This project examines the intermediate neural systems that mediate the gene-behavior relationships involv- ed in risk for development of substance use disorders (SUDs) with special focus on alcohol, cannabis, and nicotine. We will characterize this circuitry, study its interaction with two intermediate behavioral phenotypes (behavioral undercontrol and negative affectivity), and examine the contribution of selected genetic variants, and early-life stress on the neural correlates of impulsivity and negative emotionality in children with varying risk for development of SUDs in adulthood [G2 sample of the Michigan Longitudinal Study(MLS)]. We will examine these correlates during childhood and begin to characterize changes that occur during adolesc- ence. The general hypothesis is that dysregulation of the brain networks involved in processing and regula- tion of behavior and affect during childhood underlies a heightened predisposition to develop SUDs at a later age. Both behavioral undercontrol and affective dysregulation at an early age are strong predictors of SUDs later in life, and these processes are regulated by complex neuronal circuits. We will use fMRI to investigate these neural systems in a sample of 8-10 year old boys &girls (n=129) from the ongoing MLS in a longitud- inal design in which scanning occurs at 2-year intervals. It is expected that children at high risk for develop- ment of SUDs based on the risk conferred by behavioral phenotypes (measured initially as externalizing and internalizing behavior and later by developmental trajectory classes), will demonstrate alterations in the functional responses of neuronal circuitry involved in impulse control and emotional regulation. It is also ex- pected that this effect will be modified by genes and early-life stress. Changes in brain functional responses over time are expected to be influenced by risk conferred by genetic variants and early stress. As models of gene-trait-environment interaction over time are developed in the MLS, we will investigate the relationship between brain responses and these developmental phenotypes. As substance abuse problems develop in this sample, this information will be available during subsequent funding periods to determine dysfunctions in neural circuitry associated with the early development of SUDs during adolescence.

Public Health Relevance

This project will provide in-depth understanding about the intermediate neural pathways underlying susceptibility to drug use disorders, their genetic basis, and the possible interactive role of the social environment in producing variations in risk over time. Findings will have direct implications for early identific- ation, prevention, and early treatment of at-risk individuals as well as those in early stages of drug addiction.

National Institute of Health (NIH)
National Institute on Drug Abuse (NIDA)
Research Project (R01)
Project #
Application #
Study Section
Special Emphasis Panel (ZDA1-RXL-E (02))
Program Officer
Sirocco, Karen
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Michigan Ann Arbor
Schools of Medicine
Ann Arbor
United States
Zip Code
Hardee, Jillian E; Weiland, Barbara J; Nichols, Thomas E et al. (2014) Development of impulse control circuitry in children of alcoholics. Biol Psychiatry 76:708-16
Glaser, Yi G; Zubieta, Jon-Kar; Hsu, David T et al. (2014) Indirect effect of corticotropin-releasing hormone receptor 1 gene variation on negative emotionality and alcohol use via right ventrolateral prefrontal cortex. J Neurosci 34:4099-107
Heitzeg, Mary M; Villafuerte, Sandra; Weiland, Barbara J et al. (2014) Effect of GABRA2 genotype on development of incentive-motivation circuitry in a sample enriched for alcoholism risk. Neuropsychopharmacology 39:3077-86
Heitzeg, Mary M; Nigg, Joel T; Hardee, Jillian E et al. (2014) Left middle frontal gyrus response to inhibitory errors in children prospectively predicts early problem substance use. Drug Alcohol Depend 141:51-7
Zucker, Robert A (2014) Genes, brain, behavior, and context: the developmental matrix of addictive behavior. Nebr Symp Motiv 61:51-69
Falk, Emily B; Hyde, Luke W; Mitchell, Colter et al. (2013) What is a representative brain? Neuroscience meets population science. Proc Natl Acad Sci U S A 110:17615-22
Weiland, Barbara J; Welsh, Robert C; Yau, Wai-Ying Wendy et al. (2013) Accumbens functional connectivity during reward mediates sensation-seeking and alcohol use in high-risk youth. Drug Alcohol Depend 128:130-9
Villafuerte, S; Strumba, V; Stoltenberg, S F et al. (2013) Impulsiveness mediates the association between GABRA2 SNPs and lifetime alcohol problems. Genes Brain Behav 12:525-31
Villafuerte, S; Heitzeg, M M; Foley, S et al. (2012) Impulsiveness and insula activation during reward anticipation are associated with genetic variants in GABRA2 in a family sample enriched for alcoholism. Mol Psychiatry 17:511-9
Yau, Wai-Ying Wendy; Zubieta, Jon-Kar; Weiland, Barbara J et al. (2012) Nucleus accumbens response to incentive stimuli anticipation in children of alcoholics: relationships with precursive behavioral risk and lifetime alcohol use. J Neurosci 32:2544-51

Showing the most recent 10 out of 12 publications