The activity of the midbrain dopamine system reflects the valence of environmental events and modulates various brain structures to modify an organism’s behavior. A series of recent studies reported that the direct and indirect pathways in the striatum are critical for instrumental learning, but the dynamic changes in dopamine neuron activity that occur during negative reinforcement learning are still largely unclear. In the present study, by using a negative reinforcement learning paradigm employing foot shocks as aversive stimuli, bidirectional changes in substantia nigra pars compacta (SNc) dopamine neuron activity in the learning and habituation phases were observed. The results showed that in the learning phase, before mice had mastered the skill of escaping foot shocks, the presence of foot shocks induced a transient reduction in the activity of SNc dopamine neurons; however, in the habituation phase, in which the learned skill was automated, it induced a transient increase. Microinjection of a dopamine D1 receptor (D1R) or D2 receptor (D2R) antagonist into the dorsomedial striatum (DMS) significantly impaired learning behavior, suggesting that the modulatory effects of dopamine on both the direct and indirect pathways are required. Moreover, during the learning phase, excitatory synaptic transmission to DMS D2R-expressing medium spiny neurons (D2-MSNs) was potentiated. However, upon completion of the learning and habituation phases, the synapses onto D1R-expressing medium spiny neurons (D1-MSNs) were potentiated, and those onto D2-MSNs were restored to normal levels. The bidirectional changes in both SNc dopamine neuron activity and DMS synaptic plasticity might be the critical neural correlates for negative reinforcement learning.

中脑多巴胺系统的活动反映了环境事件的效价，并调节各种大脑结构以改变生物体的行为。最近的一系列研究报告说，纹状体中的直接和间接通路对于工具学习至关重要，但在负性强化学习期间发生的多巴胺神经元活动的动态变化仍不清楚。在本研究中，通过使用采用足部冲击作为厌恶刺激的负强化学习范式，观察到黑质致密部 (SNc) 多巴胺神经元在学习和习惯阶段的活动的双向变化。结果表明，在学习阶段，在老鼠掌握逃避足部冲击的技能之前，足部电击的存在导致 SNc 多巴胺神经元活性的短暂降低；然而，在习得技能被自动化的习惯化阶段，它引起了短暂的增长。将多巴胺 D1 受体 (D1R) 或 D2 受体 (D2R) 拮抗剂显微注射到背内侧纹状体 (DMS) 中会显着损害学习行为，这表明多巴胺对直接和间接途径的调节作用是必需的。此外，在学习阶段，向表达 DMS D2R 的中等棘神经元 (D2-MSNs) 的兴奋性突触传递增强。然而，在完成学习和习惯化阶段后，表达 D1R 的中等棘神经元 (D1-MSN) 上的突触增强，而 D2-MSN 上的突触恢复到正常水平。