Early-life stress alters postnatal chromatin development in the nucleus accumbens

Abstract

Early-life stress sensitizes individuals to subsequent stressors to increase lifetime risk for psychiatric disorders. Within the nucleus accumbens (NAc) — a key limbic brain region — early-life stress sensitizes both cellular and transcriptional response to later stress. However, the molecular mechanisms linking initial activation of neurons by early-life stress with continued stress sensitivity across the lifespan are poorly understood. Using a combination of activity-dependent cellular tagging and ATAC-sequencing across postnatal development, we find that early-life stress initially opens chromatin in stress-activated cells and that chromatin opening predicts gene expression response to adult stress, suggesting epigenetic priming as a mechanism of stress sensitization. Moreover, early-life stress accelerates both chromatin development within these activated cells, and H3K4me1 deposition broadly in NAc — a post-translational histone modification associated with open chromatin and epigenetic priming. By adulthood, we observed chromatin remodeling throughout the NAc, indicating that the effects of stress are long-lasting and propagate across development into the broader cell population. Lastly, through viral-mediated epigenome editing and behavioral quantification, we find that deposition of H3K4me1 in NAc during early postnatal development is sufficient to mimic early-life stress and prime hypersensitivity to subsequent stress. Together, our results show that a molecular memory of early-life stress is encoded at an epigenetic level through changes in chromatin architecture. This constitutes a novel biological mechanism by which early-life stress programs lifelong stress sensitivity.