Epistasis effects of dopamine genes on interval timing and reward magnitude in humans
Epistasis effects of dopamine genes on interval timing and reward magnitude in humans
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DOI：
10.1016/j.neuropsychologia.2012.08.002
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发表时间：
2013-01-01
期刊：
影响因子：
2.6
通讯作者：
Coslett, H. Branch
中科院分区：
文献类型：
--
作者：
Balci, Fuat;Wiener, Martin;Coslett, H. Branch
我们用一种改进的峰值法对参与者进行了测试，以调查间隔时间和奖励处理之间的关系，并检查了这种关系与三种不同的多巴胺相关基因多态之间的交互作用。这些基因多态影响主要分解突触多巴胺的儿茶酚氧甲基转移酶(COMT Val158Met多态)、主要在纹状体的D2多巴胺受体(DRD2/ANKK1-Taq1A多态)和清除纹状体突触多巴胺的多巴胺转运体(DAT 3‘VNTR变异体)的表达。这些多态性的包含使我们能够研究多巴胺系统的可分离方面，以及它们与奖赏幅度操纵在塑造定时行为方面的相互作用。选择这些基因是因为它们在奖赏处理和皮质-纹状体信息处理中的作用，这些信息处理与间隔时间有关。与最近的动物研究一致，在反应终止的时间或感知时间没有任何变化的情况下，当期待更大的回报时，人类参与者更早地启动了他们的计时预期反应。然而，这种效应仅限于四个评估的COMT和DRD2多态组合中的两个，这些组合导致前额叶高多巴胺伴随高D2密度，而低前额叶多巴胺伴随低D2密度。更大的奖励也会降低计时精度指数，其中一些与COMT多态相互作用。此外，COMT多态导致前额叶多巴胺含量较高，导致记忆变异性(相对于阈值变异性)在计时行为中的表现较弱。DAT基因多态对任何核心行为指标均无影响。这些结果表明，奖赏调节决策阈值，而不是时钟速度，这些影响是COMT和DRD2上位性效应的专有效应，这可能构成了前额叶和纹状体的平衡多巴胺传递。(C)2012爱思唯尔有限公司。保留所有权利。
We tested human participants on a modified peak procedure in order to investigate the relation between interval timing and reward processing, and examine the interaction of this relation with three different dopamine-related gene polymorphisms. These gene polymorphisms affected the expression of catechol-o-methyltransferase, which catabolizes synaptic dopamine primarily in the prefrontal cortex (COMT Val158Met polymorphism), D2 dopamine receptors primarily in the striatum (DRD2/ANKK1-Taq1a polymorphism), and dopamine transporters, which clear synaptic dopamine in the striatum (DAT 3' VNTR variant). The inclusion of these polymorphisms allowed us to investigate dissociable aspects of the dopamine system and their interaction with reward magnitude manipulations in shaping timed behavior. These genes were chosen for their roles in reward processing and cortico-striatal information processing that have been implicated for interval timing. Consistent with recent animal studies, human participants initiated their timed anticipatory responding earlier when expecting a larger reward in the absence of any changes in the timing of response termination or perceived time. This effect however was specific to two out of four evaluated COMT and DRD2 polymorphism combinations that lead to high prefrontal dopamine coupled with high D2 density and low prefrontal dopamine coupled with low D2 density. Larger rewards also decreased timing precision indices, some of which interacted with the COMT polymorphism. Furthermore, the COMT polymorphism that leads to higher prefrontal dopamine resulted in weaker manifestation of memory variability (relative to threshold variability) in timed behavior. There was no effect of DAT polymorphisms on any of the core behavioral measures. These results suggest that the reward modulates decision thresholds rather than clock speed, and that these effects are specific to COMT and DRD2 epistasis effects that presumably constitute a balanced prefrontal and striatal dopamine transmission. (C) 2012 Elsevier Ltd. All rights reserved.