Organization of flexor-extensor interactions in the mammalian spinal cord: insights from computational modelling.

KEY POINTS Alternation of flexor and extensor activity in the mammalian spinal cord is mediated by two classes of genetically identified inhibitory interneurons, V1 and V2b. The V1 interneurons are essential for high-speed locomotor activity. They secure flexor-extensor alternations in the intact cord but lose this function after hemisection, suggesting that they are activated by inputs from the contralateral side of the cord. The V2b interneurons are involved in flexor-extensor alternations in both intact cord and hemicords. We used a computational model of the spinal network, simulating the left and right rhythm-generating circuits interacting via several commissural pathways, and extended this model by incorporating V1 and V2b neuron populations involved in flexor-extensor interactions on each cord side. The model reproduces multiple experimental data on selective silencing and activation of V1 and/or V2b neurons and proposes the organization of their connectivity providing flexor-extensor alternation in the spinal cord. ABSTRACT Alternating flexor and extensor activity represents the fundamental property underlying many motor behaviours including locomotion. During locomotion this alternation appears to arise in rhythm-generating circuits and transpires at all levels of the spinal cord including motoneurons. Recent studies in vitro and in vivo have shown that flexor-extensor alternation during locomotion involves two classes of genetically identified, inhibitory interneurons: V1 and V2b. Particularly, in the isolated mouse spinal cord, abrogation of neurotransmission derived by both V1 and V2b interneurons resulted in flexor-extensor synchronization, whereas selective inactivation of only one of these neuron types did not abolish flexor-extensor alternation. After hemisection, inactivation of only V2b interneurons led to the flexor-extensor synchronization, while inactivation of V1 interneurons did not affect flexor-extensor alternation. Moreover, optogenetic activation of V2b interneurons suppressed extensor-related activity, while similar activation of V1 interneurons suppressed both flexor and extensor oscillations. Here, we address these issues using the previously published computational model of spinal circuitry simulating bilateral interactions between left and right rhythm-generating circuits. In the present study, we incorporate V1 and V2b neuron populations on both sides of the cord to make them critically involved in flexor-extensor interactions. The model reproduces multiple experimental data on the effects of hemisection and selective silencing or activation of V1 and V2b neurons and suggests connectivity profiles of these neurons and their specific roles in left-right (V1) and flexor-extensor (both V2b and V1) interactions in the spinal cord that can be tested experimentally.