Ipsilateral and Contralateral Interactions in Spinal Locomotor Circuits Mediated by V1 Neurons: Insights from Computational Modeling

Abstract

We describe and analyze a computational model of neural circuits in the mammalian spinal cord responsible for generating and shaping locomotor-like oscillations. The model represents interacting populations of spinal neurons, including the neurons that were genetically identified and characterized in a series of previous experimental studies. Here, we specifically focus on the ipsilaterally projecting V1 interneurons, their possible role in the spinal locomotor circuitry, and their involvement in the generation of locomotor oscillations. The proposed connections of these neurons and their involvement in different neuronal pathways in the spinal cord allow the model to reproduce the results of optogenetic manipulations of these neurons under different experimental conditions. We suggest the existence of two distinct populations of V1 interneurons mediating different ipsilateral and contralateral interactions within the spinal cord. The model proposes explanations for multiple experimental data concerning the effects of optogenetic silencing and activation of V1 interneurons on the frequency of locomotor oscillations in the intact cord and hemicord under different experimental conditions. Our simulations provide an important insight into the organization of locomotor circuitry in the mammalian spinal cord.

Synaptic connectivity amongst components of the locomotor central pattern generator

“…I have not included data generated from computational modeling work here. This work is of enormous importance as it provides predictions regarding the detailed synaptic connectivity that is able to account for coordinated locomotion ( Rybak et al, 2015 ; Shevtsova et al, 2015 ; Shevtsova and Rybak, 2016 ; Danner et al, 2019 ; Shevtsova et al, 2020 ; Shevtsova et al, 2022 ). It can thus lead directly to testable hypotheses and the design of experiments which investigate whether the predictions are accurate, however, it should not be taken as fact until tracing experiments prove it to be so.…”

Operation regimes of spinal circuits controlling locomotion and role of supraspinal drives and sensory feedback

“…The spinal circuitry in the model includes two RGs (as described above) interacting via a series of commissural interneuronal (CIN) pathways mediated by different sets of genetically identified commissural (V0D, V0V, and V3) and ipsilaterally projecting (V2a) interneurons, as well as some hypothetical inhibitory interneurons (Ini). The organization of these intraspinal interactions was directly drawn from our earlier models [26][27][28][29][30][31][32] that were explicitly or implicitly based on the results of molecular/genetic studies of locomotion in mice or were proposed to explain and reproduce multiple aspects of the neural control of locomotion in these studies. Specifically, V0D and V2a-V0V-Ini pathways secure left-right alternation of RG oscillations during walking and trotting at slow and higher locomotor speeds, respectively 26,27,53 .…”

“…Here, we use the term CPG for the spinal circuitry controlling and coordinating all limbs, and the term RG (rhythm generator) for the relatively independent part of the CPG that controls rhythmic movements of a single limb. We consider the CPG as a group of RGs, each controlling a single limb and interacting with each other through commissural and/or propriospinal pathways or circuits 3,[26][27][28][29][30][31][32] .…”

“…The present model is based on our previous models [26][27][28][29][30][31][32] and contains two rhythm generators (RGs) that control the left and right hindlimbs and interact through a series of commissural pathways. The RGs receive supraspinal drive, and limb sensory feedback during the extension phase.…”

Spinal V1 Inhibitory Interneuron Clades Differ in Birthdate, Projections to Motoneurons and Heterogeneity

“…Based on differential expression of calcium buffering proteins and synaptology this early study proposed a diversity of phenotypes and circuit roles for V1 interneurons. Later electrophysiological and modeling studies showed that V1 interneurons play crucial roles in shaping motor output by modulating locomotor speed, governing flexion-extension at the level of central pattern generator (CPG) half-centers and/or last-order reciprocal inhibition of antagonistic motoneurons, and providing recurrent feedback inhibition of motoneuron firing (Sapir et al, 2004; Zhang et al, 2014; Britz et al, 2015; Falgairolle and O’Donovan, 2019, 2021; Shevtsova et al, 2022). Accordingly, there is significant interest in defining the molecular identity and circuit organization of different subtypes of V1 interneurons.…”