| Summary: | Rationale/statement of the problem : Childhood maltreatment negatively impacts brain development, often producing transgenerational continuity of abusive parenting and increased risk for a range of psychiatric disorders. The biological basis for these far-reaching effects is not currently understood, but evidence suggests traumatic events could affect behavioral trajectories through changes in gene expression that are mediated by DNA methylation. Methods : To explore this, we exposed male and female infant rats to nurturing or adverse caregiving environments. We measured changes in DNA methylation and gene expression in developing and adult animals. Candidate genes were selected according to their role in brain plasticity, responsiveness to stress, and association with several psychiatric disorders. Results : Exposure to adverse caregiving environments induced long-lasting changes in cortical DNA methylation and expression of the brain-derived neurotrophic factor (BDNF) gene. In addition, females exposed to adverse caregiving environments later mistreated their own offspring, and their offspring likewise displayed altered DNA methylation. We are currently investigating the impact of nurturing vs. adverse caregiving environments on epigenetic gene regulation within a larger behaviorally relevant brain network (the medial prefrontal cortex, central/basolateral amygdala, dorsal vs. ventral hippocampus). Preliminary biochemistry data indicate caregiving experiences trigger epigenetic changes that differ between brain regions, sexes, and gene locus. Conclusions : These findings demonstrate the remarkable ability of early-life caregiving environments to produce distinct epigenetic modifications across behaviorally relevant brain regions. Our work as well as that of others suggests that DNA methylation serves as a biological pathway linking early-life adversity to long-term (and perhaps multigenerational) changes in neurobiology and behavior.
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