Linking Genetics, Brain, and Behavior to Understand Addiiction Vulnerability

独立科学家奖（K 02）申请的总体目标是支持继续 发展候选人作为一个独立的科学家，并促进候选人的跨学科 旨在更好地了解物质使用的决定因素和后果的研究计划 疾病（SUD）。然而，遗传对成瘾倾向的影响是有据可查的， 遗传因素导致成瘾行为的神经生物学机制仍然很差 明白候选人的主要理论前提是，遗传性的抑制性自我缺陷， 行为调控构成成瘾脆弱性的核心组成部分。候选人的研究使用 定量EEG和事件相关脑电位（ERP）已经确定了一些遗传性 然而，行为调节的神经生理学指标限制了电泳的空间分辨率， 免疫学方法阻碍了对潜在神经基质的鉴定。因此，候选人的 第一个职业目标是通过以下方式获得功能磁共振成像（fMRI）技术的专业知识： 正式的课程，实践培训，并与神经成像研究人员开发合作项目 在华盛顿大学。第二个职业目标是增加候选人在高级领域的专业知识 分析遗传信息纵向数据的方法，如潜在生长和潜在类别 过渡建模该研究计划借鉴了候选人正在进行的青少年和青年研究， 成年双胞胎具体的研究目标是：1）识别成瘾的神经认知内表型， 确定其共性与特异性，以及前瞻性预测物质使用的能力， 滥用; 2）通过添加功能性的，以更好地表征行为的抑制性自我调节的神经基质 神经影像学评估PI正在进行的研究，并整合遗传，fMRI和ERP数据; 3） 使用以下组合提供与成瘾易感性有关的遗传变异的功能验证： EEG、ERP、功能性MRI、神经心理学测试和诊断评估。从长远来看， 在基因、大脑功能和行为的抑制控制之间建立联系，将有助于更好地研究人类的行为。 了解成瘾的途径，并确定预防和治疗工作的目标。 相关性（见说明）： 研究已经记录了遗传因素在成瘾中的作用，但对基因如何作用知之甚少。 对复杂的行为施加影响研究神经生物学通路和认知 介导遗传对行为影响的过程将有助于更好地理解 成瘾问题，并确定预防和治疗工作的目标。

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 progrann 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 electrophy- siology 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 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. RELEVANCE (See instmctions): 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.