The Neuroepitranscriptomics of Stress: Exploring Global m6A RNA Modifications in the Brains of Mice Exposed to Early Life Stress

Abstract

Early life stress (ELS) is associated with mental health disorders that develop later on in adulthood. Mental health disorders, such as major depressive disorder (MDD) and general anxiety disorder (GAD), affect millions of people worldwide and can potentially give rise to more complicated health issues. A commonly proposed explanation for this has been stress sensitization, whereby ELS primes the adult brain to be either more susceptible or resilient to stress exposure in adulthood. While epigenetic mechanisms previously have been implicated in governing long-lasting changes in the brain, the exact molecular mechanisms mediating ELS to sensitization to stress in adulthood are not fully understood. As N6-Methyladenosine (m6A) is the most abundant RNA modification found on mRNA transcripts and has been shown to play a role in post-transcriptional regulation – including RNA splicing, nuclear export, degradation, and stability – this research investigates the role of m6A RNA modifications in the brain's response to stress as a possible molecular mediator of ELS-induced sensitivity to stress in adulthood. This study examines the effects of ELS exposure and adult stress (AS) exposure on altering global m6A levels in brain regions involved in the brain’s stress response pathway. Briefly, I observed regional differences in the levels of global m6A between the prefrontal cortex, anterior cingulate cortex, basolateral amygdala, ventral tegmental area, nucleus accumbens, and the ventral hippocampus. Further, I provide evidence suggesting ELS primes the adult brain to be more sensitive to AS, as the gene expression of m6A writers (enzymes that deposit m6A) and erasers (enzymes that remove m6A) was found to be dysregulated across all brain regions. By elucidating the molecular mechanisms underlying m6A-mediated gene regulation in response to stress, this research contributes to a better understanding of stress vulnerability and the development of psychiatric disorders such as depression and anxiety.