Transthyretin Orchestrates Vitamin B12–Induced Stress Resilience

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BackgroundChronic stress significantly contributes to mood and anxiety disorders. Previous data suggest a correlative connection between vitamin B12 supplementation, depression, and stress resilience. However, the underlying mechanisms are still poorly understood. MethodsUsing the chronic variable stress mouse model coupled with RNA sequencing, we identified vitamin B12–induced transcriptional changes related to stress resilience. Using viral-mediated gene transfer and in vivo epigenome editing, we revealed a functional pathway linking vitamin B12, DNA methylation (DNAme), and depression-like symptoms. ResultsWe identified Ttr (transthyretin) as a key sex-specific target of vitamin B12 in chronic stress. Accordingly, TTR expression was increased postmortem in the prefrontal cortex of male but not female patients with depression. Virally altered Ttr in the prefrontal cortex functionally contributed to stress- and depression-related behaviors, changes in dendritic spine morphology, and gene expression. In stressed mice, vitamin B12 reduced DNAme in the Ttr promoter region. Importantly, using in vivo epigenome editing to alter DNAme in the brains of living mice for the first time, we established a direct causal link between DNAme and Ttr and stress-associated behaviors. ConclusionsUsing state-of-the-art techniques, this study uncovered a mechanistic link between vitamin B12 supplementation, Ttr, and markers of chronic stress and depression, encouraging further studies into dietary interventions for mood disorders.