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

Published online by Cambridge University Press:  22 November 2017

Madeline B. Harms
University of Wisconsin–Madison
Rasmus Birn
University of Wisconsin–Madison
Nadine Provencal
Max Planck Institute of Psychiatry
Tobias Wiechmann
Max Planck Institute of Psychiatry
Elisabeth B. Binder
Max Planck Institute of Psychiatry
Sebastian W. Giakas
University of Wisconsin–Madison
Barbara J. Roeber
University of Wisconsin–Madison
Seth D. Pollak*
University of Wisconsin–Madison
Address correspondence and reprint requests to: Seth D. Pollak, Waisman Center, University of Wisconsin–Madison, 1500 Highland Avenue, Madison, WI 53705-2280; E-mail:


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 individuals' 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 functional magnetic resonance imaging data during an inhibitory control task, and assayed these individuals' levels of methylation in the FK506 binding protein 5 (FKBP5) gene. We found that individuals who experienced high levels of stress in childhood showed less differentiation in the dorsolateral 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.

Special Issue Articles
Copyright © Cambridge University Press 2017 

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This work was supported by National Institute of Mental Health Grant MH61285 (to S.D.P.) and Waisman Center Intellectual & Developmental Disabilities Research Center from the National Institute of Child Health and Human Development Core Grant P30-HD03352. Madeline Harms was supported by T32-MH018931. We acknowledge the assistance of M. Daniela Cornejo, Joanna Swinarska, Alex Rokni, and Anna Bechner. We also appreciate the generous participation of the individuals who agreed to partake in this study.


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