Early life experiences, the neural epigenome and affective disorder risk

Abstract

Early life stress shapes brain development during sensitive developmental windows through persistent epigenomic changes that influence gene regulation, neural circuit maturation and susceptibility to neuropsychiatric disorders. Evidence from animal models and human studies demonstrates that early adversity remodels DNA methylation, histone post-translational modifications and chromatin organization, leading to lasting alterations in transcriptional programmes. These responses are highly cell-type specific, brain-region specific and developmental-stage specific, with neurons and glia exhibiting distinct molecular adaptations that contribute to behavioural outcomes. Emerging evidence also implicates non-coding RNAs as important regulators of stress-induced gene expression, although their long-term roles remain less well defined than those of other epigenetic mechanisms. Peripheral epigenetic signatures associated with early life stress may provide accessible biomarkers of exposure and disease risk. Integrating epigenomic, transcriptomic, circuit-level and behavioural approaches will be essential for understanding biological embedding and identifying mechanisms that promote resilience and improve therapeutic interventions. Understanding how early life stress becomes biologically embedded remains a major challenge in neuroscience. In this Review, Maze and colleagues discuss recent advances in cell-type-specific epigenetic and transcriptional mechanisms underlying long-term stress susceptibility.