Effects of dopaminergic genotypes on resting state connectivity relevant to execu

描述（由申请人提供）：支持执行控制的脑功能个体变异的一个重要来源是多巴胺（DA）调节的遗传变异。细胞外DA水平因清除机制的功能多态性而变化：COMT（儿茶酚- o -甲基转移酶），一种主要在前额皮质（PFC）降解DA的酶，有两种遗传变异（Val, Met）， DAT（多巴胺转运蛋白），一种主要在纹状体释放后重新吸收多巴胺的蛋白质，有两种常见的遗传变异（10-repeat, 9-repeat）。与pfc纹状体回路对工作记忆等执行操作的重要性相一致，这两种多态性的独立、互动和叠加效应在工作记忆的功能激活中是明显的。然而，这些遗传差异是否延伸到任务执行和无任务“静息状态”的功能连接尚不清楚。在休息（无任务状态）时，缓慢的自发神经活动被组织在由时间相关区域组成的网络中，这些区域的地形与任务诱发的功能组织重叠。这些网络的完整性预示着健康的注意力控制，并在精神疾病中被破坏，如精神分裂症和多动症，其发病机制分别涉及COMT和DAT基因型。因此，了解健康静息状态连通性的遗传变异对于提示与这些疾病相关的认知障碍易感性的神经解剖学机制是重要的。我们假设COMT和DAT基因型对功能连通性的影响将在任务诱发和静息状态下平行于三个网络，即任务负性网络（默认模式）和两个任务正性网络（执行控制和显著性）。具有COMT （Val/Val, Val/Met, Met/Met）和DAT（10/ 10,9 / 10,9 /9）等位基因组合的健康成人将在工作记忆（2-back vs.固定）和休息5分钟时进行功能磁共振成像。具体目标1将检查在工作记忆过程中，COMT和DAT等位基因在激活（任务正网络）和失活（任务负网络）区域以及各自功能连接中的差异。我们将检验基因型的独立和交互（COMT X DAT方差分析）和加性（回归分析）效应。具体目标2将检查COMT和DAT等位基因在静息状态功能连接中的差异，使用来自目标1的种子（验证性分析）以及使用无模型独立成分分析（探索性分析），与Vinod Menon博士合作。我们期望识别与目的1相同的3个网络：1)任务负性网络（内侧pfc -后扣带-海马）；2)执行控制网络（背外侧pfc -外侧顶叶）；3)突出网络（前扣带-岛状叶-边缘）。在这两个分析中，我们将测试基因型差异，如Aim 1所示。这些发现将通过扩展现有知识（任务状态下的连通性）和开辟新领域（休息状态下的连通性）来提供信息。

DESCRIPTION (provided by applicant): An important source of individual variability in brain function supporting executive control is genetic variability in dopamine (DA) regulation. Extracellular DA levels vary by functional polymorphisms of clearance mechanisms: COMT (catechol-O-methyltransferase), an enzyme that degrades DA primarily in prefrontal cortex (PFC), has two genetic variants (Val, Met), and DAT (dopamine transporter), a protein that re-uptakes dopamine following release primarily in the striatum, has two common genetic variants (10-repeat, 9-repeat). Consistent with the importance of PFC-striatal circuits for executive operations such as working memory, independent, interactive, and additive effects of the two polymorphisms are apparent in functional activation during working memory. However, whether those genetic differences extend to functional connectivity during task performance and in the task-free, "resting state" is unknown. Slow spontaneous neural activity during rest (task-free state) is organized in networks comprising temporally correlated regions whose topography overlaps with task-evoked functional organization. The integrity of these networks predicts healthy attentional control and is disrupted in psychiatric disorders with executive dysfunction such as Schizophrenia and ADHD whose pathogenesis involves COMT and DAT genotypes, respectively. Thus, knowledge about genetic variability in healthy resting-state connectivity is important for suggesting neuroanatomical mechanisms of vulnerability to cognitive impairment associated with those disorders. We hypothesize that effects of COMT and DAT genotypes on functional connectivity will be paralleled in the task-evoked and resting- state in three networks, the task-negative network (default-mode) and two task-positive networks (executive control and salience). Healthy adults with combinations of COMT (Val/Val, Val/Met, Met/Met) and DAT (10/10, 9/10, 9/9) alleles will undergo fMRI during working memory (2-back vs. fixation) and during 5 mins of rest. Specific Aim 1 will examine differences by COMT and DAT alleles in activated (task-positive networks) and deactivated (task-negative network) regions and functional connectivity within each during working memory. We will examine independent and interactive (COMT X DAT ANOVA) and additive (regression analysis) effects of the genotypes. Specific Aim 2 will examine differences by COMT and DAT alleles in resting-state functional connectivity identified using seeds derived from Aim 1 (in confirmatory analysis) as well as using model-free Independent Components Analysis (in exploratory analysis), in collaboration with Dr. Vinod Menon. We expect to identify the same 3 networks as in Aim 1: 1) The task-negative network (medial PFC-posterior cingulate-hippocampus); 2) Executive control network (dorsolateral PFC-lateral parietal); and 3) Salience network (anterior cingulate-insula-limbic). In both analyses, we will test for genotype differences as in Aim 1. These findings will be informative by extending current knowledge (connectivity during task-states) and breaking new ground (connectivity during resting-state). PUBLIC HEALTH RELEVANCE: This project aims to elucidate individual differences in functional brain organization and integrity of resting state connectivity associated with two genes controlling levels of dopamine, COMT Val158Met (catechol-O- methyltransferase) and DAT (dopamine transporter) in healthy adults. It will use functional magnetic resonance imaging to characterize brain activation and functional connectivity during working memory and while subjects rest with eyes closed. Knowledge gained from the proposed studies will suggest neuroanatomical hypotheses about vulnerability to cognitive dysfunction in disorders characterized by resting- state disturbances and associated with COMT and DAT such as Schizophrenia and Attention Deficit Hyperactivity Disorder, respectively.