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，其特征是冒险行为增加，表明认知控制和奖励相关行为的持续限制以及精神病理学出现的脆弱性。研究表明，从青春期到成年期，额纹状体功能发生了显着的发育变化，这些变化是奖励和认知行为的基础。然而，影响这些过程发展的核心机制还没有得到很好的理解。多巴胺（DA）是调节大脑额纹状体区认知和奖赏相关加工的关键神经递质。在青春期，DA系统表现出独特的不成熟，这可能有助于在这段时间内奖励处理的限制。成像遗传学研究表明，直接影响DA加工的特定基因中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。DA加工中遗传驱动的变异性如何与DA可用性中与年龄相关的差异相互作用还没有很好地理解，这限制了我们理解发育中的变异性的能力。 动机复杂行为的轨迹在青少年发育过程中，将成像遗传学与脑成像研究相结合，有助于澄清已知的与年龄相关的奖励处理和认知控制差异，并有助于我们对DA对行为影响的基本理解。参与DA突触运输并可能对奖赏和认知控制系统产生影响的两种关键酶是儿茶酚-O-甲基转移酶（COMT）和多巴胺转运蛋白（DAT 1）。由于这些酶对PFC和纹状体有不同的影响，因此研究其基因型变异的影响提供了一种新的方法来检查额纹状体网络的完整性。我们将从我们正在进行的父母资助项目中的受试者那里获得唾液样本，以调查奖励处理对认知控制发展的影响的行为和神经影像学证据。我们将研究COMT基因的单核苷酸多态性（val 158 met），以及SLC 6A 3基因的可变核苷酸串联重复序列（VNTR）多态性在基于激励的认知控制的神经系统发育的背景下。本修订的具体目的是：1）表征通过SLC 6A 3和COMT表达的遗传驱动的DA变异对奖励处理和认知控制相关脑功能的影响; 2）确定与成年期相比，青春期遗传驱动的变异对所得行为相关神经回路的影响差异。多元回归和多变量成像统计方法将用于探索年龄和基因型效应和相互作用。这种综合性的神经科学方法将允许更好地理解基因和行为相关的神经系统的功能之间的关联，并支持由此产生的行为影响的推论，在青少年发展的框架内。 公共卫生相关性：我们建议调查的生物学机制的认知控制和奖励处理的发展超过青春期。这项研究的结果可以通过阐明青少年行为个体间差异的大脑基础来为发展神经科学，教育和临床方法提供信息。所获得的知识可以提供一个规范的模板的范围内的过程的青少年动机的行为，可以用来更好地表征这一时期的发展，以确定神经生物学机制的冒险行为，可以破坏生存。

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. 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.