PREVENTATIVE EFFECTS OF VALPROIC ACID ON OUTCOMES ASSOCIATED WITH CAREGIVER MALTREATMENT

Abstract

Early-life experiences play a significant role in influencing individual development. Importantly, early-life stress can negatively impact the developing brain, producing changes that may lead to psychopathy later in life. These changes can be induced epigenetically through DNA methylation. Previous work in our lab has shown that there is increased DNA methylation in the prefrontal cortex (PFC) of rats exposed to maltreatment in infancy. One way to prevent this is through the use of epigenome-modifying drugs. This project was aimed at investigating the preventative effects of valproic acid (VPA) on maltreatment-induced DNA methylation. Using a rodent model of early-life adversity, we investigated the effects of a 200, 400, or 600 mg/kg dose of VPA on DNA methylation at Bdnf exon IX and globally across the PFC. Once a successful dose of VPA was found, we additionally investigated the long-term effects of this drug on future caregiving behavior. Results show that VPA was unsuccessful at preventing this increase in methylation at Bdnf exon IX across all doses tested. However, the 400 mg/kg dose of VPA was successful in lowering methylation globally across the PFC. These findings indicate that VPA does have an epigenome-modifying effect but does not specifically influence Bdnf exon IX methylation in the PFC at the doses tested. Global methylation results indicate that VPA may have broader, genome-wide effects on methylation. Further, dams who received a 400 mg/kg dose of VPA in infancy exhibited a greater amount of aversive caregiving behaviors than those who received saline vehicle, independent of their own early-life environment. Taken together, these data provide further insight into the complex relationship between epigenetics and developmental outcomes.