Effects of dopaminergic genotypes on resting state connectivity relevant to execu

多巴胺能基因型对与执行相关的静息态连接的影响

• 批准号: 8062272
• 负责人: Chandan J Vaidya
• 金额: $ 7.53万
• 依托单位: GEORGETOWN UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-04-16 至 2013-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8062272
• 关键词: Adult; Affect; Alleles; Alzheimer' s Disease; Anatomy; Anterior; Anxiety; Area; Attention deficit hyperactivity disorder; Back; Behavior; Brain; Brain Injuries; Brain region; Catechol O-Methyltransferase; Characteristics; Childhood; Codon Nucleotides; Cognitive; Collaborations; Consensus; Consent; Corpus striatum structure; Data; Development; Disease; Dopamine; Emotional; Enzymes; Event; Eye; Frequencies; Functional Magnetic Resonance Imaging; Functional disorder; Genes; Genetic; Genetic Polymorphism; Genetic Risk; Genetic Variation; Genotype; Grouping; Hippocampus (Brain); Impaired cognition; Individual; Individual Differences; Instruction; Insula of Reil; Knowledge; Label; Lateral; Letters; Link; Maps; Measures; Medial; Mental disorders; Methionine; Modeling; Moods; Neurons; Noise; Parietal; Pathogenesis; Physiological; Prefrontal Cortex; Process; Proteins; Regression Analysis; Regulation; Research; Research Methodology; Research Personnel; Rest; Schizophrenia; Seeds; Short-Term Memory; Source; Students; Task Performances; Testing; Translating; Valine; Work; base; clinically significant; dopamine transporter; executive function; extracellular; genetic variant; independent component analysis; interest; meetings; methionylmethionine; neuroimaging; novel; operation; programs; public health relevance; relating to nervous system; sample fixation; trait; trimethionine; uptake; valyl-valyl-valine; valylvaline; visual motor

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.

描述（由申请人提供）：支持执行控制的大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异：COMT（儿茶酚-O-甲基转移酶）是一种主要在前额皮质 (PFC) 中降解 DA 的酶，有两种遗传变异（Val、Met）和 DAT（多巴胺转运蛋白），一种主要在纹状体中释放后重新摄取多巴胺的蛋白质，具有两种常见的遗传变异（10 次重复、9 次重复）。与 PFC 纹状体电路对于工作记忆等执行操作的重要性一致，两种多态性的独立、交互和相加效应在工作记忆期间的功能激活中是明显的。然而，这些遗传差异是否会扩展到任务执行期间和无任务“休息状态”下的功能连接尚不清楚。休息期间（无任务状态）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，这些区域的拓扑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，但在具有执行功能障碍的精神疾病中受到破坏，例如精神分裂症和 ADHD，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接的遗传变异性对于揭示与这些疾病相关的认知障碍的神经解剖学机制非常重要。我们假设 COMT 和 DAT 基因型对功能连接的影响在三个网络的任务诱发和静​​息状态下是平行的，即任务消极网络（默认模式）和两个任务积极网络（执行控制和显着性） 。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年人将在工作记忆（2-back 与固定）期间接受 fMRI休息5分钟期间。具体目标 1 将检查工作记忆期间激活（任务正向网络）和失活（任务负向网络）区域中 COMT 和 DAT 等位基因的差异以及每个区域内的功能连接。我们将检查基因型的独立和交互（COMT X DAT ANOVA）和加性（回归分析）效应。具体目标 2 将检查 COMT 和 DAT 等位基因在静息态功能连接方面的差异，这些差异是使用来自目标 1 的种子（在验证性分析中）以及使用无模型独立成分分析（在探索性分析中）与 Dr.维诺德·梅农.我们期望识别出与目标 1 相同的 3 个网络：1）任务负网络（内侧 PFC-后扣带回-海马）； 2）执行控制网络（背外侧PFC-外侧顶叶）； 3）显着网络（前扣带回-岛叶-边缘）。在这两项分析中，我们将测试目标 1 中的基因型差异。这些发现将通过扩展当前知识（任务状态期间的连接性）和开辟新领域（静息状态期间的连接性）来提供信息。 公共健康相关性：该项目旨在阐明健康成人中与控制多巴胺水平的两个基因 COMT Val158Met（儿茶酚-O-甲基转移酶）和 DAT（多巴胺转运蛋白）相关的功能性大脑组织和静息状态连接完整性的个体差异。它将使用功能磁共振成像来表征工作记忆期间以及受试者闭眼休息时的大脑激活和功能连接。从拟议的研究中获得的知识将提出关于以静息状态障碍为特征并与 COMT 和 DAT 相关的疾病（例如精神分裂症和注意力缺陷多动障碍）易受认知功能障碍的神经解剖学假设。

项目成果

Interactive effect of 5-HTTLPR and BDNF polymorphisms on amygdala intrinsic functional connectivity and anxiety.

5-HTTLPR 和 BDNF 多态性对杏仁核内在功能连接和焦虑的交互作用。

• 发表时间: 2019
• 作者: Loewenstern, Joshua;You, Xiaozhen;Merchant, Junaid;Gordon, Evan M;Stollstorff, Melanie;Devaney, Joseph;Vaidya, Chandan J
• 通讯作者: Vaidya, Chandan J