Abstract
Mitochondrial dysfunction was highlighted as a crucial vulnerability factor for the development of depression. However, systemic studies assessing stress-induced changes in mitochondria-associated genes in brain regions relevant to depression symptomatology remain scarce. Here, we performed a genome-wide transcriptomic study to examine mitochondrial gene expression in the prefrontal cortex (PFC) and nucleus accumbens (NAc) of mice exposed to multimodal chronic restraint stress. We identified mitochondria-associated gene pathways as most prominently affected in the PFC and with lesser significance in the NAc. A more detailed mitochondrial gene expression analysis revealed that in particular mitochondrial DNA-encoded subunits of the oxidative phosphorylation complexes were altered in the PFC. The comparison of our data with a reanalyzed transcriptome data set of chronic variable stress mice and major depression disorder subjects showed that the changes in mitochondrial DNA-encoded genes are a feature generalizing to other chronic stress-protocols as well and might have translational relevance. Finally, we provide evidence for changes in mitochondrial outputs in the PFC following chronic stress that are indicative of mitochondrial dysfunction. Collectively, our work reinforces the idea that changes in mitochondrial gene expression are key players in the prefrontal adaptations observed in individuals with high behavioral susceptibility and resilience to chronic stress.
Highlights
Mitochondrial dysfunction was highlighted as a crucial vulnerability factor for the development of depression
As compared to CTRs, mice exposed to multimodal chronic restraint stress (mCRS) showed: (1) decreased sociability, as indicated by their reduced time spent in the social interaction zone and increased social avoidance score (Fig. 1E); (2) increased immobility in the forced swim test (FST) (Fig. 1F); and (3) unaltered saccharin preference (Fig. 1G)
We revealed that mitochondrial DNA (mtDNA) genes coding for different subunits of the oxidative phosphorylation (OXPHOS) complexes in the prefrontal cortex (PFC) as affected by stress, and showed that their upregulation is observed in stress-vulnerable mice
Summary
Mitochondrial dysfunction was highlighted as a crucial vulnerability factor for the development of depression. Despite extensive clinical and preclinical research efforts carried out to date (e.g.,6–12), there is still a lack of understanding about the specific biological changes that link chronic stress with depressive symptoms Brain regions, such as the prefrontal cortex (PFC) and the nucleus accumbens (NAc) that are implicated in depression pathogenesis[11,13,14,15,16] show high susceptibility to display structural and functional alterations under exposure to chronic s tress[12,17,18,19]. We provide evidence that the here defined mitochondrial gene expression signature reflects the mice behavioral profiles and their susceptibility to chronic stress
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