School of Psychology and Neuroscience, University of St Andrews, Fife, KY16 9JP, UK.
Hotchkiss Brain Institute, University of Calgary, HMRB 168, 3330 Hospital Drive NW, Calgary, AB, T2N 4N1, Canada.
Sci Rep. 2020 Oct 2;10(1):16429. doi: 10.1038/s41598-020-73230-w.
Dopamine is well known to regulate movement through the differential control of direct and indirect pathways in the striatum that express D and D receptors respectively. The spinal cord also expresses all dopamine receptors; however, how the specific receptors regulate spinal network output in mammals is poorly understood. We explore the receptor-specific mechanisms that underlie dopaminergic control of spinal network output of neonatal mice during changes in spinal network excitability. During spontaneous activity, which is a characteristic of developing spinal networks operating in a low excitability state, we found that dopamine is primarily inhibitory. We uncover an excitatory D-mediated effect of dopamine on motoneurons and network output that also involves co-activation with D receptors. Critically, these excitatory actions require higher concentrations of dopamine; however, analysis of dopamine concentrations of neonates indicates that endogenous levels of spinal dopamine are low. Because endogenous levels of spinal dopamine are low, this excitatory dopaminergic pathway is likely physiologically-silent at this stage in development. In contrast, the inhibitory effect of dopamine, at low physiological concentrations is mediated by parallel activation of D, D, D and α receptors which is reproduced when endogenous dopamine levels are increased by blocking dopamine reuptake and metabolism. We provide evidence in support of dedicated spinal network components that are controlled by excitatory D and inhibitory D receptors that is reminiscent of the classic dopaminergic indirect and direct pathway within the striatum. These results indicate that network state is an important factor that dictates receptor-specific and therefore dose-dependent control of neuromodulators on spinal network output and advances our understanding of how neuromodulators regulate neural networks under dynamically changing excitability.
多巴胺通过分别在纹状体中表达 D 和 D 受体来调节运动，这一点是众所周知的。脊髓也表达所有的多巴胺受体；然而，特定的受体如何调节哺乳动物脊髓网络的输出还知之甚少。我们探索了基础的受体特异性机制，这些机制是在脊髓网络兴奋性变化的情况下，在新生小鼠的脊髓网络输出中发挥多巴胺能调控作用的。在自发活动中，即处于低兴奋性状态下发育中的脊髓网络的特征，我们发现多巴胺主要起抑制作用。我们发现了多巴胺对运动神经元和网络输出的兴奋性 D 介导作用，该作用还涉及与 D 受体的共同激活。关键是，这些兴奋性作用需要更高浓度的多巴胺；然而，对新生儿多巴胺浓度的分析表明，脊髓内多巴胺的内源性水平较低。由于脊髓内多巴胺的内源性水平较低，因此在发育的这个阶段，这种兴奋性多巴胺能通路可能在生理上是沉默的。相比之下，在生理浓度较低的情况下，多巴胺的抑制作用是通过平行激活 D、D、D 和 α 受体来介导的，当通过阻断多巴胺再摄取和代谢来增加内源性多巴胺水平时，这种作用会重现。我们提供了证据来支持由兴奋性 D 和抑制性 D 受体控制的专门的脊髓网络组件，这让人联想到纹状体中经典的多巴胺间接和直接途径。这些结果表明，网络状态是一个重要因素，决定了受体特异性，因此决定了神经调质对脊髓网络输出的剂量依赖性控制，并推进了我们对神经调质如何在动态变化的兴奋性下调节神经网络的理解。
