Linking Genetics, Brain, and Behavior to Understand Addiiction Vulnerability

描述（由申请人提供）：本次独立科学家奖（K02）申请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，旨在更好地理解物质使用障碍（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记录，然而，遗传因素对成瘾行为的神经生物学机制仍知之甚少。候选人的主要理论前提是，在行为的抑制性自我调节基因传递缺陷构成成瘾脆弱性的核心组成部分。该候选人使用定量脑电图和事件相关脑电位（ERPs）进行的研究已经确定了一些可遗传的行为调节神经生理指标，然而，电生理学方法的空间分辨率有限，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课程、实践培训和与华盛顿大学神经成像研究人员开展合作项目，获得功能磁共振成像（fMRI）技术方面的专业知识。第二个职业目标是提高候选人在遗传信息纵向数据分析的先进方法方面的专业知识，如潜在增长和潜在类别转换模型。该研究计划借鉴了候选人正在进行的关于青春期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，建立它们的共性与特异性，以及它们预测药物使用和滥用的能力；2)通过在PI正在进行的研究中加入功能性神经影像学评估，并整合遗传、fMRI和ERP数据，更好地表征抑制自我调节行为的神经基质；3)结合脑电图、erp、功能MRI、神经心理测试和诊断评估，对与成瘾易感性相关的基因变异进行功能验证。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。公共健康相关性：研究已经记录了遗传因素在成瘾中的作用，但对于基因如何对复杂行为施加影响却知之甚少。研究神经生物学途径和认知过程介导基因对行为的影响，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。

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.