Looking back and moving forward: Evaluating and advancing translation from animal models to human studies of early life stress and DNA methylation

Abstract

Advances in epigenetic methodologies have deepened theoretical explanations of mechanisms linking early life stress (ELS) and disease outcomes and suggest promising targets for intervention. To date, however, human studies have not capitalized on the richness of diverse animal models to derive and systematically evaluate specific and testable hypotheses. To promote cross‐species dialog and scientific advance, here we provide a classification scheme to systematically evaluate the match between characteristics of human and animal studies of ELS and DNA methylation. Three preclinical models were selected that are highly cited, and that differ in the nature and severity of the ELS manipulation as well as in the affected epigenetic loci (the licking and grooming, maternal separation, and caregiver maltreatment models). We evaluated the degree to which human studies matched these preclinical models with respect to the timing of ELS and of DNA methylation assessment, as well as the type of ELS, whether sex differences were explicitly examined, the tissue sampled, and the targeted loci. Results revealed <50% match (range of 8–83%) between preclinical models and human work on these variables. Immediate and longer‐term suggestions to improve translational specificity are offered, with the goal of accelerating scientific advance.

Early Life Stress Restricts Translational Reactivity in CA3 Neurons Associated With Altered Stress Responses in Adulthood

“…Stressful experiences at different stages of development, in both rodents and humans, have been associated with changes in gene expression under the control of epigenetic regulation (Weaver et al, 2004a,b; Korosi and Baram, 2009; Watamura and Roth, 2018). For example, acute stress increases the expression of the repressive histone marker H3K9 tri-methylation (H3K9me3) in the CA1 and DG regions of the rat dorsal hippocampus (Hunter et al, 2009).…”

Development of Threat Expression Following Infant Maltreatment: Infant and Adult Enhancement but Adolescent Attenuation

“…Here, using a rat animal model, we assessed how responses to a learned threat (following threat conditioning) changes as pups begin the transition from dependence on the mother [postnatal day (PN) 18] to adolescence, and finally adulthood, following typical maternal care and early life maltreatment. To model maltreatment, we employ the Scarcity-Adversity Model of low bedding (LB, insufficient bedding for nest building to induce maltreatment of pups) from PN8-12 (Opendak and Sullivan, 2016; Walker et al, 2017; Perry et al, 2018; Watamura and Roth, 2018).…”

“…Experiencing infant trauma and maltreatment from the caregiver has major effects on threat detection, as reflected in defensive behavior, and, on key structures within the defensive network, such as the amygdala and PFC, in both humans and animal throughout development (De Bellis et al, 1999; Gunnar et al, 2007; Lupien et al, 2009; Dannlowski et al, 2013; Gee et al, 2013b; Birn et al, 2014; Opendak and Gould, 2015; Fonzo et al, 2016; Opendak and Sullivan, 2016; Teicher et al, 2016; Heany et al, 2018; Lange et al, 2018; Roquet et al, 2018; Santiago et al, 2018; Watamura and Roth, 2018; Callaghan et al, 2019). Less well understood is how the trauma effects change during development.…”

The Impact of Stress Within and Across Generations: Neuroscientific and Epigenetic Considerations

“…130 Translational reliance on licking-and-grooming models has been questioned, suggesting that a focus on methylation changes to NR3C1 may be too narrow. 123,131,132 Also, different stress paradigms may better correlate with human models of early maltreatment. The licking-and-grooming models focus primarily on NR3C1, whereas the maltreatment model seems to have greater effect on brain-derived neurotrophic factor (BDNF) synthesis.…”