Linking Genetics, Brain, and Behavior to Understand Addiiction Vulnerability

本独立科学家奖(K02)申请的总体目标是支持继续 培养候选人成为一名独立的科学家，促进候选人的跨学科发展 旨在更好地理解物质使用的决定因素和后果的研究计划 精神障碍(SUD)。然而，基因对成瘾易感性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少。 明白了。候选人的主要理论前提是抑制性自我意识的基因传递缺陷 对行为的规范构成了成瘾脆弱性的核心组成部分。应聘者的研究使用 定量脑电和事件相关脑电位(ERPs)已经确定了一些可遗传的 然而，行为调节的神经生理学指标限制了电泳法的空间分辨率。 生理学方法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以下途径获得功能磁共振成像(FMRI)技术方面的专业知识 正式的课程、实践培训，以及与神经成像研究人员合作开发项目 在华盛顿大学。第二个职业目标是增加应聘者在高级领域的专业知识 潜在生长和潜在类别等遗传信息纵向数据的分析方法 过渡建模。这项研究计划借鉴了候选人正在进行的对青少年的研究 成年双胞胎。具体的研究目标是：1)确定成瘾的神经认知内表型和 确定它们的共性与特殊性，以及它们前瞻性预测药物使用和 滥用；2)通过增加功能来更好地表征抑制行为自我调节的神经底物 对PI正在进行的研究进行神经成像评估，并整合遗传、功能磁共振和事件相关电位数据；3) 使用组合提供与成瘾易感性有关的遗传变异的功能验证 EEG、ERPS、功能磁共振、神经心理测试和诊断评估。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带来更好的 了解成瘾的途径，并确定预防和治疗工作的目标。 相关性(请参阅说明)： 研究已经证明了遗传因素在成瘾中的作用，但对基因是如何作用的知之甚少 对复杂的行为施加影响.研究神经生物学途径和认知 调节遗传影响行为的过程将使人们更好地理解 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.