Developmental administration of valproic acid alters DNA methylation and maternal behavior

Abstract

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.

Epigenetic processes associated with neonatal spinal transection

“…DNA extracted from cervical and lumbar tissue samples was used to quantify global methylation. As described by our lab elsewhere (Collins et al., 2022; Doherty, Chajes, et al., 2019b), MethylFlash Global DNA Methylation ELISA Easy Colorimetric Kits were used according to the manufacturer's instructions (EpiGentek) to quantify genome‐wide methylation (5‐mC) by measuring light absorbance. DNA samples, along with standards (diluted to a concentration of 0.1, 0.2, 0.5, 1.0, 2.0, or 5.0), were assayed simultaneously and run in vertical duplicates.…”

The role of epigenetic mechanisms in the long‐term effects of early‐life adversity and mother–infant relationship on physiology and behavior of offspring in laboratory rats and mice

“…Valproate injections on PND6‐12 (150 mg/kg) decreased the interest in new social contacts on PND36 in rats (Gedzun et al., 2021). The injection of a dosage of 400 mg/kg to rat pups during the first week of life resulted in later maternal adverse behaviors toward their own pups in adulthood (Collins et al., 2022). Furthermore, valproate (200 mg/kg) administered on PND4‐11 led to significant delays in weight gain and motor impairments in the nesting and adolescent period (Bath & Pimentel, 2017).…”