The prefrontal cortex (PFC) is a crucial hub for the flexible modulation of recent memories (executive functions) as well as for the stable organization of remote memories. Dopamine in the PFC is implicated in both these processes and genetic variants affecting its neurotransmission might control the unique balance between cognitive stability and flexibility present in each individual. Functional genetic variants in the catechol-O-methyltransferase (COMT) gene result in a different catabolism of dopamine in the PFC. However, despite the established role played by COMT genetic variation in executive functions, its impact on remote memory formation and recall is still poorly explored. Here we report that transgenic mice overexpressing the human COMT-Val gene (COMT-Val-tg) present exaggerated remote memories (>50 days) while having unaltered recent memories (<24 h). COMT selectively and reversibly modulated the recall of remote memories as silencing COMT Val overexpression starting from 30 days after the initial aversive conditioning normalized remote memories. COMT genetic overactivity produced a selective overdrive of the endocannabinoid system within the PFC, but not in the striatum and hippocampus, which was associated with enhanced remote memories. Indeed, acute pharmacological blockade of CB1 receptors was sufficient to rescue the altered remote memory recall in COMT-Val-tg mice and increased PFC dopamine levels. These results demonstrate that COMT genetic variations modulate the retrieval of remote memories through the dysregulation of the endocannabinoid system in the PFC.

中文翻译：

---

通过前额叶皮层中内源性大麻素系统的失调，COMT的活动增强了远程记忆。

前额叶皮层（PFC）是灵活调节近期记忆（执行功能）以及稳定组织远程记忆的重要枢纽。PFC中的多巴胺与这些过程有关，影响其神经传递的遗传变异可能会控制每个人存在的认知稳定性和灵活性之间的独特平衡。儿茶酚-O-甲基转移酶（COMT）基因中的功能性遗传变异导致PFC中多巴胺的分解代谢不同。但是，尽管COMT基因变异在执行功能中发挥了确定的作用，但其对远程记忆形成和召回的影响仍未得到很好的探讨。在这里，我们报告说，过度表达人类COMT-Val基因（COMT-Val-tg）的转基因小鼠存在夸大的远程记忆（> 50天），而最近的记忆未改变（<24小时）。COMT有选择地和可逆地调节远程存储器的调用，以使COMT Val过表达从最初的厌恶条件正常化后的30天开始沉默，从而使COMT Val过表达处于沉默状态。COMT基因过度活跃导致PFC内的大麻素系统选择性超载，但纹状体和海马体中没有，这与增强的远程记忆有关。确实，对CB1受体的急性药理阻断足以挽救COMT-Val-tg小鼠改变的远程记忆召回和增加的PFC多巴胺水平。这些结果表明，COMT遗传变异通过PFC中内源性大麻素系统的失调来调节远程记忆的检索。COMT有选择地和可逆地调节远程存储器的调用，以使COMT Val过表达从最初的厌恶条件正常化后的30天开始沉默，从而使远程存储器的沉默消失。COMT基因过度活跃导致PFC内的大麻素系统选择性超载，但纹状体和海马体中没有，这与增强的远程记忆有关。确实，对CB1受体的急性药理阻断足以挽救COMT-Val-tg小鼠改变的远程记忆召回和增加的PFC多巴胺水平。这些结果表明，COMT遗传变异通过PFC中内源性大麻素系统的失调来调节远程记忆的检索。COMT有选择地和可逆地调节远程存储器的调用，以使COMT Val过表达从最初的厌恶条件正常化后的30天开始沉默，从而使远程存储器的沉默消失。COMT基因的过度活跃导致PFC内的大麻素系统选择性超速运转，而纹状体和海马体则没有，这与增强的远程记忆有关。确实，对CB1受体的急性药理阻断足以挽救COMT-Val-tg小鼠改变的远程记忆召回和增加的PFC多巴胺水平。这些结果表明，COMT遗传变异通过PFC中内源性大麻素系统的失调来调节远程记忆的检索。