A history of early life stress is an important risk factor for depressive and anxiety disorders and a range of poor health outcomes. Alterations in the neuroendocrine and immune systems, key pathways in the neurobiological response to stress, are involved in the stress-induced changes that are linked to depressive and anxiety disorders. Recent work indicates that epigenetic modifications to genes in these pathways may be a central mechanism of the effects of childhood adversity. Gene methylation is a stable form of epigenetic modification that reduces gene transcription. The glucocorticoid receptor (GR), which regulates neuroendocrine function through a negative feedback mechanism and contributes to the modulation of immune function, has been the topic of most research on this subject. There is great interest in developing peripheral blood biomarkers of risk for disorders. Abnormalities of endocrine and inflammatory function in peripheral blood can shed light on stress-related immune, vascular, and metabolic abnormalities, and there is some evidence of correspondence between peripheral and central gene regulation for some genes. Multiple genes in the glucocorticoid and inflammatory-signaling pathways are likely involved in the response to childhood adversity. Data on effects of stress exposure on adrenocortical function in MDD and PTSD are mixed with respect to the nature and direction of effects. Studies of the long-term consequences of childhood adversity in adults are limited by recall and judgment biases, a mixture of types of maltreatment, and lack of data on developmental timing. In addition, variability in the literature on adrenocortical function in MDD and PTSD necessitates a greater understanding of the nature of phenotypes and mechanisms involved. The goal of this proposal is to study the effects of chronic childhood adversity on endophenotypes including methylation of genes in the glucocorticoid and inflammatory-signaling pathways, basal and provoked measures of neuroendocrine and immune function, and glucocorticoid receptor sensitivity, as well as phenotypes including measures of coping and behavioral/emotional responses to stress, depressive and anxiety disorder symptoms and diagnose, and measures of somatic symptoms and health. These measures will be tested in a clearly articulated model to yield specific knowledge about the mechanisms of risk for stress-related disorders.

Public Health Relevance

The proposed study seeks to examine the determinants and consequences of epigenetic modifications of key genes and gene pathways in the neuroendocrine and immune systems in a sample of young adults with and without a history of chronic childhood adversity. Results of this study will provide insight into the neurobiological markers and mechanisms of illness in individuals at-risk for depressive and anxiety disorders and other poor health outcomes due childhood adversity, and provide data for new treatments and prevention approaches.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
5R01MH101107-03
Application #
9034669
Study Section
Biobehavioral Mechanisms of Emotion, Stress and Health Study Section (MESH)
Program Officer
Borja, Susan
Project Start
2014-04-17
Project End
2019-03-31
Budget Start
2016-04-01
Budget End
2017-03-31
Support Year
3
Fiscal Year
2016
Total Cost
Indirect Cost
Name
Butler Hospital (Providence, RI)
Department
Type
DUNS #
069847804
City
Providence
State
RI
Country
United States
Zip Code
Novick, Andrew M; Levandowski, Mateus L; Laumann, Laura E et al. (2018) The effects of early life stress on reward processing. J Psychiatr Res 101:80-103
Tyrka, A R; Parade, S H; Welch, E S et al. (2016) Methylation of the leukocyte glucocorticoid receptor gene promoter in adults: associations with early adversity and depressive, anxiety and substance-use disorders. Transl Psychiatry 6:e848
Tyrka, Audrey R; Ridout, Kathryn K; Parade, Stephanie H (2016) Childhood adversity and epigenetic regulation of glucocorticoid signaling genes: Associations in children and adults. Dev Psychopathol 28:1319-1331
Ridout, Kathryn K; Carpenter, Linda L; Tyrka, Audrey R (2016) The Cellular Sequelae of Early Stress: Focus on Aging and Mitochondria. Neuropsychopharmacology 41:388-9
Ganança, Licínia; Oquendo, Maria A; Tyrka, Audrey R et al. (2016) The role of cytokines in the pathophysiology of suicidal behavior. Psychoneuroendocrinology 63:296-310
Kaufman, Joan; Gelernter, Joel; Hudziak, James J et al. (2015) The Research Domain Criteria (RDoC) Project and Studies of Risk and Resilience in Maltreated Children. J Am Acad Child Adolesc Psychiatry 54:617-25