Variability in Brain Function Underlying Motivated Behavior in Adolescence

青春期动机行为背后的大脑功能变异

• 批准号: 8424544
• 负责人: BEATRIZ LUNA
• 金额: $ 15.99万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-26 至 2014-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8424544
• 关键词: 3' Untranslated Regions; Adolescence; Adolescent; Adolescent Behavior; Adolescent Development; Adult; Age; Area; Base of the Brain; Behavior; Behavioral; Behavioral Genetics; Biological; Brain; Brain imaging; Brain region; Catechols; Clinical; Cognitive; Collaborations; Complex; Corpus striatum structure; Data; Development; Dopamine; Education; Enrollment; Enzymes; Functional Magnetic Resonance Imaging; Future; Genes; Genetic; Genetic Polymorphism; Genotype; Image; Incentives; Individual; Individual Differences; Knowledge; Literature; Mediating; Methodology; Methyltransferase; Methyltransferase Gene; Neurobiology; Neurosciences; Neurotransmitters; Nucleotides; Parents; Participant; Pattern; Phase; Population; Positioning Attribute; Prefrontal Cortex; Process; Psychopathology; Publishing; Recruitment Activity; Research; Rest; Rewards; Risk-Taking; Role; Saliva; Sample Size; Sampling; Seeds; Series; Shapes; Single Nucleotide Polymorphism; Support System; Synapses; System; Tandem Repeat Sequences; Time; Variant; Ventral Striatum; age related; base; cognitive control; dopamine system; dopamine transporter; emerging adult; gene function; genetic variant; interest; motivated behavior; neural circuit; neurobiological mechanism; neurodevelopment; neuroimaging; novel; parent grant; relating to nervous system; response; reward processing; statistics; trafficking; trait; translational neuroscience; transmission process

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.

描述（由申请人提供）：青春期是一个独特的发展时期，其特点是冒险性增强，表明认知控制和奖励相关行为持续受到限制，并且容易出现精神病理学。研究表明，从青春期到成年，奖励和认知行为背后的额纹状体功能发生了显着的发育变化。然而，影响这些过程发展的核心机制尚不清楚。多巴胺 (DA) 是调节大脑额纹状体区域认知和奖励相关处理的关键神经递质。在青春期，DA 系统表现出独特的不成熟性，这可能会导致这一时期奖励处理的限制。影像遗传学研究表明，直接影响 DA 处理的特定基因中微妙的等位基因变异可以对行为相关的神经活动产生深远的影响。遗传驱动的多巴胺加工变异如何与年龄相关的多巴胺可用性差异相互作用尚不清楚，这限制了我们理解发育变异的能力 动机复杂行为的轨迹。将成像遗传学与青少年发育期间的脑成像研究相结合，可以帮助阐明奖励处理和认知控制方面已知的与年龄相关的差异，并有助于我们对 DA 对行为的影响的基本理解。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邻甲基转移酶 (COMT) 和多巴胺转运蛋白 (DAT1)。由于这些酶对 PFC 和纹状体具有不同的影响，因此研究其基因型变异的影响提供了一种检查额纹状体网络完整性的新方法。我们将从正在进行的家长资助调查中的受试者身上获取唾液样本，调查行为和神经影像证据，以了解奖励处理对认知控制发展的影响。我们将在基于激励的认知控制的发育神经系统的背景下研究 COMT 基因中的单核苷酸多态性 (val158met) 和 SLC6A3 基因的可变核苷酸串联重复 (VNTR) 多态性。本次修订的具体目的是 1) 表征通过 SLC6A3 和 COMT 表达的遗传驱动的 DA 变异对奖励处理和认知控制背后的大脑功能的影响； 2) 确定青春期与成年期遗传驱动变异对行为相关神经回路影响的差异。将使用多元回归和多变量成像统计方法来探索年龄和基因型的影响和相互作用。这种综合神经科学方法将有助于更好地理解基因与行为相关神经系统功能之间的关联，并支持在青少年发展框架内对由此产生的行为影响的推论。 公共健康相关性：我们建议研究青春期认知控制和奖励处理发展背后的生物学机制。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，为发育神经科学、教育和临床方法提供信息。所获得的知识可以提供青少年动机行为背后的一系列过程的规范模板，可以用来更好地描述这一发展时期，以便识别可能破坏生存的冒险行为的神经生物学机制。