Accepted Preprint (first posted online 11 April 2017)

    Epigenetic programming of the neuroendocrine stress response by adult life stress

    1. Marloes Henckens
    1. B Dirven, Anatomy, Radboud University Nijmegen Medical Centre, Nijmegen, Netherlands
    2. J Homberg, Cognitive Neuroscience, Radboud Universiteit Donders Institute for Brain Cognition and Behaviour, Nijmegen, Netherlands
    3. T Kozicz, Anatomy, Radboudumc, Nijmegen, Netherlands
    4. M Henckens, Cognitive Neuroscience, Radboud Universiteit Donders Institute for Brain Cognition and Behaviour, Nijmegen, Netherlands
    1. Correspondence: Bart Dirven, Email: bart.dirven{at}


    The hypothalamic-pituitary adrenal (HPA) axis is critically involved in the neuroendocrine regulation of stress adaptation, and the restoration of homeostasis following stress exposure. Dysregulation of this axis is associated with stress-related pathologies like major depressive disorder, post-traumatic stress disorder, panic disorder, and chronic anxiety. It has long been understood that stress during early life can have a significant lasting influence on the development of the neuroendocrine system and its neural regulators, partially by modifying epigenetic regulation of gene expression, with implications for health and well-being in later life. Evidence is accumulating that epigenetic plasticity also extends to adulthood, proposing it as a mechanism by which psychological trauma later in life can long-lastingly affect HPA-axis function, brain plasticity, neuronal function, and behavioural adaptation to neuropsychological stress. Further corroborating this claim is the phenomenon that these epigenetic changes correlate with the behavioural consequences of trauma exposure. Thereby, epigenetic modifications provide a putative molecular mechanism by which the behavioural phenotype and transcriptional / translational potential of genes involved in HPA-axis regulation can change drastically in response to environmental challenges, and appear an important target for treatment of stress-related disorders. However, improved insight is required to increase their therapeutic (drug) potential. Here, we provide an overview of the growing body of literature describing the epigenetic modulation of the (primarily neuroendocrine) stress response as a consequence of adult life stress and interpret the implications for - and the challenges involved in applying this knowledge to - the identification and treatment of stress-related psychiatric disorders.

    • Received 19 January 2017
    • Revision received 17 March 2017
    • Accepted 11 April 2017
    • Accepted Preprint first posted online on 11 April 2017