Touponse Gavin C, Pomrenze Matthew B, Yassine Teema, Mehta Viraj, Denomme Nicholas, Zhang Zihui, Malenka Robert C, Eshel Neir
Department of Psychiatry and Behavioral Sciences, Stanford University, Stanford, CA 94305.
These authors contributed equally to this work.
bioRxiv. 2025 Jun 21:2025.06.18.660394. doi: 10.1101/2025.06.18.660394.
Effort is costly: given a choice, we tend to avoid it. But in many cases, effort adds value to the ensuing rewards. From ants to humans, individuals prefer rewards that had been harder to achieve. This counterintuitive process may promote reward-seeking even in resource-poor environments, thus enhancing evolutionary fitness. Despite its ubiquity, the neural mechanisms supporting this behavioral effect are poorly understood. Here we show that effort amplifies the dopamine response to an otherwise identical reward, and this amplification depends on local modulation of dopamine axons by acetylcholine. High-effort rewards evoke rapid acetylcholine release from local interneurons in the nucleus accumbens. Acetylcholine then binds to nicotinic receptors on dopamine axon terminals to augment dopamine release when reward is delivered. Blocking the cholinergic modulation blunts dopamine release selectively in high-effort contexts, impairing effortful behavior while leaving low-effort reward consumption intact. These results reconcile studies, which have long demonstrated that acetylcholine can trigger dopamine release directly through dopamine axons; with studies that failed to observe such modulation, but did not examine high-effort contexts. Our findings uncover a mechanism that drives effortful behavior through context-dependent local interactions between acetylcholine and dopamine axons.
如果有选择，我们往往会避免努力。但在许多情况下，努力会为随之而来的回报增添价值。从蚂蚁到人类，个体都更喜欢那些更难获得的回报。这个违反直觉的过程可能会促进即使在资源匮乏环境中的奖赏寻求行为，从而提高进化适应性。尽管这种现象普遍存在，但支持这种行为效应的神经机制却知之甚少。在这里，我们表明努力会放大对原本相同奖赏的多巴胺反应，而且这种放大依赖于乙酰胆碱对多巴胺轴突的局部调节。高努力程度的奖赏会引发伏隔核中局部中间神经元快速释放乙酰胆碱。当奖赏出现时，乙酰胆碱随后会与多巴胺轴突末端的烟碱型受体结合，以增加多巴胺的释放。阻断胆碱能调节会在高努力程度的情况下选择性地减弱多巴胺释放，损害努力行为，而不影响低努力程度奖赏的摄取。这些结果调和了长期以来证明乙酰胆碱可直接通过多巴胺轴突触发多巴胺释放的研究，以及未能观察到这种调节但未研究高努力程度情况的研究。我们的发现揭示了一种通过乙酰胆碱和多巴胺轴突之间依赖情境的局部相互作用来驱动努力行为的机制。
