Childhood maltreatment, in the form of abuse and neglect, is a major public health problem. Maltreated children have elevated rates of internalizing psychopathology and are at high risk for a broad range of adverse outcomes. Infants and young children are at the greatest risk of maltreatment and may have the most severe squeal of maltreatment. Insofar as primary prevention of maltreatment is often not feasible, the identification of factors that influence positive outcomes in maltreated children is critically important. Genetic risk and protective factors appear to play an important role in the behavioral squeal of childhood maltreatment. A number of recent studies have identified specific genes that interact with childhood adversity to produce risk for major depression and anxiety-related traits in adults and children. These include genes that regulate monoamine neurotransmission and neuroendocrine function. One likely mechanism of gene-environment interactions is that risk genes may confer sensitivity to stress, possibly through altered functioning of the HPA axis. A substantial body of evidence documents dysregulation of HPA axis function in animal models of early adversity. A growing body of research in children and adults with a history of early maltreatment provides evidence of dysfunction of this stress system (which may be reflected in exaggerated or attenuated cortisol responses). Converging lines of evidence from preclinical and clinical studies indicate that excessive activation of the HPA axis may be toxic and result in alterations of brain structure and function in circuitry involved in major depression and other disorders. In addition to enduring neuroendocrine effects of early-life stress, such HPA axis hyperactivity may in part result from gene variants involved in the regulation of this stress axis. The goal of the present application is to identify genetic and neuroendocrine predictors of behavior problems and psychopathology in maltreated preschoolers. Genes that regulate monoamine or HPA axis function will be examined based on involvement in neural pathways implicated in these behavioral problems as well as prior empirical associations with internalizing disorders and maltreatment. Further, we seek to determine whether alterations in HPA axis function mediate these relationships. A follow-up assessment will examine prospective relationships between these biomarkers and behavioral outcomes as well as the stability of associations of neuroendocrine activity with behavior. These results should provide valuable information regarding the development of affective and behavioral problems in maltreated children that could guide treatment and prevention efforts as well as direction for future clinical research efforts.

Public Health Relevance

The proposed study seeks to elucidate neurobiological and social risk and protective factors for behavior problems in maltreated children. Results of this study may provide insight into the neurobiological markers and mechanisms of psychopathology in these vulnerable children. Such information may contribute to future treatment and prevention efforts.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
5R01MH083704-02
Application #
8010183
Study Section
Psychosocial Development, Risk and Prevention Study Section (PDRP)
Program Officer
Sarampote, Christopher S
Project Start
2010-01-01
Project End
2014-11-30
Budget Start
2010-12-01
Budget End
2011-11-30
Support Year
2
Fiscal Year
2011
Total Cost
$453,422
Indirect Cost
Name
Butler Hospital (Providence, RI)
Department
Type
DUNS #
069847804
City
Providence
State
RI
Country
United States
Zip Code
02906
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Parade, Stephanie H; Parent, Justin; Rabemananjara, Kantoniony et al. (2017) Change in FK506 binding protein 5 (FKBP5) methylation over time among preschoolers with adversity. Dev Psychopathol 29:1627-1634
Parade, Stephanie H; Novick, Andrew M; Parent, Justin et al. (2017) Stress exposure and psychopathology alter methylation of the serotonin receptor 2A (HTR2A) gene in preschoolers. Dev Psychopathol 29:1619-1626
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
Parade, Stephanie H; Ridout, Kathryn K; Seifer, Ronald et al. (2016) Methylation of the Glucocorticoid Receptor Gene Promoter in Preschoolers: Links With Internalizing Behavior Problems. Child Dev 87:86-97
Ridout, Kathryn K; Ridout, Samuel J; Price, Lawrence H et al. (2016) Depression and telomere length: A meta-analysis. J Affect Disord 191:237-47
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
Tyrka, Audrey R; Parade, Stephanie H; Valentine, Thomas R et al. (2015) Adversity in preschool-aged children: Effects on salivary interleukin-1?. Dev Psychopathol 27:567-76

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