Zhang Qiang, Cheng Yi, Zhou Mei, Dai Yue
Shanghai Key Laboratory of Multidimensional Information Processing, School of Communication and Electronic Engineering, East China Normal University, Shanghai, China.
School of Physical Education, Yunnan University, Kunming, China.
Front Comput Neurosci. 2022 Apr 14;16:809599. doi: 10.3389/fncom.2022.809599. eCollection 2022.
Locomotion is a fundamental movement in vertebrates produced by spinal networks known as central pattern generators (CPG). During fictive locomotion cat lumbar motoneurons (MNs) exhibit changes in membrane properties, including hyperpolarization of voltage threshold, reduction of afterhyperpolarization and input resistance, and amplification of nonlinear membrane properties. Both modeling and electrophysiological studies suggest that these changes can be produced by upregulating voltage-gated sodium channel (VGSC), persistent sodium (NaP), or L-type calcium channel (LTCC) or downregulating delayed-rectifier potassium (K(DR)) or calcium-dependent potassium channel (KCa) in spinal MNs. Further studies implicate that these channel modulations increase motor output and facilitate MN recruitment. However, it remains unknown how the channel modulation of CPG networks or MN pools affects the rhythmic generation of locomotion and force production of skeletal muscle during locomotion. In order to investigate this issue, we built a two-level CPG model composed of excitatory interneuron pools (Exc-INs), coupled reciprocally with inhibitory interneuron pools (Inh-INs), and projected to the flexor-extensor MN pools innervating skeletal muscles. Each pool consisted of 100 neurons with membrane properties based on cat spinal neurons. VGSC, K(DR), NaP, KCa, LTCC, and H-current channels were included in the model. Simulation results showed that (1) upregulating VGSC, NaP, or LTCC or downregulating KCa in MNs increased discharge rate and recruitment of MNs, thus facilitating locomotor pattern formation, increased amplitude of electroneurogram (ENG) bursting, and enhanced force generation of skeletal muscles. (2) The same channel modulation in Exc-INs increased the firing frequency of the Exc-INs, facilitated rhythmic generation, and increased flexor-extensor durations of step cycles. (3) Contrarily, downregulation of NaP or LTCC in MNs or Exc-INs or both CPG (Exc-INs and Inh-INs) and MNs disrupted locomotor pattern and reduced or even blocked the ENG bursting of MNs and force generation of skeletal muscles. (4) Pharmacological experiments showed that bath application of 25 μM nimodipine or 2 μM riluzole completely blocked fictive locomotion in isolated rat spinal cord, consistent with simulation results. We concluded that upregulation of VGSC, NaP, or LTCC or downregulation of KCa facilitated rhythmic generation and force production during walking, with NaP and LTCC playing an essential role.
运动是脊椎动物的一种基本运动，由被称为中枢模式发生器（CPG）的脊髓网络产生。在虚拟运动期间，猫的腰段运动神经元（MNs）表现出膜特性的变化，包括电压阈值的超极化、后超极化和输入电阻的降低，以及非线性膜特性的增强。建模和电生理研究均表明，这些变化可通过上调脊髓MNs中的电压门控钠通道（VGSC）、持续性钠通道（NaP）或L型钙通道（LTCC），或下调延迟整流钾通道（K(DR)）或钙依赖性钾通道（KCa）来产生。进一步的研究表明，这些通道调节可增加运动输出并促进MNs的募集。然而，CPG网络或MN池的通道调节如何影响运动过程中运动的节律性产生和骨骼肌的力量产生仍不清楚。为了研究这个问题，我们构建了一个两级CPG模型，该模型由兴奋性中间神经元池（Exc-INs）组成，与抑制性中间神经元池（Inh-INs）相互耦合，并投射到支配骨骼肌的屈伸MN池中。每个池由100个具有基于猫脊髓神经元膜特性的神经元组成。模型中包含了VGSC、K(DR)、NaP、KCa、LTCC和H电流通道。模拟结果表明：（1）上调MNs中的VGSC、NaP或LTCC或下调KCa可增加MNs的放电率和募集，从而促进运动模式的形成，增加肌电图（ENG）爆发的幅度，并增强骨骼肌的力量产生。（2）Exc-INs中相同的通道调节可增加Exc-INs的放电频率，促进节律性产生，并增加步周期的屈伸持续时间。（3）相反，MNs或Exc-INs中NaP或LTCC的下调，或CPG（Exc-INs和Inh-INs）和MNs两者的下调都会破坏运动模式，并减少甚至阻断MNs的ENG爆发和骨骼肌的力量产生。（4）药理学实验表明，在离体大鼠脊髓中浴用25μM尼莫地平或2μM利鲁唑可完全阻断虚拟运动，这与模拟结果一致。我们得出结论，上调VGSC、NaP或LTCC或下调KCa可促进行走过程中的节律性产生和力量产生，其中NaP和LTCC起关键作用。
