2024年10月16日，《自然》杂志在线发表了美国科学家的一项最新研究成果。来自哈佛医学院Pascal S. Kaeser研究组的研究发现，多巴胺动态对于运动不是必需的，但能促进奖励反应。

研究人员表明，动作电位诱导的多巴胺释放对于运动启动不是必需的，但有助于奖励导向的行为。研究人员通过敲除多巴胺神经元特异性的释放位点组织蛋白RIM，破坏了动作电位诱导的多巴胺释放。在这些小鼠中，体内快速的多巴胺动态受到严重影响，但基础多巴胺水平依然存在，且完全支持自发运动。

相反，利血平介导的多巴胺耗竭或多巴胺受体的阻断则会破坏运动启动。多巴胺前体l-DOPA逆转了利血平引起的运动迟缓症，但并未恢复快速的多巴胺动态，这进一步证实了这些动态对于运动启动是非必要的。

与自发运动不同的是，RIM基因敲除的小鼠在奖励导向的行为中表现出缺陷。在条件位置偏好和双气味区分任务中，这些小鼠能够有效学习区分提示信号，表明奖励学习在RIM缺失后依然存在。然而，它们的表现活力有所下降。在概率性提示-奖励关联任务中，多巴胺动态和通过预期舔舐评估的条件反应受到破坏。

这些研究结果表明，动作电位诱导的多巴胺释放对运动功能和运动启动的亚秒精度并非必要，但在奖励引导的行为中促进了动机和表现力。

研究人员表示，多巴胺信号传递模式在受体激活的动力学和空间分布上存在差异。关于这些模式如何影响运动功能、动机和学习，长期以来存在争论。

附：英文原文

Title: Dopamine dynamics are dispensable for movement but promote reward responses

Author: Cai, Xintong, Liu, Changliang, Tsutsui-Kimura, Iku, Lee, Joon-Hyuk, Guo, Chong, Banerjee, Aditi, Lee, Jinoh, Amo, Ryunosuke, Xie, Yudi, Patriarchi, Tommaso, Li, Yulong, Watabe-Uchida, Mitsuko, Uchida, Naoshige, Kaeser, Pascal S.

Issue&Volume: 2024-10-16

Abstract: Dopamine signalling modes differ in kinetics and spatial patterns of receptor activation1,2. How these modes contribute to motor function, motivation and learning has long been debated3,4,5,6,7,8,9,10,11,12,13,14,15,16,17,18,19,20,21. Here we show that action-potential-induced dopamine release is dispensable for movement initiation but supports reward-oriented behaviour. We generated mice with dopamine-neuron-specific knockout of the release site organizer protein RIM to disrupt action-potential-induced dopamine release. In these mice, rapid in vivo dopamine dynamics were strongly impaired, but baseline dopamine persisted and fully supported spontaneous movement. Conversely, reserpine-mediated dopamine depletion or blockade of dopamine receptors disrupted movement initiation. The dopamine precursor L-DOPA reversed reserpine-induced bradykinesia without restoring fast dopamine dynamics, a result that substantiated the conclusion that these dynamics are dispensable for movement initiation. In contrast to spontaneous movement, reward-oriented behaviour was impaired in dopamine-neuron-specific RIM knockout mice. In conditioned place preference and two-odour discrimination tasks, the mice effectively learned to distinguish the cues, which indicates that reward-based learning persists after RIM ablation. However, the performance vigour was reduced. During probabilistic cue-reward association, dopamine dynamics and conditioned responses assessed through anticipatory licking were disrupted. These results demonstrate that action-potential-induced dopamine release is dispensable for motor function and subsecond precision of movement initiation but promotes motivation and performance during reward-guided behaviours.

DOI: 10.1038/s41586-024-08038-z

Source: https://www.nature.com/articles/s41586-024-08038-z