Variability in Brain Function Underlying Motivated Behavior in Adolescence

描述（由申请人提供）：青春期是一个独特的发展时期，其特点是高度冒险，表明认知控制和奖励相关行为的持续限制，以及精神病理出现的脆弱性。研究表明，从青春期到成年期，奖励和认知行为背后的额纹状体功能发生了显著的发育变化。然而，影响这些过程发展的核心机制尚不清楚。多巴胺（DA）是大脑额纹状体区域中调节认知和奖励相关加工的关键神经递质。在青少年时期，DA系统表现出独特的不成熟，这可能导致这一时期奖励处理的限制。成像遗传学研究表明，直接影响DA处理的特定基因的微妙等位基因变异可能对行为相关的神经活动产生深远影响。基因驱动的数据处理变异性如何与年龄相关的数据可用性差异相互作用，这限制了我们理解发育变异性的能力

DESCRIPTION (provided by applicant): 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.