Linking Genetics, Brain, and Behavior to Understand Addiiction Vulnerability

描述(由申请人提供)：本次申请独立科学家奖(K02)的总体目标是支持候选人作为一名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。遗传因素对成瘾易感性的影响已经有了很好的文献记载，然而，遗传因素对成瘾行为的神经生物学机制仍然知之甚少。候选人的主要理论前提是，行为抑制性自我调节的基因传递缺陷构成了成瘾易感性的核心组成部分。这位候选人使用定量脑电和事件相关脑电位(ERPs)的研究已经确定了一些可遗传的行为调节神经生理学指标，然而，电生理学方法有限的空间分辨率阻碍了对潜在神经基质的识别。因此，应聘者的第一个职业目标是通过正式的课程作业、实践培训以及与华盛顿大学神经成像研究人员开发合作项目，获得功能磁共振成像(FMRI)技术方面的专业知识。第二个职业目标是增加候选人在分析遗传信息的纵向数据方面的高级方法方面的专业知识，例如潜在生长和潜在阶级转变模型。该研究计划借鉴了候选人正在进行的对青春期和年轻成年双胞胎的研究。具体的研究目标是：1)确定成瘾的神经认知内表型，并建立它们的共性和特异性，以及它们前瞻性预测药物使用和滥用的能力；2)通过在PI正在进行的研究中增加功能神经成像评估并整合遗传、功能磁共振和事件相关电位数据，更好地表征行为抑制性自我调节的神经基础；3)结合EEG、ERPS、功能MRI、神经心理测试和诊断评估，对与成瘾易感性有关的基因变异提供功能验证。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，并确定预防和治疗努力的目标。与公共健康相关：研究已经证明了遗传因素在成瘾中的作用，但对基因如何影响复杂的行为知之甚少。研究调节遗传影响行为的神经生物学途径和认知过程将有助于更好地理解成瘾的途径，并确定预防和治疗努力的目标。

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.