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运动通过纹状体神经元中的多巴胺和腺苷激活 PKA。

Locomotion activates PKA through dopamine and adenosine in striatal neurons.

机构信息

Vollum Institute, Oregon Health and Science University, Portland, OR, USA.

Department of Neurosurgery and Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Palo Alto, CA, USA.

出版信息

Nature. 2022 Nov;611(7937):762-768. doi: 10.1038/s41586-022-05407-4. Epub 2022 Nov 9.

DOI:10.1038/s41586-022-05407-4
PMID:36352228
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC10752255/
Abstract

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. 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 of a PKA sensor 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 D receptor. However, indirect pathway SPNs exhibited a greater increase in PKA activity, which was largely abolished through the blockade of adenosine A receptors. In agreement with these results, fibre photometry measurements of an adenosine sensor 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.

摘要

纹状体功能的经典模型预测，动物的运动与多巴胺对直接和间接通路纹状体棘突投射神经元（SPN）中蛋白激酶 A（PKA）的相反调节有关。然而，在运动过程中，背外侧 SPN 中的 PKA 的精确动力学仍有待确定。其他神经调质是否参与也不清楚。在这里，我们表明两种类型的 SPN 中的 PKA 活性对于正常运动是必不可少的。我们使用通过梯度折射率透镜的 PKA 传感器的双光子荧光寿命成像，在运动过程中测量了小鼠背外侧纹状体中单个 SPN 中的 PKA 活性。与经典观点一致，多巴胺通过多巴胺 D 受体在运动过程中激活直接通路 SPN 中的 PKA 活性。然而，间接通路 SPN 表现出更大的 PKA 活性增加，通过阻断腺苷 A 受体，该增加大部分被消除。与这些结果一致，腺苷传感器的光纤光度测量显示在运动过程中细胞外腺苷急性增加。功能上，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，协调运动过程中 SPN 中的 PKA 活性和纹状体的正常功能。

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