Organization of left–right coordination of neuronal activity in the mammalian spinal cord: Insights from computational modelling

Abstract

Key pointsr Coordination of neuronal activity between left and right sides of the mammalian spinal cord is provided by several sets of commissural interneurons (CINs) whose axons cross the midline. Genetically identified inhibitory V0 D and excitatory V0 V CINs and ipsilaterally projecting excitatory V2a interneurons were shown to secure left-right alternation at different locomotor speeds.r We have developed computational models of neuronal circuits in the spinal cord that include left and right rhythm-generating centres interacting bilaterally via three parallel pathways mediated by V0 D , V2a-V0 V and V3 neuron populations.r The models reproduce the experimentally observed speed-dependent left-right coordination in normal mice and the changes in coordination seen in mutants lacking specific neuron classes.r The models propose an explanation for several experimental results and provide insights into the organization of the spinal locomotor network and parallel CIN pathways involved in gait control at different locomotor speeds.Abstract Different locomotor gaits in mammals, such as walking or galloping, are produced by coordinated activity in neuronal circuits in the spinal cord. Coordination of neuronal activity between left and right sides of the cord is provided by commissural interneurons (CINs), whose axons cross the midline. In this study, we construct and analyse two computational models of spinal locomotor circuits consisting of left and right rhythm generators interacting bilaterally via several neuronal pathways mediated by different CINs. The CIN populations incorporated in the models include the genetically identified inhibitory (V0 D ) and excitatory (V0 V ) subtypes of V0 CINs and excitatory V3 CINs. The model also includes the ipsilaterally projecting excitatory V2a interneurons mediating excitatory drive to the V0 V CINs. The proposed network architectures and CIN connectivity allow the models to closely reproduce and suggest mechanistic explanations for several experimental observations. These phenomena include: different speed-dependent contributions of V0 D and V0 V CINs and V2a interneurons to left-right alternation of neural activity, switching gaits between the left-right alternating walking-like activity and the left-right synchronous hopping-like pattern in mutants lacking specific neuron classes, and speed-dependent asymmetric changes of flexor and extensor phase durations. The models provide insights into the architecture of spinal network and the organization of parallel inhibitory and excitatory CIN pathways and suggest explanations for how these pathways maintain alternating and synchronous gaits at different locomotor speeds. The models propose testable predictions about the neural organization and operation of mammalian locomotor circuits.

Decoding the organization of spinal circuits that control locomotion

“…Furthermore, V2a neurons project to V0 V neurons 83 and to motor neurons 88 . They are also active over a wide range of locomotor frequencies 89,90 but fire more strongly at higher frequencies 91 , which is compatible with a subpopulation of V2a neurons being involved in directly driving the V0 V pathway at higher speeds of locomotion 53 (FIG. 3c).…”

“…A recent modelling study has incorporated the V0 D –V0 V population pathways in a general model of the limb locomotor network and has proposed a scheme for the connectivity and recruitment of the different CNs during different speeds of locomotion 53 . Such connectivity and recruitment patterns await further studies.…”

“…The presence of flexor-and extensor-rhythm generation does not exclude the fact that flexor bursting might be predominant under certain circumstances. Thus, locomotor activity is readily modelled with dominant flexor bursting 53 and when the composite flexor-and extensor-related lateral motor column is genetically converted into a flexor-related motor column, flexor bursting is still possible in the absence of extensor bursting 80,82 ; this has led to the speculation that flexor bursting is the phylogenetic expression of burst activation of the axial muscles in leg-less animals 80,82 .…”

“…The expression of I NaP may be regulated as a consequence of changes in extracellular calcium and potassium concentrations during locomotion, suggesting that I NaP -mediated pacemaker properties are activated during network activity 117 . Blockade of the persistent sodium conductance severely affects the ability to produce a rhythmic motor output 114,115 , and expression of I NaP in excitatory neurons in network models readily endows the network with rhythmogenic properties 53 . However, blocking I NaP impairs the spiking mechanism in neurons, including motor neurons 115 .…”

The spinal control of locomotion and step-to-step variability in left-right symmetry from slow to moderate speeds

“…An emerging consensus is that the spinal mechanisms at slow frequencies are different from those at higher ones (Shevtsova et al 2015;Talpalar et al 2013). Although we can only speculate, it is also possible that an increase in speed activates neuronal mechanisms that help reduce step-to-step variability.…”