Early-life adversity (ELA), often clinically referred to as “adverse childhood experiences (ACE),” is the exposure to stress-inducing events in childhood that can result in poor health outcomes. ELA negatively affects neurodevelopment in children and adolescents resulting in several behavioral deficits and increasing the risk of developing a myriad of neuropsychiatric disorders later in life. The neurobiological mechanisms by which ELA alters neurodevelopment in childhood have been the focus of numerous reviews. However, a comprehensive review of the mechanisms affecting adolescent neurodevelopment (i.e., synaptic pruning and myelination) is lacking. Synaptic pruning and myelination are glia-driven processes that are imperative for brain circuit refinement during the transition from adolescence to adulthood. Failure to optimize brain circuitry between key brain structures involved in learning and memory, such as the hippocampus and prefrontal cortex, leads to the emergence of maladaptive behaviors including increased anxiety or reduced executive function. As such, we review preclinical and clinical literature to explore the immediate and lasting effects of ELA on brain circuit development and refinement. Finally, we describe a number of therapeutic interventions best-suited to support adolescent neurodevelopment in children with a history of ELA.

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Exposure to adversity in early development has powerful and potentially lasting consequences on behavior. Previous work in our laboratory using female Long-Evans rats has demonstrated that exposure to early-life maltreatment manifests into alterations in dam behavior, including a perpetuation of the maltreatment phenotype.These observed behavioral changes coincide with changes in epigenetic activity in the prefrontal cortex (PFC). Further, treating dams with a chromatin modifying agent (Zebularine) normalizes methylation and maltreatment phenotypes, suggesting a link between epigenetic programming and phenotypic outcomes. Here, we sought to investigate if administration of a chromatin modifying agent concurrent with the experience of maltreatment normalizes epigenetic activity associated with maltreatment and alters behavioral trajectories. Administration of valproic acid (VPA) transiently lowered levels of global DNA methylation in the PFC, regardless of exposure to nurturing care or maltreatment. When VPA-exposed animals reached adulthood, they engaged in more adverse behaviors toward their offspring. These data provide further evidence linking epigenetic changes in the developing brain with effects on behavior.

Behavioral epigenetics posits that both nature and nurture must be considered when determining the etiology of behavior or disease. The epigenome displays a remarkable ability to respond to environmental input in early sensitive periods but also throughout the lifespan. These responses are dependent on environmental context and lead to behavioral outcomes. While early adversity has been shown to perpetuate issues of mental health, there are numerous intervention strategies shown efficacious to ameliorate these effects. This includes diet, exercise, childhood intervention programs, pharmacological therapeutics, and talk therapies. Understanding the underlying mechanisms of the ability of the epigenome to adapt in different contexts is essential to advance our understanding of mechanisms of adversity and pathways to resilience. The present review draws on evidence from both humans and animal models to explore the responsivity of the epigenome to adversity and its malleability to intervention. Behavioral epigenetics research is also discussed in the context of public health practice and policy, as it provides a meaningful source of evidence concerning child development and disease intervention and prevention.

Early life stress (ELS) in the form of trauma or caregiver abuse and neglect is often associated with psychopathology. However, not everyone exposed to ELS develops a pathology; others display resilience, or the ability to adapt and persevere despite ongoing adversity. Several molecular moderator variables between ELS and behavioral phenotypes have been proposed, including single nucleotide polymorphisms (SNPs) and epigenetic markers. Specifically, several SNPs and aberrant methylation or expression of genes associated with neurotransmitter systems and brain-derived neurotrophic factor have been associated with anxiety, depression or schizophrenia. The present review seeks to explore the relationship between SNPs, epigenomics and disease, and offer data to suggest several SNPs may also predict specific treatment efficacy and psychological resilience. Due to this discrepancy in the literature, it is critical that environmental moderators be equally considered in determining the ontology of resilient or pathological phenotypes; this includes the infant-caregiver relationship, and the degree of control, magnitude, and type of the stressor experienced. Finally, we will offer evidence to suggest that several intervention strategies, including drug treatment, environmental enrichment, or exercise can ameliorate many of the psychological, biological, and molecular consequences of ELS exposure, and help shift one toward a resilient phenotype.