Department of Psychiatry and Behavioral Sciences, University of Washington, Seattle, WA, USA.
Department of Pharmacology, University of Washington, Seattle, WA, USA.
Sci Adv. 2023 Aug 11;9(32):eadg8869. doi: 10.1126/sciadv.adg8869.
Dopamine is broadly implicated in reinforcement learning, but how patterns of dopamine activity are generated is poorly resolved. Here, we demonstrate that two ion channels, Kv4.3 and BKCa1.1, regulate the pattern of dopamine neuron firing and dopamine release on different time scales to influence separate phases of reinforced behavior in mice. Inactivation of Kv4.3 in VTA dopamine neurons increases ex vivo pacemaker activity and excitability that is associated with increased in vivo firing rate and ramping dynamics before lever press in a learned instrumental paradigm. Loss of Kv4.3 enhances performance of the learned response and facilitates extinction. In contrast, loss of BKCa1.1 increases burst firing and phasic dopamine release that enhances learning of an instrumental response and enhances extinction burst lever pressing in early extinction that is associated with a greater change in activity between reinforced and unreinforced actions. These data demonstrate that disruption of intrinsic regulators of neuronal activity differentially affects dopamine dynamics during reinforcement and extinction learning.
多巴胺广泛参与强化学习，但多巴胺活动模式的产生方式仍不清楚。本文中，我们证明了两种离子通道 Kv4.3 和 BKCa1.1 可在不同时间尺度上调节多巴胺神经元的放电模式和多巴胺释放，从而影响小鼠强化行为的不同阶段。在条件性位置偏好范式中，损毁 VTA 多巴胺神经元中的 Kv4.3 会增加体外起搏器活动和兴奋性，这与体内放电率增加以及按压杠杆前的斜坡动力学有关。Kv4.3 的缺失会增强习得反应的表现并促进消退。相比之下，BKCa1.1 的缺失会增加爆发性放电和相位性多巴胺释放，从而增强对工具性反应的学习，并增强早期消退过程中的消退爆发性杠杆按压，这与强化和非强化动作之间的活动变化更大有关。这些数据表明，神经元活动的内在调节因子的破坏会在强化和消退学习过程中对多巴胺动力学产生不同的影响。
