美国俄勒冈健康与科学大学Haining Zhong课题组发现，运动通过多巴胺和纹状体神经元的腺苷激活PKA。相关论文于2022年11月9日在线发表在《自然》杂志上。

研究人员表示，纹状体功能的经典模型预测，动物运动与多巴胺对直接和间接途径纹状体棘突投射神经元（SPN）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的精确动态变化仍有待确定。目前还不清楚其他神经调节因子是否参与其中。

研究人员表明，两种类型SPN中的PKA活动对正常的运动是必不可少的。利用双光子荧光寿命成像的PKA传感器，研究人员测量了运动时小鼠背外侧纹状体单个SPN的PKA活动。与传统观点一致，多巴胺在运动过程中通过多巴胺D1受体激活直接通路SPN的PKA活性。然而，间接通路SPN表现出更大的PKA活性增加，这在很大程度上通过阻断腺苷A2A受体而被取消。与这些结果相一致的是，腺苷传感器的纤维光度测量显示，运动过程中细胞外腺苷急性增加。在功能上，拮抗多巴胺或腺苷受体导致SPN PKA活性、神经元活性和运动的不同变化。

这些研究结果表明，急性腺苷积累与多巴胺释放相互作用，并在动物运动过程中协调SPN的PKA活性和纹状体的正常功能。

附：英文原文

Title: Locomotion activates PKA through dopamine and adenosine in striatal neurons

Author: Ma, Lei, Day-Cooney, Julian, Benavides, Omar Jidar, Muniak, Michael A., Qin, Maozhen, Ding, Jun B., Mao, Tianyi, Zhong, Haining

Issue&Volume: 2022-11-09

Abstract: The canonical model of striatal function predicts that animal locomotion is associated with the opposing regulation of protein kinaseA (PKA) in direct and indirect pathway striatal spiny projection neurons (SPNs) by dopamine1,2,3,4,5,6,7. 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 imaging8,9,10 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 D1receptor. However, indirect pathway SPNs exhibited a greater increase in PKA activity, which was largely abolished through the blockade of adenosine A2Areceptors. 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.

DOI: 10.1038/s41586-022-05407-4

Source: https://www.nature.com/articles/s41586-022-05407-4