Transthyretin orchestrates vitamin B12-induced stress resilience

Abstract

AbstractChronic stress significantly contributes to mood- and anxiety disorders. Previous and current data suggest a correlative connection between vitamin B12 supplementation, depression, and stress resilience. However, the underlying mechanisms are still poorly understood. This study reveals a molecular pathway that functionally connects vitamin B12, DNA methylation (DNAme), and stress resilience. We identified Transthyretin (Ttr) as a sex-specific key target of vitamin B12 action in chronic stress. Accordingly,TTRexpression was increased postmortem in the prefrontal cortex of male, but not female, depressed patients. Virally alteredTtrin 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 theTtrpromoter region. Importantly, usingin vivoepigenome editing to alter DNAme in the brains of living mice for the first time, we establish a direct causal link between DNAme onTtrand stress-associated behaviors. In summary, using state-of-the-art techniques, this study uncovers a mechanistic link between cobalamin supplementation and markers of chronic stress and depression, encouraging further studies into environmental interventions for mood disorders.