Early life stress, FK506 binding protein 5 gene (FKBP5) methylation, and inhibition-related prefrontal function: A prospective longitudinal study

Abstract

Individuals who have experienced high levels of childhood stress are at increased risk for a wide range of behavioral problems that persist into adulthood, yet the neurobiological and molecular mechanisms underlying these associations remain poorly understood. Many of the difficulties observed in stress-exposed children involve problems with learning and inhibitory control. This experiment was designed to test individual’s ability to learn to inhibit responding during a laboratory task. To do so, we measured stress-exposure among a community sample of school-aged children, and then followed these children for a decade. Those from the highest and lowest quintiles of childhood stress exposure were invited to return to our laboratory as young adults. At that time, we reassessed their life stress exposure, acquired fMRI data during an inhibitory control task, and assayed these individuals’ levels of methylation in the FKBP5 gene. We found that individuals who experienced high levels of stress in childhood showed less differentiation in the dorso-lateral prefrontal cortex between error and correct trials during inhibition. This effect was associated only with childhood stress exposure and not by current levels of stress in adulthood. In addition, FKBP5 methylation mediated the association between early life stress and inhibition-related prefrontal activity. These findings are discussed in terms of using multiple levels of analyses to understand the ways in which adversity in early development may affect adult behavioral adaptation.

Molecular and Behavioral Effects of Infant Maltreatment across Generations in Rhesus Monkeys

“…The CpGs found demethylated in prior human studies 26,35,42,78–80 and in this report are spatially central to a functional enhancer element that harbors glucocorticoid response elements (GREs) in intron 7 of FKBP5 . These GREs regulate the dynamic transcriptional response of FKBP5 and thus HPA axis activity, the stress response and glucocorticoid negative feedback 26,34,35,42,78,79,81,82 . Our findings in macaques are consistent with that literature, showing that DNA methylation in the central CpG5 position of the FKBP5 intron 7 GRE in the macaque gene influence GR binding in vitro , and are subsequently associated with differential FKBP5 regulation of GR feedback and peripheral cortisol levels.…”

“…Several human studies support a role for FKBP5 DNA demethylation in response to ELS 35,42,78–80 . Importantly, a study in survivors of the Holocaust suggested additional intergenerational effects of trauma exposure on FKBP5 DNA methylation in the offspring 26 .…”

Child Maltreatment, Delayed Reward Discounting, and Alcohol and Other Drug Use Problems: The Moderating Role of Heart Rate Variability

“…Similarly, Oshri et al (2017) found that adolescents who reported child abuse and neglect evinced higher levels of impulsive behaviors, and adults who reported child maltreatment evinced compromised DRD. In addition, recent research using fMRI technology demonstrates that early life stress can adversely affect executive control functions that are tied to DRD, such as working memory (Bickel et al, 2011), response inhibition (Harms et al, 2017) and reward salience in both animal (O’Connor, Moloney, Glennon, Vlachou, & Cryan, 2015) and human samples (Birn et al, 2017; Oswald et al, 2014).…”

Association of Different Types of Childhood Maltreatment With Emotional Responding and Response Control Among Youths

“…16,17,18,19 Two studies examining response control reported increased responsiveness within the dorsal cingulate cortex and midcingulate cortex and precentral and postcentral gyri during response control in maltreated children and adolescents. 16,17 However, 2 other studies using similar tasks reported that a history of childhood maltreatment in women 18 and a history of exposure to childhood stress in adults 19 were associated with decreased responsiveness in the frontal or frontal-parietal regions of the brain. Moreover, a 2016 study 20 reported a history of childhood maltreatment was associated with significantly reduced activation during sustained attention within regions of the brain in adults, including the left inferior cortex, dorsolateral prefrontal cortex, insula, and temporal cortex, compared with healthy controls.…”