The primary aim of the current application is to test a novel model of how the relative responsiveness of reward- and threat-related neural circuits interact with life stress to predict drug use in a large cohort of adolescents and young adults. The application also aims to identify genetic profiles representing variability in key neuromodulatory pathways that predict these interactions. To address these specific aims the application will collect measures of: 1) core behavioral processes that serve as risk factors for drug use and abuse, 2) brain circuits supporting threat and reward responsiveness as well as behavioral control, 3) the experience of stressful life events and 4) DNA sequence variation in 600 18-22 year old undergraduates. All measures will be collected using the existing extensive research infrastructure of the Duke Neurogenetics Study. Innovative analytic strategies for modeling individual differences will be applied to these data in the service of identifying behavioral, neurobiological, environmental and genetic mechanisms mediating variability in risk behaviors. The predictive utility of our findings for informing developmental trajectories of drug use, abuse, and dependence will be tested through federated studies. These studies are collecting overlapping measures in both community samples as well as longitudinal samples of patients and individuals at high risk (e.g., low SES, positive family history). Data federation wil also provide replication data sets and/or additional power for testing novel associations between neural, genetic, and environmental variation and the emergence of psychopathology. Furthermore, existing collaborations with investigators using animal models of human behavior and disease as well as those conducting epidemiological gene-environment interaction research will facilitate unique translational projects based on our findings. These collaborations will allo for identification of both detailed molecular mechanisms and broader clinical relevance. Collectively, the research proposed will reveal mechanisms and pathways that predict psychopathology with a focus on drug use and the transition to abuse, which represents a major thrust of current research supported by NIDA and is consistent with the Research Domain Criteria (RDoC) emphasis on classifying psychopathology based on dimensions of observable behavior and neurobiological measures.

Public Health Relevance

The proposed research offers a unique opportunity to identify specific markers of brain function, genetics, experience, and behavior that: 1) predict an individual's risk for drug use, 2) inform the likelihood of transitioning from use to abuse and 3) highlight new targets for better treatment and prevention of drug abuse and comorbid mental illnesses.

National Institute of Health (NIH)
National Institute on Drug Abuse (NIDA)
Research Project (R01)
Project #
Application #
Study Section
Biobehavioral Regulation, Learning and Ethology Study Section (BRLE)
Program Officer
Sirocco, Karen
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Duke University
Schools of Arts and Sciences
United States
Zip Code
Carey, Caitlin E; Knodt, Annchen R; Conley, Emily Drabant et al. (2017) Reward-related ventral striatum activity links polygenic risk for attention-deficit/hyperactivity disorder to problematic alcohol use in young adulthood. Biol Psychiatry Cogn Neurosci Neuroimaging 2:180-187
Trampush, J W; Yang, M L Z; Yu, J et al. (2017) GWAS meta-analysis reveals novel loci and genetic correlates for general cognitive function: a report from the COGENT consortium. Mol Psychiatry 22:336-345
Swartz, Johnna R; Prather, Aric A; Hariri, Ahmad R (2017) Threat-related amygdala activity is associated with peripheral CRP concentrations in men but not women. Psychoneuroendocrinology 78:93-96
Agrawal, A; Chou, Y-L; Carey, C E et al. (2017) Genome-wide association study identifies a novel locus for cannabis dependence. Mol Psychiatry :
Scult, M A; Paulli, A R; Mazure, E S et al. (2017) The association between cognitive function and subsequent depression: a systematic review and meta-analysis. Psychol Med 47:1-17
Gard, Arianna M; Waller, Rebecca; Shaw, Daniel S et al. (2017) The long reach of early adversity: Parenting, stress, and neural pathways to antisocial behavior in adulthood. Biol Psychiatry Cogn Neurosci Neuroimaging 2:582-590
Swartz, Johnna R; Prather, Aric A; Di Iorio, Christina R et al. (2017) A Functional Interleukin-18 Haplotype Predicts Depression and Anxiety through Increased Threat-Related Amygdala Reactivity in Women but Not Men. Neuropsychopharmacology 42:419-426
Scult, Matthew A; Knodt, Annchen R; Hanson, Jamie L et al. (2017) Individual differences in regulatory focus predict neural response to reward. Soc Neurosci 12:419-429
Di Iorio, Christina R; Carey, Caitlin E; Michalski, Lindsay J et al. (2017) Hypothalamic-pituitary-adrenal axis genetic variation and early stress moderates amygdala function. Psychoneuroendocrinology 80:170-178
Scult, Matthew A; Knodt, Annchen R; Swartz, Johnna R et al. (2017) Thinking and Feeling: Individual Differences in Habitual Emotion Regulation and Stress-Related Mood are Associated with Prefrontal Executive Control. Clin Psychol Sci 5:150-157

Showing the most recent 10 out of 57 publications