Differential Methylation of Genes in the Medial Prefrontal Cortex of Developing and Adult Rats Following Exposure to Maltreatment or Nurturing Care During Infancy

Abstract

Quality of maternal care in infancy is an important contributing factor in the development of behavior and psychopathology. One way maternal care could affect behavioral trajectories is through environmentally induced epigenetic alterations within brain regions known to play prominent roles in cognition, emotion regulation, and stress responsivity. Whereas such research has largely focused on the hippocampus or hypothalamus, the prefrontal cortex (PFC) has only just begun to receive attention. The current study was designed to determine whether exposure to maltreatment or nurturing care is associated with differential methylation of candidate gene loci (bdnf and reelin) within the medial PFC (mPFC) of developing and adult rats. Using a within-litter design, infant male and female rats were exposed to an adverse or nurturing caregiving environment outside their home cage for 30 min per day during the first postnatal week. Additional littermates remained with their biological caregiver within the home cage during the manipulations. We observed that infant rats subjected to caregiver maltreatment emitted more audible and ultrasonic vocalizations than littermates subjected to nurturing care either within or outside of the home cage. While we found no maltreatment-induced changes in bdnf DNA methylation present in infancy, sex-specific alterations were present in the mPFC of adolescents and adults that had been exposed to maltreatment. Furthermore, while maltreated females showed differences in reelin DNA methylation that were transient, males exposed to maltreatment and both males and females exposed to nurturing care outside the home cage showed differences in reelin methylation that emerged by adulthood. Our results demonstrate the ability of infant-caregiver interactions to epigenetically mark genes known to play a prominent role in cognition and psychiatric disorders within the mPFC. Furthermore, our data indicate the remarkable complexity of alterations that can occur, with both transient and later emerging DNA methylation differences that could shape developmental trajectories and underlie gender differences in outcomes.

Association of brain-derived neurotrophic factor DNA methylation and reduced white matter integrity in the anterior corona radiata in major depression

“…Previous animal studies in infant rats have reported that adversity during the first postnatal week leads to increased BDNF DNA methylation and consequently decreased BDNF mRNA levels in the PFC in adulthood (Roth et al, 2009). Similarly, increased BDNF DNA methylation in the medial PFC has also been reported in adolescent and adult rats after maltreatment during infancy (Blaze et al, 2013). Our results are in line with those of above-mentioned studies.…”

Bdnf DNA methylation modifications in the hippocampus and amygdala of male and female rats exposed to different caregiving environments outside the homecage

“…We previously showed that brief, but repeated, exposure to caregiver maltreatment (i.e. being stepped on, dropped, dragged, actively avoided, and roughly handled) produces DNA methylation modifications that are present in both the developing and adult whole (Roth, Lubin, Funk, & Sweatt, 2009) and medial (Blaze, Scheuing, & Roth, 2013) prefrontal cortex. Here we extend these results by experimentally assessing whether caregiver maltreatment (as well as repeated exposure to a nurturing foster dam, an additional experimental manipulation we always employ) alters DNA methylation within two additional behaviorally- relevant brain regions, the hippocampus and amygdala.…”

The complex neurobiology of resilient functioning after child maltreatment

“…For example, the gender differences in methylation processes (Blaze, Scheuing, & Roth, 2013;Doherty, Forster, & Roth, 2016), brain responsivity (Crozier, Wang, Huettel, & De Bellis, 2014) and brain structure after CM (Calem et al, 2017;De Bellis et al, 2015;Paquola et al, 2016;Samplin, Ikuta, Malhotra, Szeszko, & Derosse, 2013;Sarah Whittle et al, 2009) may be critical for the understanding of the neural mechanisms of resilient functioning after CM and future studies could investigate this further using gender-sensitive study designs. Moreover, we were not able to discuss whether the neurobiology of resilient functioning depends on the age at which CM occurred.…”