On the Organization of the Locomotor CPG: Insights From Split-Belt Locomotion and Mathematical Modeling

Abstract

Rhythmic limb movements during locomotion are controlled by central pattern generator (CPG) circuits located in the spinal cord. It is considered that these circuits are composed of individual rhythm generators (RGs) for each limb interacting with each other through multiple commissural and long propriospinal circuits. The organization and operation of each RG are not fully understood, and different competing theories exist about interactions between its flexor and extensor components, as well as about leftright commissural interactions between the RGs. The central idea of circuit organization proposed in this study is that with an increase of excitatory input to each RG (or an increase in locomotor speed) the rhythmogenic mechanism of the RGs changes from "flexor-driven" rhythmicity to a "classical half-center" mechanism. We test this hypothesis using our experimental data on changes in duration of stance and swing phases in the intact and spinal cats walking on the ground or tied-belt treadmills (symmetric conditions) or split-belt treadmills with different left and right belt speeds (asymmetric conditions). We compare these experimental data with the results of mathematical modeling, in which simulated CPG circuits operate in similar symmetric and asymmetric conditions with matching or differing control drives to the left and right RGs. The obtained results support the proposed concept of state-dependent changes in RG operation and specific commissural interactions between the RGs. The performed simulations and mathematical analysis of model operation under different conditions provide new insights into CPG network organization and limb coordination during locomotion.

The role of V3 neurons in speed-dependent interlimb coordination during locomotion in mice

“…The neurons in the F and E half-centers incorporate a slowly inactivating persistent sodium current (INaP) and are connected by excitatory synaptic connections that allow them to generate synchronized populational bursting activity in a certain range of an external brainstem drive. As in our previous models (Rybak et al, 2013(Rybak et al, , 2015Molkov et al, 2015;Shevtsova et al, 2015;Danner et al, 2016Danner et al, , 2017Danner et al, , 2019Shevtsova and Rybak, 2016;Ausborn et al, 2019Ausborn et al, , 2021Latash et al, 2020), only the F half-centers operate in a bursting regime and generate intrinsically rhythmic activity, while the E half-centers receive a relatively high tonic drive and are tonically active if uncoupled. The E half-centers generate rhythmic activity only due to inhibition from the intrinsically oscillating F half-centers.…”

“…The basic architecture of the model has been developed for several years to be able to reproduce experimental data from multiple independent experimental studies (Rybak et al, 2013(Rybak et al, , 2015Molkov et al, 2015;Shevtsova et al, 2015;Danner et al, 2016Danner et al, , 2017Danner et al, , 2019Shevtsova and Rybak, 2016;Ausborn et al, 2019Ausborn et al, , 2021Latash et al, 2020) and was extended here to incorporate the results of experimental studies described above. The detailed schematic of the model is shown in Figure 7 and its major components are shown in Figure 8 and described below.…”

“…This spinal circuitry includes rhythmgenerating circuits (Graham Brown, 1911, 1914 and multiple commissural, propriospinal, premotor, and pattern formation neurons (Grillner, 2006;Kiehn, 2006Kiehn, , 2011Kiehn, , 2016Rybak et al, 2006aRybak et al, , 2006bRybak et al, , 2013Rybak et al, , 2015Jankowska, 2008;McCrea and Rybak, 2008;Danner et al, 2016Danner et al, , 2017Danner et al, , 2019Ausborn et al, 2021). It is commonly accepted that each limb is controlled by a separate spinal rhythm generator (RG) (Forssberg et al, 1980;Thibaudier et al, 2013;Frigon, 2017;Danner et al, 2019;Latash et al, 2020) and that RGs controlling left and right forelimbs and left and right hindlimbs are located on the corresponding sides of cervical and lumbar enlargements of the spinal cord, respectively (Kato, 1990;Ballion et al, 2001;Juvin et al, 2005Juvin et al, , 2012. The left and right lumbar and cervical circuits are connected through multiple types of local commissural interneurons (CINs), which coordinate left-right activities (Stein, 1976;Butt and Kiehn, 2003;Quinlan and Kiehn, 2007;Talpalar et al, 2013;Bellardita and Kiehn, 2015;Rybak et al, 2015;Shevtsova et al, 2015).…”

State- and Condition-Dependent Modulation of the Hindlimb Locomotor Pattern in Intact and Spinal Cats Across Speeds

“…We followed ARRIVE guidelines for animal studies (Percie du Sert et al, 2020). In our effort to reduce the number of animals used in research, we used these cats in other studies to answer different scientific questions (Latash et al, 2020;Harnie et al, 2019Harnie et al, , 2021Merlet et al, 2020Merlet et al, , 2021.…”

Computational Modeling of Spinal Locomotor Circuitry in the Age of Molecular Genetics

“…Thus, state-dependent modulation of the neuronal components of the rhythm generators could set different operating regimes appropriate for the locomotor task at hand. For example, Latash et al [125] showed that a model implementing a transition from a flexor-dominant regime at low locomotor frequencies to a classical half-center regime at high frequencies can explain the left-right asymmetries of split-belt locomotion in spinal cats [126,127].…”