Department of Translational Neuroscience, Brain Center Rudolf Magnus, University Medical Center Utrecht, 3584 CG Utrecht, The Netherlands.
Molecular Neuroscience, Swammerdam Institute for Life Sciences, University of Amsterdam, 1090 GE Amsterdam, The Netherlands.
J Neurosci. 2021 Jun 9;41(23):5004-5014. doi: 10.1523/JNEUROSCI.2744-20.2021. Epub 2021 Apr 22.
Associating natural rewards with predictive environmental cues is crucial for survival. Dopamine (DA) neurons of the ventral tegmental area (VTA) are thought to play a crucial role in this process by encoding reward prediction errors (RPEs) that have been hypothesized to play a role in associative learning. However, it is unclear whether this signal is still necessary after animals have acquired a cue-reward association. In order to investigate this, we trained mice to learn a Pavlovian cue-reward association. After learning, mice show robust anticipatory and consummatory licking behavior. As expected, calcium activity of VTA DA neurons goes up for cue presentation as well as reward delivery. Optogenetic inhibition during the moment of reward delivery disrupts learned behavior, even in the continued presence of reward. This effect is more pronounced over trials and persists on the next training day. Moreover, outside of the task licking behavior and locomotion are unaffected. Similarly to inhibitions during the reward period, we find that inhibiting cue-induced dopamine (DA) signals robustly decreases learned licking behavior, indicating that cue-related DA signals are a potent driver for learned behavior. Overall, we show that inhibition of either of these DA signals directly impairs the expression of learned associative behavior. Thus, continued DA signaling in a learned state is necessary for consolidating Pavlovian associations. Dopamine (DA) neurons of the ventral tegmental area (VTA) have long been suggested to be necessary for animals to associate environmental cues with rewards that they predict. Here, we use time-locked optogenetic inhibition of these neurons to show that the activity of these neurons is directly necessary for performance on a Pavlovian conditioning task, without affecting locomotor per se These findings provide further support for the direct importance of second-by-second DA neuron activity in associative learning.
将自然奖励与预测环境线索联系起来对生存至关重要。腹侧被盖区（VTA）的多巴胺（DA）神经元被认为在这个过程中起着至关重要的作用，通过编码奖励预测误差（RPE），这些误差被假设在联想学习中起作用。然而，在动物获得线索-奖励关联后，这种信号是否仍然是必要的还不清楚。为了研究这一点，我们训练老鼠学习一种条件性的线索-奖励关联。学习后，老鼠表现出强烈的预期和完成性舔舐行为。正如预期的那样，VTA DA 神经元的钙活性在提示呈现和奖励传递时都会上升。在奖励传递的时刻进行光遗传学抑制会破坏已习得的行为，即使在奖励继续存在的情况下也是如此。这种效应在试验中更为明显，并在第二天的训练中持续存在。此外，在任务之外，舔舐行为和运动不受影响。与奖励期间的抑制作用类似，我们发现抑制诱导的多巴胺（DA）信号会强烈降低习得的舔舐行为，这表明与线索相关的 DA 信号是习得行为的有力驱动因素。总的来说，我们表明，抑制这些 DA 信号中的任何一个都会直接损害已习得的联想行为的表达。因此，在已习得的状态下持续的 DA 信号传递对于巩固条件性关联是必要的。腹侧被盖区（VTA）的多巴胺（DA）神经元长期以来一直被认为是动物将环境线索与它们预测的奖励联系起来所必需的。在这里，我们使用这些神经元的时间锁定光遗传学抑制来表明，这些神经元的活动直接是执行条件性适应任务所必需的，而不会影响运动本身。这些发现为 DA 神经元活动在联想学习中的直接重要性提供了进一步的支持。
