Linking Genetics, Brain, and Behavior to Understand Addiiction Vulnerability

将遗传学、大脑和行为联系起来以了解成瘾脆弱性

• 批准号: 8104236
• 负责人: Andrey P. Anokhin
• 金额: $ 11.77万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-07-15 至 2014-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8104236
• 关键词: Addictive Behavior; Adolescence; Adolescent; Age; Alcohol or Other Drugs use; Alleles; Anterior; Attention; Basal Ganglia; Behavior; Behavior Control; Behavioral; Brain; Characteristics; Cognitive; Complex; Conflict (Psychology); DNA; Data; Decision Making; Development; Diagnostic; Disease; Disinhibition; Electroencephalography; Electrophysiology (science); Epidemiology; Etiology; Evaluation; Event; Frequencies; Functional Magnetic Resonance Imaging; Functional disorder; Funding; Genes; Genetic; Genetic Polymorphism; Genetic Risk; Genetic Structures; Genotype; Goals; Growth; Health; Heritability; Imaging Techniques; Independent Scientist Award; Individual; Individual Differences; Informal Social Control; Interdisciplinary Study; Knowledge; Label; Lateral; Lead; Link; Maintenance; Measures; Mediating; Methods; Modeling; Monitor; National Institute of Drug Abuse; Neural Pathways; Neurobiology; Neurocognitive; Neuropsychological Tests; Neurosciences Research; Outcome; Participant; Pathway interactions; Pattern; Phenotype; Prefrontal Cortex; Prevention; Process; Psychopathology; Punishment; Regulation; Research; Research Personnel; Resolution; Rewards; Risk; Risk Factors; Role; Sampling; Scientist; Specificity; Structural Models; Substance Addiction; Substance Use Disorder; Substance abuse problem; System; Testing; Time; Training; Twin Multiple Birth; Twin Studies; Universities; Validation; Washington; addiction; base; brain behavior; career; cingulate cortex; cognitive control; cognitive neuroscience; computerized data processing; design; developmental genetics; early adolescence; endophenotype; follow-up; genetic association; genetic linkage; genetic variant; independent component analysis; indexing; neurobiological mechanism; neuroimaging; neuromechanism; neurophysiology; neuropsychological; programs; prospective; relating to nervous system; response; young adult

DESCRIPTION (provided by applicant): The overall goal of this application for an Independent Scientist Award (K02) is to support the continuing development of the candidate as an independent scientist and facilitate the candidate's interdisciplinary research program aimed at a better understanding the determinants and consequences of substance use disorders (SUD). Genetic influences on the liability to addiction are well documented, however, neurobiological mechanisms by which genetic factors contribute to addictive behaviors remain poorly understood. The candidate's major theoretical premise is that genetically transmitted deficits in inhibitory self regulation of behavior constitute a core component of addiction vulnerability. The candidate's research using quantitative EEG and event-related brain potentials (ERPs) has identified a number of heritable neurophysiological indicators of behavioral regulation, however, limited spatial resolution of electrophysiology methods impedes the identification of the underlying neural substrates. Accordingly, the candidate's first career objective is to gain expertise in functional magnetic resonance imaging (fMRI) techniques through formal coursework, hands-on training, and developing collaborative projects with neuroimaging researchers at Washington University. The second career objective is to increase the candidate's expertise in advanced methods for the analysis of genetically informative longitudinal data such as latent growth and latent class transition modeling. The research plan draws upon the candidate's ongoing studies of adolescent and young adult twins. Specific research aims are: 1) to identify neurocognitive endophenotypes for addiction and establish their commonality versus specificity and their ability to prospectively predict substance use and abuse; 2) to better characterize neural substrates of inhibitory self-regulation of behavior by adding functional neuroimaging assessments to the PI's ongoing studies and integrating genetic, fMRI, and ERP data; 3) to provide a functional validation of genetic variants implicated in addiction vulnerability using a combination of EEG, ERPs, functional MRI, neuropsychological testing, and diagnostic assessments. In the long run, establishing the links between genes, brain function, and inhibitory control of behavior will lead to a better understanding of the pathways to addiction and identify targets for prevention and treatment efforts. PUBLIC HEALTH RELEVANCE: Research has documented the role of genetic factors in addictions, but very little is known about how genes exert their influence' on complex behaviors. Investigating the neurobiological pathways and cognitive processes mediating genetic influences on behavior will lead to a better understanding of the pathways to addiction and identify targets for prevention and treatment efforts.

独立科学家奖（K 02）的总体目标是支持候选人作为独立科学家的持续发展，并促进候选人的跨学科研究计划，旨在更好地了解物质使用障碍（SUD）的决定因素和后果。遗传因素对成瘾倾向的影响已被充分证明，然而，遗传因素导致成瘾行为的神经生物学机制仍然知之甚少。这位候选人的主要理论前提是，行为抑制性自我调节的遗传缺陷构成了成瘾脆弱性的核心组成部分。该候选人使用定量EEG和事件相关脑电位（ERP）的研究已经确定了许多行为调节的遗传神经生理指标，然而，电生理方法的有限空间分辨率阻碍了对潜在神经基质的识别。因此，候选人的第一个职业目标是通过正式的课程，实践培训和与华盛顿大学的神经成像研究人员合作开发项目来获得功能性磁共振成像（fMRI）技术的专业知识。第二个职业目标是提高候选人在分析遗传信息纵向数据的先进方法方面的专业知识，如潜在增长和潜在阶级转变建模。该研究计划借鉴了候选人正在进行的青少年和年轻成年双胞胎的研究。具体的研究目标是：1）识别成瘾的神经认知内表型，并建立其共性与特异性以及前瞻性预测物质使用和滥用的能力; 2）通过在PI正在进行的研究中增加功能性神经成像评估并整合遗传，fMRI和ERP数据，更好地表征行为抑制性自我调节的神经基质; 3）使用EEG、ERPs、功能性MRI、神经心理学测试和诊断评估的组合来提供与成瘾易感性有关的遗传变异的功能验证。从长远来看，建立基因、大脑功能和行为抑制控制之间的联系将有助于更好地理解成瘾的途径，并确定预防和治疗的目标。 公共卫生相关性：研究已经证明了遗传因素在成瘾中的作用，但对基因如何对复杂行为施加影响却知之甚少。调查神经生物学途径和认知过程介导的遗传对行为的影响将导致更好地了解成瘾的途径，并确定预防和治疗工作的目标。