Adolescence is a unique period of development characterized by heightened risk-taking indicating continued limitations in cognitive control and reward related behaviors as well as vulnerabilities for the emergence of psychopathology. Studies have shown significant developmental changes in frontostriatal function underlying reward and cognitive behaviors from adolescence to adulthood. However, the core mechanisms influencing the development of these processes are not well understood. Dopamine (DA) is a key neurotransmitter in the modulation of cognitive and reward-related processing in frontostriatal regions of the brain. During adolescence, the DA system demonstrates unique immaturities which may contribute to limitations in reward processing during this time. Imaging genetics studies have shown that subtle allelic variations in specific genes that directly impact DA processing, can have profound impact on behaviorally relevant neural activity. How genetically-driven variability in DA processing interacts with age-related differences in DA availablity are not well understood limiting our ability to understand variability in developmental trajectories of motivated complex behavior. Incorporating imaging genetics with brain-imaging studies during adolescent development can help clarify known age-related differences in reward processing and cognitive control as well as contribute to our basic understanding of DA's effect on behavior. Two crucial enzymes involved in the synaptic trafficking of DA and likely to have impact on reward and cognitive control systems are catechol-o-methyltransferase (COMT) and the dopamine transporter (DAT1). Because these enzymes have differential effects on PFC and striatum, investigating effects of their genotypic variation offers a new way to examine the integrity of frontostriatal networks. We will obtain saliva samples from subjects in our ongoing parent grant investigating behavioral and neuroimaging evidence for the effects of reward processing on the development of cognitive control. We will study a single nucleotide polymorphism (val158met) in the COMT gene, and a variable-nucleotide tandem repeat (VNTR) polymorphism of the SLC6A3 gene within the context of the development neural systems underlying incentive-based cognitive control.
The specific aims of this revision are to 1) characterize the influence of genetically-driven DA variation expressed through SLC6A3 and COMT on brain function underlying reward processing and cognitive control;2) To identify differences in the influence of genetically- driven variation on resulting behaviorally-relevant neural circuitry in adolescence compared to adulthood. Multiple regression and multi-variate imaging statistics methodologies will be used to explore age and genotype effects and interactions. This integrative neuroscience approach will allow greater understanding of associations between genes and the function of behaviorally relevant neural systems and support inferences about resulting behavioral implications, within a framework of adolescent development.

Public Health Relevance

We propose to investigate biological mechanisms underlying the development of cognitive control and reward processing over adolescence. Results from this research can inform developmental neuroscience, education, and clinical approaches by elucidating the brain basis of inter-individual differences in adolescent behavior. The knowledge acquired can provide a normative template of the range of processes underlying adolescent motivated behavior that can be used to better characterize this period of development in order to identify neurobiological mechanisms of risk taking behavior that can undermine survival.

National Institute of Health (NIH)
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Exploratory/Developmental Grants (R21)
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Cognition and Perception Study Section (CP)
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Freund, Lisa S
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University of Pittsburgh
Schools of Medicine
United States
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Di Martino, Adriana; Fair, Damien A; Kelly, Clare et al. (2014) Unraveling the miswired connectome: a developmental perspective. Neuron 83:1335-53