Department of Neuroscience and Brain Technologies, Istituto Italiano di Tecnologia, Genoa, Italy.
Department of Biotechnology and Life Sciences, and Neuroscience Center, University of Insubria, Busto Arsizio, Italy.
Mol Psychiatry. 2018 Apr;23(4):1040-1050. doi: 10.1038/mp.2017.126. Epub 2017 Jun 20.
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.
前额皮质（PFC）是灵活调节近期记忆（执行功能）以及稳定组织远期记忆的关键枢纽。PFC 中的多巴胺参与了这两个过程，影响其神经传递的遗传变异可能控制了每个个体中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 中多巴胺的不同代谢。然而，尽管 COMT 遗传变异在执行功能中发挥了既定作用，但它对远程记忆形成和回忆的影响仍未得到充分探索。在这里，我们报告说，过度表达人 COMT-Val 基因的转基因小鼠表现出夸张的远程记忆（>50 天），而近期记忆不变（<24 小时）。COMT 选择性地和可逆地调节远程记忆的回忆，因为从最初的厌恶条件开始 30 天后沉默 COMT Val 过表达可以使远程记忆正常化。COMT 遗传过度活跃导致 PFC 内内源性大麻素系统选择性超速运转，但纹状体和海马体则没有，这与增强的远程记忆有关。事实上，急性药理学阻断 CB1 受体足以挽救 COMT-Val-tg 小鼠改变的远程记忆回忆，并增加 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。
