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

Abstract

Reorganization of the brain’s epigenetic landscape occurs alongside early adversity in both human and non-human animals. Whether this reorganization is simply incidental to or is a causal mechanism of the behavioral abnormalities that result from early adversity is important to understand. Using the scarcity-adversity model of low nesting resources in Long Evans rats, our lab has previously reported specific epigenetic and behavioral trajectories occurring in response to early disruption of the caregiving environment. To further probe that relationship, the current work investigates the ability of the epigenome-modifying drug sodium butyrate to prevent maltreatment-induced methylation changes when administered alongside maltreatment. Following exposure to the scarcity-adversity model, during which drug was administered prior to each caregiving session, methylation of Brain-derived Neurotrophic Factor (Bdnf) IX DNA was examined in the Prefrontal Cortex (PFC) of male and female pups at postnatal day (PN) 8. As our previous work reports, increased methylation at this exon of Bdnf in the PFC is a stable epigenetic change across the lifespan that occurs in response to early maltreatment, thus giving us a suitable starting point to investigate pharmacological prevention of maltreatment-induced epigenetic marks. Here we also examined off-target effects of sodium butyrate by assessing methylation in another region of Bdnf (exon IV) not affected in the infant brain as well as global levels of methylation in the brain region of interest. Results indicate that a 400 mg/kg (but not 300 mg/kg) dose of sodium butyrate is effective in preventing the maltreatment-induced rise in methylation at Bdnf exon IX in the PFC of male (but not female) infant pups. Administration of sodium butyrate did not affect the methylation status of Bdnf IV or overall levels of global methylation in the PFC, suggesting potential specificity of this drug. These data provide us an avenue forward for investigating whether the relationship between adversity-induced epigenetic outcomes in our model can be manipulated to improve behavioral outcomes.