Influence of COMT Gene Polymorphism on fMRI-assessed Sustained and Transient Activity during a Working Memory Task
Influence of COMT Gene Polymorphism on fMRI-assessed Sustained and Transient Activity during a Working Memory Task
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DOI：
10.1162/jocn.2009.21318
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发表时间：
2010-07-01
影响因子：
3.2
通讯作者：
Nyberg, Lars
中科院分区：
文献类型：
--
作者：
de Frias, Cindy M.;Marklund, Petter;Nyberg, Lars
儿茶酚 O-甲基转移酶 (COMT) 基因编码一种对前额皮质 (PFC) 中多巴胺 (DA) 降解至关重要的酶，并且含有对认知很重要的单核苷酸多态性 (val/met)。根据强直阶段假说，携带低酶活性等位基因 (met) 的个体的特征是 PFC 中强直 DA 活性增强，促进工作记忆中的持续认知表征。 Val 携带者减少了皮质下区域的强直性但增强了阶段性多巴胺能活性，从而增强了认知灵活性。我们通过使用混合阻塞/事件相关功能磁共振成像在 2-back 工作记忆测试中分离持续和短暂的大脑活动来测试强直阶段 DA 假设。参与者是从人群中随机招募的男性（Betula 研究），由 11 名met/met 和 11 名 val/val 携带者组成，年龄在 50 至 65 岁之间，年龄、教育程度和认知能力相匹配。基因型组之间的 2-back 表现没有差异。 Met 携带者在工作记忆更新阶段表现出更大的瞬时内侧颞叶反应，而 val 携带者在维持阶段表现出更大的持续 PFC 激活。这些结果支持 DA 功能的强直阶段理论，阐明 COMT val(158)met 多态性对工作记忆不同组成部分的具体表型影响。
The catechol O-methyltransferase (COMT) gene-encoding an enzyme that is essential for the degradation of dopamine (DA) in prefrontal cortex (PFC)-contains a single nucleotide polymorphism (val/met) important for cognition. According to the tonic-phasic hypothesis, individuals carrying the low-enzyme- activity allele (met) are characterized by enhanced tonic DA activity in PFC, promoting sustained cognitive representations in working memory. Val carriers have reduced tonic but enhanced phasic dopaminergic activity in subcortical regions, enhancing cognitive flexibility. We tested the tonic-phasic DA hypothesis by dissociating sustained and transient brain activity during performance on a 2-back working memory test using mixed blocked/event-related functional magnetic resonance imaging. Participants were men recruited from a random sample of the population (the Betula study) and consisted of 11 met/met and 11 val/val carriers aged 50 to 65 years, matched on age, education, and cognitive performance. There were no differences in 2-back performance between genotype groups. Met carriers displayed a greater transient medial temporal lobe response in the updating phase of working memory, whereas val carriers showed a greater sustained PFC activation in the maintenance phase. These results support the tonic-phasic theory of DA function in elucidating the specific phenotypic influence of the COMT val(158)met polymorphism on different components of working memory.