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Childhood adversity and epigenetic regulation of glucocorticoid signaling genes: Associations in children and adults

Published online by Cambridge University Press:  03 October 2016

Audrey R. Tyrka ,
Kathryn K. Ridout  and
Stephanie H. Parade
Audrey R. Tyrka*
Affiliation:
Butler Hospital Brown University Alpert Medical School
Kathryn K. Ridout
Affiliation:
Butler Hospital Brown University Alpert Medical School
Stephanie H. Parade
Affiliation:
Brown University Alpert Medical School E. P. Bradley Hospital
*
Address correspondence and reprint requests to: Audrey R. Tyrka, Butler Hospital, 345 Blackstone Boulevard, Providence, RI 02906; E-mail: [email protected].
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Abstract

Early childhood experiences have lasting effects on development, including the risk for psychiatric disorders. Research examining the biologic underpinnings of these associations has revealed the impact of childhood maltreatment on the physiologic stress response and activity of the hypothalamus–pituitary–adrenal axis. A growing body of literature supports the hypothesis that environmental exposures mediate their biological effects via epigenetic mechanisms. Methylation, which is thought to be the most stable form of epigenetic change, is a likely mechanism by which early life exposures have lasting effects. We present recent evidence related to epigenetic regulation of genes involved in hypothalamus–pituitary–adrenal axis regulation, namely, the glucocorticoid receptor gene (nuclear receptor subfamily 3, group C, member 1 [NR3C1]) and FK506 binding protein 51 gene (FKBP5), after childhood adversity and associations with risk for psychiatric disorders. Implications for the development of interventions and future research are discussed.

Type
Special Section Articles
Information
Development and Psychopathology , Volume 28 , Special Issue 4pt2: Epigenetics: Development, Psychopathology, Resilience, and Preventive Intervention , November 2016 , pp. 1319 - 1331
Copyright
Copyright © Cambridge University Press 2016 

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References

Anacker, C., Zunszain, P. A., Carvalho, L. A., & Pariante, C. M. (2011). The glucocorticoid receptor: Pivot of depression and of antidepressant treatment? Psychoneuroendocrinology, 36, 415–425.Google Scholar
Armstrong, D. A., Lesseur, C., Conradt, E., Lester, B. M., & Marsit, C. J. (2014). Global and gene-specific DNA methylation across multiple tissues in early infancy: Implications for children's health research. FASEB Journal, 28, 2088–2097.Google Scholar
Barden, N. (2004). Implication of the hypothalamic–pituitary–adrenal axis in the physiopathology of depression. Journal of Psychiatry & Neuroscience, 29, 185–193.Google ScholarPubMed
Benjet, C., Borges, G., & Medina-Mora, M. E. (2010). Chronic childhood adversity and onset of psychopathology during three life stages: Childhood, adolescence and adulthood. Journal of Psychiatric Research, 44, 732–740.Google Scholar
Bernard, K., Hostinar, C. E., & Dozier, M. (2015). Intervention effects on diurnal cortisol rhythms of Child Protective Services-referred infants in early childhood: Preschool follow-up results of a randomized clinical trial. JAMA Pediatrics, 169, 112–119.Google Scholar
Bernard, K., Zwerling, J., & Dozier, M. (2015). Effects of early adversity on young children's diurnal cortisol rhythms and externalizing behavior. Developmental Psychobiology. Advance online publication.Google Scholar
Binder, E. B. (2009). The role of FKBP5, a co-chaperone of the glucocorticoid receptor in the pathogenesis and therapy of affective and anxiety disorders. Psychoneuroendocrinology, 34(Suppl. 1), S186–S195.Google Scholar
Bloss, E. B., Janssen, W. G., McEwen, B. S., & Morrison, J. H. (2010). Interactive effects of stress and aging on structural plasticity in the prefrontal cortex. Journal of Neuroscience, 30, 6726–6731.Google Scholar
Bosch, N. M., Riese, H., Reijneveld, S. A., Bakker, M. P., Verhulst, F. C., Ormel, J., et al. (2012). Timing matters: Long term effects of adversities from prenatal period up to adolescence on adolescents’ cortisol stress response. The TRAILS study. Psychoneuroendocrinology, 37, 1439–1447.CrossRefGoogle ScholarPubMed
Bottiglieri, T. (2013). Folate, vitamin B(1)(2), and S-adenosylmethionine. Psychiatric Clinics of North America, 36, 1–13.CrossRefGoogle Scholar
Braithwaite, E. C., Kundakovic, M., Ramchandani, P. G., Murphy, S. E., & Champagne, F. A. (2015). Maternal prenatal depressive symptoms predict infant NR3C1 1F and BDNF IV DNA methylation. Epigenetics, 10, 408–417.Google Scholar
Braquehais, M. D., Picouto, M. D., Casas, M., & Sher, L. (2012). Hypothalamic–pituitary–adrenal axis dysfunction as a neurobiological correlate of emotion dysregulation in adolescent suicide. World Journal of Pediatrics, 8, 197–206.CrossRefGoogle ScholarPubMed
Brenet, F., Moh, M., Funk, P., Feierstein, E., Viale, A. J., Socci, N. D., et al. (2011). DNA methylation of the first exon is tightly linked to transcriptional silencing. PLOS ONE, 6, e14524.CrossRefGoogle ScholarPubMed
Brown, D. W., Anda, R. F., Tiemeier, H., Felitti, V. J., Edwards, V. J., Croft, J. B., et al. (2009). Adverse childhood experiences and the risk of premature mortality. American Journal of Preventive Medicine, 37, 389–396.Google Scholar
Bruce, J., Fisher, P. A., Graham, A. M., Moore, W. E., Peake, S. J., Mannering, A. M., et al. (2013). Patterns of brain activation in foster children and nonmaltreated children during an inhibitory control task. Developmental Psychopathology, 25, 931–941.Google Scholar
Carpenter, L. L., Carvalho, J. P., Tyrka, A. R., Wier, L. M., Mello, A. F., Mello, M. F., et al. (2007). Decreased adrenocorticotropic hormone and cortisol responses to stress in healthy adults reporting significant childhood maltreatment. Biological Psychiatry, 62, 1080–1087.CrossRefGoogle ScholarPubMed
Carpenter, L. L., Shattuck, T. T., Tyrka, A. R., Geracioti, T. D., & Price, L. H. (2011). Effect of childhood physical abuse on cortisol stress response. Psychopharmacology (Berlin), 214, 367–375.CrossRefGoogle ScholarPubMed
Carpenter, L. L., Tyrka, A. R., Ross, N. S., Khoury, L., Anderson, G. M., & Price, L. H. (2009). Effect of childhood emotional abuse and age on cortisol responsivity in adulthood. Biological Psychiatry, 66, 69–75.Google Scholar
Cicchetti, D., & Gunnar, M. R. (2008). Integrating biological measures into the design and evaluation of preventive interventions. Developmental Psychopathology, 20, 737–743.Google Scholar
Cicchetti, D., & Lynch, M. (1993). Toward an ecological/transactional model of community violence and child maltreatment: Consequences for children's development. Psychiatry, 56, 96–118.Google Scholar
Cicchetti, D., Rogosch, F. A., Toth, S. L., & Sturge-Apple, M. L. (2011). Normalizing the development of cortisol regulation in maltreated infants through preventive interventions. Developmental Psychopathology, 23, 789–800.Google Scholar
Cioffi, D. L., Hubler, T. R., & Scammell, J. G. (2011). Organization and function of the FKBP52 and FKBP51 genes. Current Opinion in Pharmacology, 11, 308–313.CrossRefGoogle ScholarPubMed
Cohen, S., Janicki-Deverts, D., & Miller, G. E. (2007). Psychological stress and disease. Journal of the American Medial Association, 298, 1685–1687.CrossRefGoogle ScholarPubMed
Combs-Ronto, L. A., Olson, S. L., Lunkenheimer, E. S., & Sameroff, A. J. (2009). Interactions between maternal parenting and children's early disruptive behavior: Bidirectional associations across the transition from preschool to school entry. Journal of Abnormal Child Psychology, 37, 1151–1163.Google Scholar
Conradt, E., Hawes, K., Guerin, D., Armstrong, D. A., Marsit, C. J., Tronick, E., et al. (2016). The contributions of maternal sensitivity and maternal depressive symptoms to epigenetic processes and neuroendocrine functioning. Child Development, 87, 73–85.CrossRefGoogle ScholarPubMed
Conradt, E., Lester, B. M., Appleton, A. A., Armstrong, D. A., & Marsit, C. J. (2013). The roles of DNA methylation of NR3C1 and 11beta-HSD2 and exposure to maternal mood disorder in utero on newborn neurobehavior. Epigenetics, 8, 1321–1329.Google Scholar
Dadds, M. R., Moul, C., Hawes, D. J., Mendoza Diaz, A., & Brennan, J. (2015). Individual differences in childhood behavior disorders associated with epigenetic modulation of the cortisol receptor gene. Child Development, 86, 1311–1320.Google Scholar
Dammann, G., Teschler, S., Haag, T., Altmuller, F., Tuczek, F., & Dammann, R. H. (2011). Increased DNA methylation of neuropsychiatric genes occurs in borderline personality disorder. Epigenetics, 6, 1454–1462.Google Scholar
Daskalakis, N. P., & Yehuda, R. (2014). Site-specific methylation changes in the glucocorticoid receptor exon 1F promoter in relation to life adversity: Systematic review of contributing factors. Frontiers in Neuroscience, 8, 369.CrossRefGoogle ScholarPubMed
Deaton, A. M., & Bird, A. (2011). CpG islands and the regulation of transcription. Genes & Development, 25, 1010–1022.Google Scholar
De Bellis, M. D., & Zisk, A. (2014). The biological effects of childhood trauma. Child and Adolescent Psychiatric Clinics of North America, 23, 185–222.CrossRefGoogle ScholarPubMed
de Kloet, E. R., Joels, M., & Holsboer, F. (2005). Stress and the brain: From adaptation to disease. Nature Reviews Neuroscience, 6, 463–475.Google Scholar
Detich, N., Bovenzi, V., & Szyf, M. (2003). Valproate induces replication-independent active DNA demethylation. Journal of Biological Chemistry, 278, 27586–27592.Google Scholar
Detich, N., Hamm, S., Just, G., Knox, J. D., & Szyf, M. (2003). The methyl donor S-adenosylmethionine inhibits active demethylation of DNA: A candidate novel mechanism for the pharmacological effects of S-adenosylmethionine. Journal of Biological Chemistry, 278, 20812–20820.CrossRefGoogle ScholarPubMed
Dong, E., Chen, Y., Gavin, D. P., Grayson, D. R., & Guidotti, A. (2010). Valproate induces DNA demethylation in nuclear extracts from adult mouse brain. Epigenetics, 5, 730–735.Google Scholar
Dong, E., Nelson, M., Grayson, D. R., Costa, E., & Guidotti, A. (2008). Clozapine and sulpiride but not haloperidol or olanzapine activate brain DNA demethylation. Proceedings of the National Academy of Sciences, 105, 13614–13619.Google Scholar
Doom, J. R., Cicchetti, D., & Rogosch, F. A. (2014). Longitudinal patterns of cortisol regulation differ in maltreated and nonmaltreated children. Journal of the American Academy of Child & Adolescent Psychiatry, 53, 1206–1215.Google Scholar
Doom, J. R., & Gunnar, M. R. (2013). Stress physiology and developmental psychopathology: Past, present, and future. Developmental Psychopathology, 25, 1359–1373.Google Scholar
Dozier, M., Peloso, E., Lewis, E., Laurenceau, J. P., & Levine, S. (2008). Effects of an attachment-based intervention on the cortisol production of infants and toddlers in foster care. Developmental Psychopathology, 20, 845–859.Google Scholar
Duman, R. S. (2009). Neuronal damage and protection in the pathophysiology and treatment of psychiatric illness: Stress and depression. Dialogues in Clinical Neuroscience, 11, 239–255.Google Scholar
Elzinga, B. M., Roelofs, K., Tollenaar, M. S., Bakvis, P., van Pelt, J., & Spinhoven, P. (2008). Diminished cortisol responses to psychosocial stress associated with lifetime adverse events a study among healthy young subjects. Psychoneuroendocrinology, 33, 227–237.CrossRefGoogle ScholarPubMed
Faravelli, C., Lo Sauro, C., Lelli, L., Pietrini, F., Lazzeretti, L., Godini, L., et al. (2012). The role of life events and HPA axis in anxiety disorders: A review. Current Pharmaceutical Design, 18, 5663–5674.CrossRefGoogle ScholarPubMed
Felitti, V. J., Anda, R. F., Nordenberg, D., Williamson, D. F., Spitz, A. M., Edwards, V., et al. (1998). Relationship of childhood abuse and household dysfunction to many of the leading causes of death in adults: The Adverse Childhood Experiences (ACE) Study. American Journal of Preventive Medicine, 14, 245–258.Google Scholar
Fisher, P. A., Stoolmiller, M., Gunnar, M. R., & Burraston, B. O. (2007). Effects of a therapeutic intervention for foster preschoolers on diurnal cortisol activity. Psychoneuroendocrinology, 32, 892–905.CrossRefGoogle ScholarPubMed
Fisher, P. A., Van Ryzin, M. J., & Gunnar, M. R. (2011). Mitigating HPA axis dysregulation associated with placement changes in foster care. Psychoneuroendocrinology, 36, 531–539.Google Scholar
Fries, E., Hesse, J., Hellhammer, J., & Hellhammer, D. H. (2005). A new view on hypocortisolism. Psychoneuroendocrinology, 30, 1010–1016.Google Scholar
Fries, G. R., Vasconcelos-Moreno, M. P., Gubert, C., dos Santos, B. T., Sartori, J., Eisele, B., et al. (2015). Hypothalamic–pituitary–adrenal axis dysfunction and illness progression in bipolar disorder. International Journal of Neuropsychopharmacology. Advance online publication.Google Scholar
Galon, J., Franchimont, D., Hiroi, N., Frey, G., Boettner, A., Ehrhart-Bornstein, M., et al. (2002). Gene profiling reveals unknown enhancing and suppressive actions of glucocorticoids on immune cells. FASEB Journal, 16, 61–71.Google Scholar
Gonzalez, A. (2013). The impact of childhood maltreatment on biological systems: Implications for clinical interventions. Paediatrics & Child Health, 18, 415–418.Google ScholarPubMed
Gormley, G. J., Lowy, M. T., Reder, A. T., Hospelhorn, V. D., Antel, J. P., & Meltzer, H. Y. (1985). Glucocorticoid receptors in depression: Relationship to the dexamethasone suppression test. American Journal of Psychiatry, 142, 1278–1284.Google Scholar
Green, J. G., McLaughlin, K. A., Berglund, P. A., Gruber, M. J., Sampson, N. A., Zaslavsky, A. M., et al. (2010). Childhood adversities and adult psychiatric disorders in the national comorbidity survey replication: I. Associations with first onset of DSM-IV disorders. Archives of General Psychiatry, 67, 113–123.Google Scholar
Guerry, J. D., & Hastings, P. D. (2011). In search of HPA axis dysregulation in child and adolescent depression. Clinical Child and Family Psychology Review, 14, 135–160.Google Scholar
Gunnar, M. R., & Vazquez, D. M. (2001). Low cortisol and a flattening of expected daytime rhythm: Potential indices of risk in human development. Developmental Psychopathology, 13, 515–538.Google Scholar
Heim, C., Ehlert, U., & Hellhammer, D. H. (2000). The potential role of hypocortisolism in the pathophysiology of stress-related bodily disorders. Psychoneuroendocrinology, 25, 1–35.Google Scholar
Heinrich, A., Buchmann, A. F., Zohsel, K., Dukal, H., Frank, J., Treutlein, J., et al. (2015). Alterations of glucocorticoid receptor gene methylation in externalizing disorders during childhood and adolescence. Behavior Genetics, 45, 529–536.Google Scholar
Herman, J. P., McKlveen, J. M., Solomon, M. B., Carvalho-Netto, E., & Myers, B. (2012). Neural regulation of the stress response: Glucocorticoid feedback mechanisms. Brazilian Journal of Medical and Biological Research, 45, 292–298.Google Scholar
Hernando-Herraez, I., Garcia-Perez, R., Sharp, A. J., & Marques-Bonet, T. (2015). DNA methylation: Insights into human evolution. PLOS Genetics, 11, e1005661.Google Scholar
Hohne, N., Poidinger, M., Merz, F., Pfister, H., Bruckl, T., Zimmermann, P., et al. (2015). FKBP5 genotype-dependent DNA methylation and mRNA regulation after psychosocial stress in remitted depression and healthy controls. International Journal of Neuropsychopharmacology. Advance online publication.Google Scholar
Hompes, T., Izzi, B., Gellens, E., Morreels, M., Fieuws, S., Pexsters, A., et al. (2013). Investigating the influence of maternal cortisol and emotional state during pregnancy on the DNA methylation status of the glucocorticoid receptor gene (NR3C1) promoter region in cord blood. Journal of Psychiatric Research, 47, 880–891.Google Scholar
Ising, M., Depping, A. M., Siebertz, A., Lucae, S., Unschuld, P. G., Kloiber, S., et al. (2008). Polymorphisms in the FKBP5 gene region modulate recovery from psychosocial stress in healthy controls. European Journal of Neuroscience, 28, 389–398.Google Scholar
Kadmiel, M., & Cidlowski, J. A. (2013). Glucocorticoid receptor signaling in health and disease. Trends in Pharmacological Sciences, 34, 518–530.CrossRefGoogle ScholarPubMed
Kashimoto, R. K., Toffoli, L. V., Manfredo, M. H., Volpini, V. L., Martins-Pinge, M. C., Pelosi, G. G., et al. (2016). Physical exercise affects the epigenetic programming of rat brain and modulates the adaptive response evoked by repeated restraint stress. Behavioural Brain Research, 296, 286–289.Google Scholar
Kertes, D. A., Kamin, H. S., Hughes, D. A., Rodney, N. C., Bhatt, S., & Mulligan, C. J. (2016). Prenatal maternal stress predicts methylation of genes regulating the hypothalamic–pituitary–adrenocortical system in mothers and newborns in the Democratic Republic of Congo. Child Development, 87, 61–72.Google Scholar
Klaassens, E. R., Giltay, E. J., van Veen, T., Veen, G., & Zitman, F. G. (2010). Trauma exposure in relation to basal salivary cortisol and the hormone response to the dexamethasone/CRH test in male railway employees without lifetime psychopathology. Psychoneuroendocrinology, 35, 878–886.Google Scholar
Klaassens, E. R., van Noorden, M. S., Giltay, E. J., van Pelt, J., van Veen, T., & Zitman, F. G. (2009). Effects of childhood trauma on HPA-axis reactivity in women free of lifetime psychopathology. Progress in Neuro-Psychopharmacology and Biological Psychiatry, 33, 889–894.Google Scholar
Klengel, T., Mehta, D., Anacker, C., Rex-Haffner, M., Pruessner, J. C., Pariante, C. M., et al. (2013). Allele-specific FKBP5 DNA demethylation mediates gene–childhood trauma interactions. Nature Neuroscience, 16, 33–41.Google Scholar
Kosten, T. A., Huang, W., & Nielsen, D. A. (2014). Sex and litter effects on anxiety and DNA methylation levels of stress and neurotrophin genes in adolescent rats. Developmental Psychobiology, 56, 392–406.Google Scholar
Kosten, T. A., & Nielsen, D. A. (2014). Litter and sex effects on maternal behavior and DNA methylation of the Nr3c1 exon 17 promoter gene in hippocampus and cerebellum. International Journal of Developmental Neuroscience, 36, 5–12.Google Scholar
Kundakovic, M., Lim, S., Gudsnuk, K., & Champagne, F. A. (2013). Sex-specific and strain-dependent effects of early life adversity on behavioral and epigenetic outcomes. Frontiers in Psychiatry, 4, 78.Google Scholar
Labonte, B., Azoulay, N., Yerko, V., Turecki, G., & Brunet, A. (2014). Epigenetic modulation of glucocorticoid receptors in posttraumatic stress disorder. Translational Psychiatry, 4, e368.Google Scholar
Labonte, B., Yerko, V., Gross, J., Mechawar, N., Meaney, M. J., Szyf, M., et al. (2012). Differential glucocorticoid receptor exon 1(B), 1(C), and 1(H) expression and methylation in suicide completers with a history of childhood abuse. Biological Psychiatry, 72, 41–48.Google Scholar
Lakshminarasimhan, H., & Chattarji, S. (2012). Stress leads to contrasting effects on the levels of brain derived neurotrophic factor in the hippocampus and amygdala. PLOS ONE, 7, e30481.Google Scholar
Laryea, G., Muglia, L., Arnett, M., & Muglia, L. J. (2015). Dissection of glucocorticoid receptor-mediated inhibition of the hypothalamic–pituitary–adrenal axis by gene targeting in mice. Frontiers in Neuroendocrinology, 36, 150–164.Google Scholar
Laurent, H. K., Gilliam, K. S., Bruce, J., & Fisher, P. A. (2014). HPA stability for children in foster care: Mental health implications and moderation by early intervention. Developmental Psychobiology, 56, 1406–1415.CrossRefGoogle ScholarPubMed
Lee, R. S., & Sawa, A. (2014). Environmental stressors and epigenetic control of the hypothalamic–pituitary–adrenal axis. Neuroendocrinology, 100, 278–287.Google Scholar
Leszczynska-Rodziewicz, A., Szczepankiewicz, A., Narozna, B., Skibinska, M., Pawlak, J., Dmitrzak-Weglarz, M., et al. (2014). Possible association between haplotypes of the FKBP5 gene and suicidal bipolar disorder, but not with melancholic depression and psychotic features, in the course of bipolar disorder. Neuropsychiatric Disease and Treatment, 10, 243–248.Google Scholar
Levenson, J. M., Roth, T. L., Lubin, F. D., Miller, C. A., Huang, I. C., Desai, P., et al. (2006). Evidence that DNA (cytosine-5) methyltransferase regulates synaptic plasticity in the hippocampus. Journal of Biological Chemistry, 281, 15763–15773.Google Scholar
Lillycrop, K. A., Slater-Jefferies, J. L., Hanson, M. A., Godfrey, K. M., Jackson, A. A., & Burdge, G. C. (2007). Induction of altered epigenetic regulation of the hepatic glucocorticoid receptor in the offspring of rats fed a protein-restricted diet during pregnancy suggests that reduced DNA methyltransferase-1 expression is involved in impaired DNA methylation and changes in histone modifications. British Journal of Nutrition, 97, 1064–1073.Google Scholar
Liyanage, V. R., Jarmasz, J. S., Murugeshan, N., Del Bigio, M. R., Rastegar, M., & Davie, J. R. (2014). DNA modifications: Function and applications in normal and disease States. Biology (Basel), 3, 670–723.Google Scholar
Lowy, M. T., Reder, A. T., Gormley, G. J., & Meltzer, H. Y. (1988). Comparison of in vivo and in vitro glucocorticoid sensitivity in depression: Relationship to the dexamethasone suppression test. Biological Psychiatry, 24, 619–630.Google Scholar
Lupien, S. J., McEwen, B. S., Gunnar, M. R., & Heim, C. (2009). Effects of stress throughout the lifespan on the brain, behaviour and cognition. Nature Reviews Neuroscience, 10, 434–445.Google Scholar
Lutz, P. E., & Turecki, G. (2014). DNA methylation and childhood maltreatment: From animal models to human studies. Neuroscience, 264, 142–156.Google Scholar
Maccari, S., Krugers, H. J., Morley-Fletcher, S., Szyf, M., & Brunton, P. J. (2014). The consequences of early-life adversity: Neurobiological, behavioural and epigenetic adaptations. Journal of Neuroendocrinology, 26, 707–723.CrossRefGoogle ScholarPubMed
Martin-Blanco, A., Ferrer, M., Soler, J., Salazar, J., Vega, D., Andion, O., et al. (2014). Association between methylation of the glucocorticoid receptor gene, childhood maltreatment, and clinical severity in borderline personality disorder. Journal of Psychiatric Research, 57, 34–40.Google Scholar
McCrory, E., De Brito, S. A., & Viding, E. (2010). Research review: The neurobiology and genetics of maltreatment and adversity. Journal of Child Psychology and Psychiatry, 51, 1079–1095.Google Scholar
McEwen, B. S. (2007). Physiology and neurobiology of stress and adaptation: Central role of the brain. Physiological Reviews, 87, 873–904.Google Scholar
McEwen, B. S. (2013). The brain on stress: Toward an integrative approach to brain, body, and behavior. Perspectives on Psychological Science, 8, 673–675.Google Scholar
McEwen, B. S. (2015). Preserving neuroplasticity: Role of glucocorticoids and neurotrophins via phosphorylation. Proceedings of the National Academy of Sciences, 112, 15544–15545.Google Scholar
McEwen, B. S., Bowles, N. P., Gray, J. D., Hill, M. N., Hunter, R. G., Karatsoreos, I. N., et al. (2015). Mechanisms of stress in the brain. Nature Neuroscience, 18, 1353–1363.Google Scholar
McEwen, B. S., Nasca, C., & Gray, J. D. (2016). Stress effects on neuronal structure: Hippocampus, amygdala, and prefrontal cortex. Neuropsychopharmacology, 41, 3–23.Google Scholar
Menke, A., & Binder, E. B. (2014). Epigenetic alterations in depression and antidepressant treatment. Dialogues in Clinical Neuroscience, 16, 395–404.CrossRefGoogle ScholarPubMed
Menke, A., Klengel, T., Rubel, J., Bruckl, T., Pfister, H., Lucae, S., et al. (2013). Genetic variation in FKBP5 associated with the extent of stress hormone dysregulation in major depression. Genes, Brain and Behavior, 12, 289–296.Google Scholar
Miller, C. A., & Sweatt, J. D. (2007). Covalent modification of DNA regulates memory formation. Neuron, 53, 857–869.Google Scholar
Miller, G. E., Chen, E., & Zhou, E. S. (2007). If it goes up, must it come down? Chronic stress and the hypothalamic–pituitary–adrenocortical axis in humans. Psychological Bulletin, 133, 25–45.Google Scholar
Milutinovic, S., D'Alessio, A. C., Detich, N., & Szyf, M. (2007). Valproate induces widespread epigenetic reprogramming which involves demethylation of specific genes. Carcinogenesis, 28, 560–571.Google Scholar
Mitra, R., & Sapolsky, R. M. (2008). Acute corticosterone treatment is sufficient to induce anxiety and amygdaloid dendritic hypertrophy. Proceedings of the National Academy of Sciences, 105, 5573–5578.Google Scholar
Moffitt, T. E., & Klaus-Grawe 2012 Think Tank. (2013). Childhood exposure to violence and lifelong health: Clinical intervention science and stress-biology research join forces. Development and Psychopathology, 25, 1619–1634.Google Scholar
Moore, L. D., Le, T., & Fan, G. (2013). DNA methylation and its basic function. Neuropsychopharmacology, 38, 23–38.Google Scholar
Morris, M. C., Compas, B. E., & Garber, J. (2012). Relations among posttraumatic stress disorder, comorbid major depression, and HPA function: A systematic review and meta-analysis. Clinical Psychology Review, 32, 301–315.Google Scholar
Mulligan, C. J., D'Errico, N. C., Stees, J., & Hughes, D. A. (2012). Methylation changes at NR3C1 in newborns associate with maternal prenatal stress exposure and newborn birth weight. Epigenetics, 7, 853–857.Google Scholar
Na, K. S., Chang, H. S., Won, E., Han, K. M., Choi, S., Tae, W. S., et al. (2014). Association between glucocorticoid receptor methylation and hippocampal subfields in major depressive disorder. PLOS ONE, 9, e85425.Google Scholar
Needham, B. L., Smith, J. A., Zhao, W., Wang, X., Mukherjee, B., Kardia, S. L., et al. (2015). Life course socioeconomic status and DNA methylation in genes related to stress reactivity and inflammation: The multi-ethnic study of atherosclerosis. Epigenetics, 10, 958–969.Google Scholar
Nelson, E. M., & Spieker, S. J. (2013). Intervention effects on morning and stimulated cortisol responses among toddlers in foster care. Infant Mental Health Journal, 34, 211–221.Google Scholar
Oberlander, T. F., Weinberg, J., Papsdorf, M., Grunau, R., Misri, S., & Devlin, A. M. (2008). Prenatal exposure to maternal depression, neonatal methylation of human glucocorticoid receptor gene (NR3C1) and infant cortisol stress responses. Epigenetics, 3, 97–106.Google Scholar
Palma-Gudiel, H., Cordova-Palomera, A., Leza, J. C., & Fananas, L. (2015). Glucocorticoid receptor gene (NR3C1) methylation processes as mediators of early adversity in stress-related disorders causality: A critical review. Neuroscience & Biobehavioral Reviews, 55, 520–535.Google Scholar
Pan, P., Fleming, A. S., Lawson, D., Jenkins, J. M., & McGowan, P. O. (2014). Within- and between-litter maternal care alter behavior and gene regulation in female offspring. Behavioral Neuroscience, 128, 736–748.Google Scholar
Paquette, A. G., Lester, B. M., Koestler, D. C., Lesseur, C., Armstrong, D. A., & Marsit, C. J. (2014). Placental FKBP5 genetic and epigenetic variation is associated with infant neurobehavioral outcomes in the RICHS cohort. PLOS ONE, 9, e104913.Google Scholar
Paquette, A. G., Lester, B. M., Lesseur, C., Armstrong, D. A., Guerin, D. J., Appleton, A. A., et al. (2015). Placental epigenetic patterning of glucocorticoid response genes is associated with infant neurodevelopment. Epigenomics, 7, 767–779.Google Scholar
Parade, S. H., Ridout, K. K., Seifer, R., Armstrong, D. A., Marsit, C. J., McWilliams, M. A., et al. (2016). Methylation of the glucocorticoid receptor gene promoter in preschoolers: Links with internalizing behavior problems. Child Development, 87, 86–97.CrossRefGoogle ScholarPubMed
Perry, N. B., Mackler, J. S., Calkins, S. D., & Keane, S. P. (2014). A transactional analysis of the relation between maternal sensitivity and child vagal regulation. Developmental Psychology, 50, 784–793.CrossRefGoogle ScholarPubMed
Provencal, N., Suderman, M. J., Guillemin, C., Massart, R., Ruggiero, A., Wang, D., et al. (2012). The signature of maternal rearing in the methylome in rhesus macaque prefrontal cortex and T cells. Journal of Neuroscience, 32, 15626–15642.Google Scholar
Pryce, C. R., Ruedi-Bettschen, D., Dettling, A. C., Weston, A., Russig, H., Ferger, B., et al. (2005). Long-term effects of early-life environmental manipulations in rodents and primates: Potential animal models in depression research. Neuroscience & Biobehavioral Reviews, 29, 649–674.Google Scholar
Radtke, K. M., Ruf, M., Gunter, H. M., Dohrmann, K., Schauer, M., Meyer, A., et al. (2011). Transgenerational impact of intimate partner violence on methylation in the promoter of the glucocorticoid receptor. Translational Psychiatry, 1, e21.Google Scholar
Rao, R. P., Anilkumar, S., McEwen, B. S., & Chattarji, S. (2012). Glucocorticoids protect against the delayed behavioral and cellular effects of acute stress on the amygdala. Biological Psychiatry, 72, 466–475.Google Scholar
Reis, F. M., Almada, R. C., Fogaca, M. V., & Brandao, M. L. (2015). Rapid activation of glucocorticoid receptors in the prefrontal cortex mediates the expression of contextual conditioned fear in rats. Cerebral Cortex. Advance online publication.Google Scholar
Ridout, K. K., Carpenter, L. L., & Tyrka, A. R. (2016). The cellular sequelae of early stress: Focus on aging and mitochondria. Neuropsychopharmacology, 41, 388–389.Google Scholar
Ridout, S. J., Ridout, K. K., Kao, H. T., Carpenter, L. L., Philip, N. S., Tyrka, A. R., et al. (2015). Telomeres, early-life stress and mental illness. Advances in Psychosomatic Medicine, 34, 92–108.Google Scholar
Rifkin-Graboi, A., Kong, L., Sim, L. W., Sanmugam, S., Broekman, B. F., Chen, H., et al. (2015). Maternal sensitivity, infant limbic structure volume and functional connectivity: A preliminary study. Translational Psychiatry, 5, e668.Google Scholar
Roberts, S., Keers, R., Lester, K. J., Coleman, J. R., Breen, G., Arendt, K., et al. (2015). HPA axis related genes and response to psychological therapies: Genetics and epigenetics. Depression and Anxiety, 32, 861–870.Google Scholar
Rodrigues, G. M. Jr., Toffoli, L. V., Manfredo, M. H., Francis-Oliveira, J., Silva, A. S., Raquel, H. A., et al. (2015). Acute stress affects the global DNA methylation profile in rat brain: Modulation by physical exercise. Behavioural Brain Research, 279, 123–128.Google Scholar
Rohleder, N., Joksimovic, L., Wolf, J. M., & Kirschbaum, C. (2004). Hypocortisolism and increased glucocorticoid sensitivity of pro-inflammatory cytokine production in Bosnian war refugees with posttraumatic stress disorder. Biological Psychiatry, 55, 745–751.Google Scholar
Romens, S. E., McDonald, J., Svaren, J., & Pollak, S. D. (2015). Associations between early life stress and gene methylation in children. Child Development, 86, 303–309.Google Scholar
Ruttle, P. L., Shirtcliff, E. A., Serbin, L. A., Fisher, D. B., Stack, D. M., & Schwartzman, A. E. (2011). Disentangling psychobiological mechanisms underlying internalizing and externalizing behaviors in youth: Longitudinal and concurrent associations with cortisol. Hormones and Behavior, 59, 123–132.Google Scholar
Schmidt, U., Buell, D. R., Ionescu, I. A., Gassen, N. C., Holsboer, F., Cox, M. B., et al. (2015). A role for synapsin in FKBP51 modulation of stress responsiveness: Convergent evidence from animal and human studies. Psychoneuroendocrinology, 52, 43–58.Google Scholar
Skupio, U., Tertil, M., Sikora, M., Golda, S., Wawrzczak-Bargiela, A., & Przewlocki, R. (2015). Behavioral and molecular alterations in mice resulting from chronic treatment with dexamethasone: Relevance to depression. Neuroscience, 286, 141–150.CrossRefGoogle ScholarPubMed
Slopen, N., Koenen, K. C., & Kubzansky, L. D. (2014). Cumulative adversity in childhood and emergent risk factors for long-term health. Journal of Pediatrics, 164, 631–638.Google Scholar
Slopen, N., McLaughlin, K. A., & Shonkoff, J. P. (2014). Interventions to improve cortisol regulation in children: A systematic review. Pediatrics, 133, 312–326.CrossRefGoogle ScholarPubMed
Steiger, H., Labonte, B., Groleau, P., Turecki, G., & Israel, M. (2013). Methylation of the glucocorticoid receptor gene promoter in bulimic women: Associations with borderline personality disorder, suicidality, and exposure to childhood abuse. International Journal of Eating Disorders, 46, 246–255.Google Scholar
Struber, N., Struber, D., & Roth, G. (2014). Impact of early adversity on glucocorticoid regulation and later mental disorders. Neuroscience & Biobehavioral Reviews, 38, 17–37.Google Scholar
Suzuki, A., Matsumoto, Y., Sadahiro, R., Enokido, M., Goto, K., & Otani, K. (2014). Relationship of the FKBP5 C/T polymorphism with dysfunctional attitudes predisposing to depression. Comprehensive Psychiatry, 55, 1422–1425.Google Scholar
Szczepankiewicz, A., Leszczynska-Rodziewicz, A., Pawlak, J., Narozna, B., Rajewska-Rager, A., Wilkosc, M., et al. (2014). FKBP5 polymorphism is associated with major depression but not with bipolar disorder. Journal of Affective Disorders, 164, 33–37.Google Scholar
Szyf, M. (2013). The genome- and system-wide response of DNA methylation to early life adversity and its implication on mental health. Canadian Journal of Psychiatry, 58, 697–704.Google Scholar
Szyf, M. (2015). Epigenetics, a key for unlocking complex CNS disorders? Therapeutic implications. European Neuropsychopharmacology, 25, 682–702.Google Scholar
Tatro, E. T., Everall, I. P., Kaul, M., & Achim, C. L. (2009). Modulation of glucocorticoid receptor nuclear translocation in neurons by immunophilins FKBP51 and FKBP52: Implications for major depressive disorder. Brain Research, 1286, 1–12.Google Scholar
Tottenham, N., & Sheridan, M. A. (2009). A review of adversity, the amygdala and the hippocampus: A consideration of developmental timing. Frontiers in Human Neuroscience, 3, 68.Google Scholar
Turner, J. D., Alt, S. R., Cao, L., Vernocchi, S., Trifonova, S., Battello, N., et al. (2010). Transcriptional control of the glucocorticoid receptor: CpG islands, epigenetics and more. Biochemical Pharmacology, 80, 1860–1868.Google Scholar
Turner, J. D., Pelascini, L. P., Macedo, J. A., & Muller, C. P. (2008). Highly individual methylation patterns of alternative glucocorticoid receptor promoters suggest individualized epigenetic regulatory mechanisms. Nucleic Acids Research, 36, 7207–7218.CrossRefGoogle ScholarPubMed
Turner, J. D., Vernocchi, S., Schmitz, S., & Muller, C. P. (2014). Role of the 5′-untranslated regions in post-transcriptional regulation of the human glucocorticoid receptor. Biochimica et Biophysica Acta, 1839, 1051–1061.Google Scholar
Tyrka, A. R., Burgers, D. E., Philip, N. S., Price, L. H., & Carpenter, L. L. (2013). The neurobiological correlates of childhood adversity and implications for treatment. Acta Psychiatrica Scandinavica, 128, 434–447.Google Scholar
Tyrka, A. R., Kelly, M. M., Graber, J. A., DeRose, L., Lee, J. K., Warren, M. P., et al. (2010). Behavioral adjustment in a community sample of boys: Links with basal and stress-induced salivary cortisol concentrations. Psychoneuroendocrinology, 35, 1167–1177.Google Scholar
Tyrka, A. R., Lee, J. K., Graber, J. A., Clement, A. M., Kelly, M. M., DeRose, L., et al. (2012). Neuroendocrine predictors of emotional and behavioral adjustment in boys: Longitudinal follow-up of a community sample. Psychoneuroendocrinology, 37, 2042–2046.Google Scholar
Tyrka, A. R., Parade, S. H., Eslinger, N. M., Marsit, C. J., Lesseur, C., Armstrong, D. A., et al. (2015). Methylation of exons 1D, 1F, and 1H of the glucocorticoid receptor gene promoter and exposure to adversity in preschool-aged children. Development and Psychopathology, 27, 577–585.Google Scholar
Tyrka, A. R., Price, L. H., Marsit, C., Walters, O. C., & Carpenter, L. L. (2012). Childhood adversity and epigenetic modulation of the leukocyte glucocorticoid receptor: Preliminary findings in healthy adults. PLOS ONE, 7, e30148.Google Scholar
Tyrka, A. R., Wier, L., Price, L. H., Ross, N., Anderson, G. M., Wilkinson, C. W., et al. (2008). Childhood parental loss and adult hypothalamic–pituitary–adrenal function. Biological Psychiatry, 63, 1147–1154.Google Scholar
van Andel, H. W., Jansen, L. M., Grietens, H., Knorth, E. J., & van der Gaag, R. J. (2014). Salivary cortisol: A possible biomarker in evaluating stress and effects of interventions in young foster children? European Child & Adolescent Psychiatry, 23, 3–12.Google Scholar
van der Knaap, L. J., Riese, H., Hudziak, J. J., Verbiest, M. M., Verhulst, F. C., Oldehinkel, A. J., et al. (2014). Glucocorticoid receptor gene (NR3C1) methylation following stressful events between birth and adolescence: The TRAILS study. Translational Psychiatry, 4, e381.Google Scholar
van der Knaap, L. J., van Oort, F. V., Verhulst, F. C., Oldehinkel, A. J., & Riese, H. (2015). Methylation of NR3C1 and SLC6A4 and internalizing problems: The TRAILS study. Journal of Affective Disorders, 180, 97–103.Google Scholar
van der Kooij, M. A., Grosse, J., Zanoletti, O., Papilloud, A., & Sandi, C. (2015). The effects of stress during early postnatal periods on behavior and hippocampal neuroplasticity markers in adult male mice. Neuroscience, 311, 508–518.Google Scholar
van Donkelaar, E. L., Vaessen, K. R., Pawluski, J. L., Sierksma, A. S., Blokland, A., Canete, R., et al. (2014). Long-term corticosterone exposure decreases insulin sensitivity and induces depressive-like behaviour in the C57BL/6NCrl mouse. PLOS ONE, 9, e106960.Google Scholar
Van Zomeren-Dohm, A. A., Pitula, C. E., Koss, K. J., Thomas, K., & Gunnar, M. R. (2015). FKBP5 moderation of depressive symptoms in peer victimized, post-institutionalized children. Psychoneuroendocrinology, 51, 426–430.Google Scholar
van Zuiden, M., Geuze, E., Willemen, H. L., Vermetten, E., Maas, M., Heijnen, C. J., et al. (2011). Pre-existing high glucocorticoid receptor number predicting development of posttraumatic stress symptoms after military deployment. American Journal of Psychiatry, 168, 89–96.Google Scholar
Vukojevic, V., Kolassa, I. T., Fastenrath, M., Gschwind, L., Spalek, K., Milnik, A., et al. (2014). Epigenetic modification of the glucocorticoid receptor gene is linked to traumatic memory and post-traumatic stress disorder risk in genocide survivors. Journal of Neuroscience, 34, 10274–10284.Google Scholar
Vyas, A., Jadhav, S., & Chattarji, S. (2006). Prolonged behavioral stress enhances synaptic connectivity in the basolateral amygdala. Neuroscience, 143, 387–393.Google Scholar
Weaver, I. C., Cervoni, N., Champagne, F. A., D'Alessio, A. C., Sharma, S., Seckl, J. R., et al. (2004). Epigenetic programming by maternal behavior. Nature Neuroscience, 7, 847–854.Google Scholar
Weaver, I. C., Meaney, M. J., & Szyf, M. (2006). Maternal care effects on the hippocampal transcriptome and anxiety-mediated behaviors in the offspring that are reversible in adulthood. Proceedings of the National Academy of Sciences, 103, 3480–3485.Google Scholar
Weder, N., Zhang, H., Jensen, K., Yang, B. Z., Simen, A., Jackowski, A., et al. (2014). Child abuse, depression, and methylation in genes involved with stress, neural plasticity, and brain circuitry. Journal of the American Academy of Child & Adolescent Psychiatry, 53, 417–424.Google Scholar
Wislowska-Stanek, A., Lehner, M., Skorzewska, A., Maciejak, P., Szyndler, J., Turzynska, D., et al. (2013). Corticosterone modulates fear responses and the expression of glucocorticoid receptors in the brain of high-anxiety rats. Neuroscience Letters, 533, 17–22.Google Scholar
Witzmann, S. R., Turner, J. D., Meriaux, S. B., Meijer, O. C., & Muller, C. P. (2012). Epigenetic regulation of the glucocorticoid receptor promoter 1(7) in adult rats. Epigenetics, 7, 1290–1301.Google Scholar
Yehuda, R. (2001). Biology of posttraumatic stress disorder. Journal of Clinical Psychiatry, 62, 41–46.Google Scholar
Yehuda, R., Daskalakis, N. P., Bierer, L. M., Bader, H. N., Klengel, T., Holsboer, F., et al. (2015). Holocaust exposure induced intergenerational effects on FKBP5 methylation. Biological Psychiatry. Advance online publication.Google Scholar
Yehuda, R., Daskalakis, N. P., Desarnaud, F., Makotkine, I., Lehrner, A. L., Koch, E., et al. (2013). Epigenetic biomarkers as predictors and correlates of symptom improvement following psychotherapy in combat veterans with PTSD. Frontiers in Psychiatry, 4, 118.Google Scholar
Yehuda, R., Flory, J. D., Bierer, L. M., Henn-Haase, C., Lehrner, A., Desarnaud, F., et al. (2015). Lower methylation of glucocorticoid receptor gene promoter 1F in peripheral blood of veterans with posttraumatic stress disorder. Biological Psychiatry, 77, 356–364.Google Scholar
Yehuda, R., Flory, J. D., Pratchett, L. C., Buxbaum, J., Ising, M., & Holsboer, F. (2010). Putative biological mechanisms for the association between early life adversity and the subsequent development of PTSD. Psychopharmacology (Berlin), 212, 405–417.Google Scholar
Yehuda, R., Golier, J. A., Bierer, L. M., Mikhno, A., Pratchett, L. C., Burton, C. L., et al. (2010). Hydrocortisone responsiveness in Gulf War veterans with PTSD: Effects on ACTH, declarative memory hippocampal [(18)F]FDG uptake on PET. Psychiatry Research, 184, 117–127.Google Scholar
Yehuda, R., Halligan, S. L., Grossman, R., Golier, J. A., & Wong, C. (2002). The cortisol and glucocorticoid receptor response to low dose dexamethasone administration in aging combat veterans and Holocaust survivors with and without posttraumatic stress disorder. Biological Psychiatry, 52, 393–403.Google Scholar
Yehuda, R., & Seckl, J. (2011). Mini Review: Stress-related psychiatric disorders with low cortisol levels: A metabolic hypothesis. Endocrinology, 152, 4496–4503.Google Scholar
Yehuda, R., Yang, R. K., Golier, J. A., Tischler, L., Liong, B., & Decker, K. (2004). Effect of topiramate on glucocorticoid receptor mediated action. Neuropsychopharmacology, 29, 433–439.Google Scholar
Yehuda, R., Yang, R. K., Guo, S. L., Makotkine, I., & Singh, B. (2003). Relationship between dexamethasone-inhibited lysozyme activity in peripheral mononuclear leukocytes and the cortisol and glucocorticoid receptor response to dexamethasone. Journal of Psychiatric Research, 37, 471–477.Google Scholar
Zannas, A. S., & Binder, E. B. (2014). Gene–environment interactions at the FKBP5 locus: Sensitive periods, mechanisms and pleiotropism. Genes, Brain and Behavior, 13, 25–37.Google Scholar
Zhang, T. Y., Labonte, B., Wen, X. L., Turecki, G., & Meaney, M. J. (2013). Epigenetic mechanisms for the early environmental regulation of hippocampal glucocorticoid receptor gene expression in rodents and humans. Neuropsychopharmacology, 38, 111–123.Google Scholar
Zohar, J., Yahalom, H., Kozlovsky, N., Cwikel-Hamzany, S., Matar, M. A., Kaplan, Z., et al. (2011). High dose hydrocortisone immediately after trauma may alter the trajectory of PTSD: Interplay between clinical and animal studies. European Neuropsychopharmacology, 21, 796–809.Google Scholar