多巴胺研究重磅突破：揭示纹状体多巴胺和腺苷通过增加PKA活性反向调控运动功能

中文摘要

纹状体功能的经典模型认为，动物运动与多巴胺对直接和间接途径纹状体棘投射神经元（SPN）中蛋白激酶A（PKA）的反向调节有关。然而，运动过程中背外侧SPN中PKA的精确动力学仍有待确定。目前还不清楚这是否涉及其他神经调节物质。这项研究表明，这两种类型的SPN中的PKA活性对正常运动至关重要。使用双光子荧光寿命成像的梯度折射率透镜对PKA分子探针进行成像，研究人员测量了运动期间小鼠背外侧纹状体单个SPN内的PKA活性。与经典观点一致，多巴胺通过多巴胺D1受体在运动过程中激活了直接通路SPN中的PKA活性。然而，间接途径SPN表现出更为明显的PKA活性增加，通过阻断腺苷A2A受体，PKA活性基本上被抑制。与这些结果一致，腺苷传感器的纤维光测量显示运动期间细胞外腺苷急剧增加。在功能上，多巴胺或腺苷受体的拮抗导致SPN PKA活性、神经元活性和运动的明显变化。总之，他们的结果表明，急性腺苷积累与多巴胺释放相互作用，以协调SPN中的PKA活性和动物运动过程中的纹状体功能。

英文摘要

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 dopamine1-7. 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 imaging8-10 of a PKA sensor10 through gradient index lenses, we measured PKA activity within inpidual 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 A2A 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.