Reinforcement learning models postulate that neurons that release dopamine encode information about action and action outcome, and provide a teaching signal to striatal spiny projection neurons in the form of dopamine release1. Dopamine is thought to guide learning via dynamic and differential modulation of protein kinase A (PKA) in each class of spiny projection neuron2. However, the real-time relationship between dopamine and PKA in spiny projection neurons remains untested in behaving animals. Here we monitor the activity of dopamine-releasing neurons, extracellular levels of dopamine and net PKA activity in spiny projection neurons in the nucleus accumbens of mice during learning. We find positive and negative modulation of dopamine that evolves across training and is both necessary and sufficient to explain concurrent fluctuations in the PKA activity of spiny projection neurons. Modulations of PKA in spiny projection neurons that express type-1 and type-2 dopamine receptors are dichotomous, such that these neurons are selectively sensitive to increases and decreases, respectively, in dopamine that occur at different phases of learning. Thus, PKA-dependent pathways in each class of spiny projection neuron are asynchronously engaged by positive or negative dopamine signals during learning.

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多巴胺在学习中对 PKA 的细胞类型特异性异步调节

强化学习模型假设释放多巴胺的神经元编码有关动作和动作结果的信息，并以多巴胺释放的形式向纹状体多刺投射神经元提供教学信号。多巴胺被认为通过对每一类棘状投射神经元2 中蛋白激酶A (PKA) 的动态和差异调制来指导学习。然而，多巴胺和 PKA 在多刺投射神经元中的实时关系仍未在行为动物中进行测试。在这里，我们在学习期间监测小鼠伏隔核中多巴胺释放神经元的活动、多巴胺的细胞外水平和净 PKA 活动。我们发现多巴胺的正向和负向调制在训练过程中不断演变，这对于解释多刺投射神经元 PKA 活动的同时波动是必要和充分的。表达 1 型和 2 型多巴胺受体的棘状投射神经元中 PKA 的调节是二分法的，因此这些神经元分别选择性地对不同学习阶段发生的多巴胺的增加和减少敏感。因此，每一类棘状投射神经元中依赖于 PKA 的通路在学习过程中被正或负多巴胺信号异步参与。分别在不同学习阶段发生的多巴胺中。因此，每一类棘状投射神经元中依赖于 PKA 的通路在学习过程中被正或负多巴胺信号异步参与。分别在不同学习阶段发生的多巴胺中。因此，每一类棘状投射神经元中依赖于 PKA 的通路在学习过程中被正或负多巴胺信号异步参与。