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 N⁶-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.

中文翻译：

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大脑深部刺激的慢性不可预测的轻度应激小鼠模型中腹侧被盖区的转录组

应用于伏隔核（NAc）的深部脑刺激（DBS）可以缓解主要抑郁症的抑郁症状。我们通过评估慢性不可预测的轻度抑郁症（CUMS）小鼠模型中NAc-DBS后腹侧被盖区（VTA）的基因表达和RNA甲基化变化来研究这种作用的机制。测量了接受CUMS，然后接受DBS和整个转录组的m ⁶小鼠的VTA中的基因表达和N ^6-甲基腺苷（m ⁶ A）水平在进行基因本体分析之前，使用免疫沉淀的甲基化RNA和微阵列分析变化。与NAc-DBS相比，VTA中与神经递质受体，转运蛋白，转录因子，神经元活性，突触功能以及有丝分裂原激活的蛋白激酶和多巴胺信号传导相关的基因的表达水平上调。此外，m ⁶ A修饰包括甲基化和甲基化不足，并且变化与某些基因的上调正相关。此外，某些基因的DBS逆转了CUMS对基因表达和m ⁶ A-mRNA修饰的影响。有趣的是，虽然某些基因的表达没有被DBS改变，但长期刺激确实改变了它们的m ⁶修改。NAc-DBS诱导的修饰很大程度上与CUMS小鼠中基因的上调相关，但有时与基因下调相关。我们的发现改善了对DBS抑制抑郁的分子机制的当前理解。