The canonical model of striatal function predicts that animal locomotion is associated with the opposing regulation of protein kinase A (PKA) in direct and indirect pathway striatal spiny projection neurons (SPNs) by dopamine^{1,2,3,4,5,6,7}. However, the precise dynamics of PKA in dorsolateral SPNs during locomotion remain to be determined. It is also unclear whether other neuromodulators are involved. Here we show that PKA activity in both types of SPNs is essential for normal locomotion. Using two-photon fluorescence lifetime imaging^8,9,10 of a PKA sensor¹⁰ through gradient index lenses, we measured PKA activity within individual SPNs of the mouse dorsolateral striatum during locomotion. Consistent with the canonical view, dopamine activated PKA activity in direct pathway SPNs during locomotion through the dopamine D₁ receptor. However, indirect pathway SPNs exhibited a greater increase in PKA activity, which was largely abolished through the blockade of adenosine A_2A receptors. In agreement with these results, fibre photometry measurements of an adenosine sensor¹¹ revealed an acute increase in extracellular adenosine during locomotion. Functionally, antagonism of dopamine or adenosine receptors resulted in distinct changes in SPN PKA activity, neuronal activity and locomotion. Together, our results suggest that acute adenosine accumulation interplays with dopamine release to orchestrate PKA activity in SPNs and proper striatal function during animal locomotion.

纹状体功能的经典模型预测动物运动与多巴胺^{1,2,3,4,5,6,7}对直接和间接途径纹状体多棘投射神经元 (SPN) 中蛋白激酶 A (PKA) 的相反调节有关。然而，运动过程中背外侧 SPN 中 PKA 的精确动态仍有待确定。还不清楚是否涉及其他神经调节剂。在这里，我们表明两种类型的 SPN 中的 PKA 活性对于正常运动至关重要。通过梯度折射率透镜使用PKA传感器¹⁰的双光子荧光寿命成像^8、9、10 ，我们测量了运动过程中小鼠背外侧纹状体的各个SPN内的PKA活性。与经典观点一致，多巴胺在通过多巴胺 D ₁受体运动期间激活直接途径 SPN 中的 PKA 活性。然而，间接途径 SPN 表现出 PKA 活性的更大增加，这在很大程度上通过腺苷 A _2A受体的阻断而被消除。与这些结果一致，腺苷传感器¹¹的光纤光度测量揭示了运动过程中细胞外腺苷的急剧增加。从功能上讲，多巴胺或腺苷受体的拮抗作用导致 SPN PKA 活性、神经元活性和运动的明显变化。总之，我们的结果表明，急性腺苷积累与多巴胺释放相互作用，协调 SPN 中的 PKA 活性和动物运动过程中的适当纹状体功能。