Danner Simon M, Wilshin Simon D, Shevtsova Natalia A, Rybak Ilya A
Department of Neurobiology and Anatomy, Drexel University College of Medicine, Philadelphia, PA, USA.
Structure and Motion Laboratory, The Royal Veterinary College, University of London, London, UK.
J Physiol. 2016 Dec 1;594(23):6947-6967. doi: 10.1113/JP272787. Epub 2016 Nov 8.
Quadrupeds express different gaits depending on speed of locomotion. Central pattern generators (one per limb) within the spinal cord generate locomotor oscillations and control limb movements. Neural interactions between these generators define interlimb coordination and gait. We present a computational model of spinal circuits representing four rhythm generators with left-right excitatory and inhibitory commissural and fore-hind inhibitory interactions within the cord. Increasing brainstem drive to all rhythm generators and excitatory commissural interneurons induces an increasing frequency of locomotor oscillations accompanied by speed-dependent gait changes from walk to trot and to gallop and bound. The model closely reproduces and suggests explanations for multiple experimental data, including speed-dependent gait transitions in intact mice and changes in gait expression in mutants lacking certain types of commissural interneurons. The model suggests the possible circuit organization in the spinal cord and proposes predictions that can be tested experimentally.
As speed of locomotion is increasing, most quadrupeds, including mice, demonstrate sequential gait transitions from walk to trot and to gallop and bound. The neural mechanisms underlying these transitions are poorly understood. We propose that the speed-dependent expression of different gaits results from speed-dependent changes in the interactions between spinal circuits controlling different limbs and interlimb coordination. As a result, the expression of each gait depends on (1) left-right interactions within the spinal cord mediated by different commissural interneurons (CINs), (2) fore-hind interactions on each side of the spinal cord and (3) brainstem drives to rhythm-generating circuits and CIN pathways. We developed a computational model of spinal circuits consisting of four rhythm generators (RGs) with bilateral left-right interactions mediated by V0 CINs (V0 and V0 sub-types) providing left-right alternation, and conditional V3 CINs promoting left-right synchronization. Fore and hind RGs mutually inhibited each other. We demonstrate that linearly increasing excitatory drives to the RGs and V3 CINs can produce a progressive increase in the locomotor speed accompanied by sequential changes of gaits from walk to trot and to gallop and bound. The model closely reproduces and suggests explanations for the speed-dependent gait expression observed in vivo in intact mice and in mutants lacking V0 or all V0 CINs. Specifically, trot is not expressed after removal of V0 CINs, and only bound is expressed after removal of all V0 CINs. The model provides important insights into the organization of spinal circuits and neural control of locomotion.
四足动物根据运动速度表现出不同的步态。脊髓内的中枢模式发生器（每个肢体一个）产生运动振荡并控制肢体运动。这些发生器之间的神经相互作用决定了肢体间的协调和步态。我们提出了一个脊髓回路的计算模型，该模型代表四个节律发生器，在脊髓内具有左右兴奋性和抑制性连合以及前后抑制性相互作用。增加脑干对所有节律发生器和兴奋性连合中间神经元的驱动会导致运动振荡频率增加，同时伴随着从行走、小跑、飞奔到跳跃的速度依赖性步态变化。该模型紧密再现并解释了多个实验数据，包括完整小鼠中速度依赖性步态转变以及缺乏某些类型连合中间神经元的突变体中步态表达的变化。该模型揭示了脊髓中可能的回路组织，并提出了可通过实验验证的预测。
随着运动速度增加，包括小鼠在内的大多数四足动物会表现出从行走、小跑、飞奔到跳跃的连续步态转变。这些转变背后的神经机制尚不清楚。我们提出，不同步态的速度依赖性表达源于控制不同肢体的脊髓回路之间相互作用以及肢体间协调的速度依赖性变化。因此，每种步态的表达取决于：（1）由不同连合中间神经元（CINs）介导的脊髓内左右相互作用；（2）脊髓每一侧的前后相互作用；（3）脑干对节律产生回路和CIN通路的驱动。我们开发了一个脊髓回路的计算模型，该模型由四个节律发生器（RGs）组成，由V0 CINs（V0和V0亚型）介导的双侧左右相互作用提供左右交替，条件性V3 CINs促进左右同步。前后RG相互抑制。我们证明，线性增加对RG和V3 CINs的兴奋性驱动可以使运动速度逐渐增加，同时伴随着从行走、小跑、飞奔到跳跃的步态顺序变化。该模型紧密再现并解释了在完整小鼠体内以及缺乏V0或所有V0 CINs的突变体中观察到的速度依赖性步态表达。具体而言，去除V0 CINs后不会表现出小跑，去除所有V0 CINs后仅表现出跳跃。该模型为脊髓回路的组织和运动的神经控制提供了重要见解。
