Proj 4: Genetics (197-223)

对执行功能(EFS)的分子遗传学研究检测了多巴胺(DA)相关基因的作用，为DA调节执行控制的广泛观点提供了一些支持。然而，这些研究对目前对EFS的理解几乎没有影响，因为它们通常只检查了很少的DA基因，并且专注于通过单个额叶测试测量的总体执行控制，而不是认知文献中确定的可分离的、理论上定义的EFS。这个项目的目标是结合计算模型使用分子遗传分析来更详细地说明DA系统如何调节三个相互关联但可分离的EFS-抑制优势反应、更新工作记忆和改变思维模式。通过这样做，它将开始跨越心理、计算和神经生物学层面上目前对EFS的理解。主要数据集将是来自814对17岁双胞胎个体的现有EF数据。我们的多变量分析表明，三个EF潜在变量具有高度的遗传性，反映了共同和独特的遗传影响。该项目将迈出重要的下一步，明确不同的DA相关基因如何影响EFS中常见和独特的遗传变异。具体地说，我们将(1)使用EF任务的计算模型来生成预测并将结果纳入遗传分析，目的是开发更详细的模型，说明DA系统如何动态地调节执行控制；(2)检查大量DA相关基因的多态对每个EF的差异的程度，以及三个EF的贡献是否不同；以及(3)对从相同或可比较的EF任务收集的数据进行平行分析，这些数据是选择学习、行为和/或注意力问题的受试者正在进行的三项研究的一部分。对临床极端组和未选定样本的结果进行比较，将提供有关DA如何调节EFS的额外信息来源，并作为中心研究人员及其合作者目前正在收集的这些和其他临床样本的未来翻译研究的基础。因此，拟议的研究结果将有助于更好地理解DA如何调节正常年轻人的不同EFS，对与健康和临床人群的日常认知功能和EF缺陷有关的公共卫生问题具有广泛的影响。

Molecular genetic studies of executive functions (EFs) examining the roles of dopamine-(DA) related genes have provided some support for the widely held view that DA modulates executive control. However, these studies have had little impact on current understanding of EFs, because they have usually only examined very few DA genes and have focused on gross executive control as measured by individual frontal-lobe tests, rather than separable, theoretically defined EFs identified in the cognitive literature. The goal of this project is to use molecular genetic analyses in concert with computational modeling to specify in more detail how the DA system regulates three correlated but separable EFs - inhibiting prepotent responses, updating working memory, and shifting mental sets. In doing so, it will begin to bridge current understanding of EFs across the psychological, computational, and neurobiological levels. The primary dataset will be existing EF data from 814 individual twins aged 17. Our multivariate analyses indicate that the three EF latent variables are highly heritable and reflect both common and unique genetic influences. This project will take the important next step of specifying how different DA-related genes influence the common and unique genetic variance in EFs. Specifically, we will (1) use computational models of EF tasks to both generate predictions and incorporate results for genetic analyses, with the goal of developing more detailed models of how the DA system dynamically regulates executive control; (2) examine the extent to which polymorphisms in a large set of DA-related genes contribute to variance in each EF, and whether the contributions differ for the three EFs; and (3) conduct parallel analyses on data from identical or comparable EF tasks collected as part of three ongoing studies of subjects selected for learning, conduct, and/or attention problems. Comparison of the results for the clinically extreme groups versus unselected samples will provide an additional source of information about how DA modulates EFs and serve as a foundation for future translational research in these and other clinical samples that are currently being collected by Center investigators and their collaborators. Hence, the results of the proposed study will contribute to a better understanding of how DA modulates different EFs in normal young adults, with broad implications for public health issues related to everyday cognitive functioning and EF deficits in both healthy and clinical populations.