively correlated with the upregulation of some genes. Moreover, the effects of CUMS on gene expression and m6A-mRNA modification were reversed by DBS for some genes. Interestingly, while the expression of certain genes was not changed by DBS, long-term stimulation did alter their m6A modifications. NAc-DBS-induced modifications are correlated largely with upregulation but sometimes downregulation of genes in CUMS mice. Our findings improve the current understanding of the molecular mechanisms underlying DBS effects on depression.
Highlights
Deep brain stimulation (DBS) involves the implantation of electrodes within specific brain regions that provide electrical stimulation to the brain in order to create a therapeutic effect [1]
Depressive symptoms in patients with treatment-resistant depression can be alleviated over a period of weeks by nucleus accumbens (NAc)-DBS at a high frequency (145 Hz) [4]; long-term treatment appears to be the important factor in significantly reducing the depressive symptoms of these patients [5,6,7]
Our results suggested that in the dopaminergic ventral tegmental area (VTA)/substantia nigra/caudate putamen/ NAc circuitry [37,38,39,40], genes such as Drd2, Drd4, Pde1b, Kcnj6, Syn1, Syn2, and Syn3 have been implicated in dopaminergic signaling [32], and some of these genes were affected by Chronic unpredictable mild stress (CUMS) at the gene expression level, with these effects being reversed by DBS (Supplementary Tables S1, S4, and S9)
Summary
Deep brain stimulation (DBS) involves the implantation of electrodes within specific brain regions that provide electrical stimulation to the brain in order to create a therapeutic effect [1]. In a depression mouse model, repeated high-frequency stimulation produces a robust antidepressant effect, whereas acute stimulation is ineffective [8]. These findings suggest that at least some of the behavioral changes induced by NAc-DBS may require changes in the brain that occur over longer periods, such as modulation of neuroplasticity [8]. MDD is an interesting candidate for the treatment with DBS because its pathology involves changes to the regulation of gene expression in various neuronal groups [10,11]. It is possible that the longterm use of DBS could correct the behavioral changes
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