Epitranscriptome of the ventral tegmental area in a deep brain-stimulated chronic unpredictable mild stress mouse model

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 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.

Mechanism of METTL3‐mediated m6A modification in depression‐induced cognitive deficits

“…The behavior tests indicated that CUMS rats were presented with weakened sucrose preference, prolonged immobility time and escape latency, reduced traveling distance, shortened time to explore new objects and enter the open arms, and decreased time in the target quadrant and crossing‐platform number, indicating cognitive deficits in CUMS rats. Previous study has demonstrated that CUMS elevates m6A modification level in the DD mouse model and the abolishment of m6A modification promotes the antidepressant activity (Song, Du, Gao, & Yang, 2020; Wu et al, 2021). Accordingly, METTL3 along with m6A level was found to be increased in CUMS rats, in line with METTL3 upregulation in AD‐related cognitive deficits (Han et al, 2020; Mathoux et al, 2021).…”

Running from Stress: Neurobiological Mechanisms of Exercise-Induced Stress Resilience

“…Moreover, the deficiency of Mettl3 and Fto indicates the role of m6A/m regulatory genes in stress resilience [ 137 ]. m6A-mRNA methylation in the VTA increases in response to CUMS in comparison to unstressed animals [ 138 ]. Yan et al (2022) showed that treadmill exercise in RNA m6A homeostasis in the PFC plays a role by improving the resilience against CRS for one hour for 14 days [ 139 ].…”

Epigenetic regulation in major depression and other stress-related disorders: molecular mechanisms, clinical relevance and therapeutic potential

“… 374 Another study showed that NAc-deep brain stimulation (DBS) could reverse the impacts of CUMS on gene expression and m 6 A-mRNA modification for certain genes, but the m 6 A-regulating enzymes were not detected. 375 …”