Pharmacological Manipulation of DNA Methylation in Adult Female Rats Normalizes Behavioral Consequences of Early-Life Maltreatment

Abstract

Exposure to adversity early in development alters brain and behavioral trajectories. Data continue to accumulate that epigenetic mechanisms are a mediating factor between early-life adversity and adult behavioral phenotypes. Previous work from our laboratory has shown that female Long-Evans rats exposed to maltreatment during infancy display both aberrant forced swim behavior and patterns of brain DNA methylation in adulthood. Therefore, we examined the possibility of rescuing the aberrant forced swim behavior in maltreated-adult females by administering an epigenome-modifying drug (zebularine) at a dose previously shown to normalize DNA methylation. We found that zebularine normalized behavior in the forced swim test in maltreated females such that they performed at the levels of controls (females that had been exposed to only nurturing care during infancy). These data help link DNA methylation to an adult phenotype in our maltreatment model, and more broadly provide additional evidence that non-targeted epigenetic manipulations can change behavior associated with early-life adversity.

Animal Models and Their Contribution to Our Understanding of the Relationship Between Environments, Epigenetic Modifications, and Behavior

“…Lastly, the maltreatment-induced gene changes can be mitigated with strategies that alter DNA methylation (in this study, they used a drug known to alter DNA methylation called zebularine). Keller, Doherty, and Roth [86] recently extended these findings to show zebularine administration in adulthood can also improve some of the behavioral deficits caused by maltreatment (forced swim behavior in this study). Together, work from various animal models show that environmental or pharmacological interventions are beneficial to individuals who do not receive adequate care early in life, just like you see in the clinical literature, but provide insight into the brain mechanisms of necessary targets.…”

“…Demonstrating translational relevance of these findings, McGowan et al [85] found increased methylation of NR3C1 gene (human equivalent of GR), decreased NR3C1 expression, and decreased NGFI-A binding in the hippocampus of individuals with a history of child abuse. In similar fashion, mean NR3C1 DNA methylation levels are increased in depressed individuals with a history of abuse, with methylation at specific CG sites within NR3C1 exon 1F related to childhood emotional abuse severity [86].…”

Preventing epigenetic traces of caregiver maltreatment: A role for HDAC inhibition

“…It is critical to synapse function (Lu et al, 2014), and its dysregulation is associated with negative behavioral outcomes related to both cognitive and mood disorders (Chen et al, 2006; Kim et al, 2007; Komulainen et al, 2008; Marais et al, 2009). Previous work from our lab demonstrates the highly dynamic epigenetic response of this gene to our paradigm of disrupted caregiving, and we have provided extensive evidence that it exhibits maltreatment‐induced methylation changes that vary by age, sex, brain region, and exon examined (Blaze and Roth, 2017; Blaze et al, 2013; Doherty et al, 2016; Roth et al, 2009, 2014), changes that may contribute to maltreatment‐induced behavioral outcomes previously reported by our lab (Doherty, Blaze, et al, 2017; Keller et al, 2018; Roth et al, 2009). One of these changes, an increase in methylation at exon IX of Bdnf following early maltreatment, remains stable across the lifespan in the Prefrontal Cortex (PFC) (Roth et al, 2009).…”

DNA Methyltransferases in Depression: An Update

“…These specific gene expression changes can affect the balance of neurotransmitters and therefore cause depression symptoms. This is supported by the observation that the DNA methylation was dynamically regulated, and environmental enrichment in adolescent rats that were exposed to adversity stressors rescued the DNA methylation profiles and recovered their typically observed behavior in non-treated animals (47), and DNA methylation inhibitor zebularine normalized the aberrant behavior in FST observed in rats exposed to maltreatment during infancy (48).…”