Dual-mode operation of neuronal networks involved in left-right alternation
TL;DR: It is shown that ablation of a group of transcriptionally defined commissural neurons—the V0 population—leads to a quadrupedal hopping at all frequencies of locomotion, with two subgroups of V0 neurons required for the existence of left–right alternating modes at different speeds of locomotions.
Abstract: All forms of locomotion are repetitive motor activities that require coordinated bilateral activation of muscles. The executive elements of locomotor control are networks of spinal neurons that determine gait pattern through the sequential activation of motor-neuron pools on either side of the body axis. However, little is known about the constraints that link left-right coordination to locomotor speed. Recent advances have indicated that both excitatory and inhibitory commissural neurons may be involved in left-right coordination. But the neural underpinnings of this, and a possible causal link between these different groups of commissural neurons and left-right alternation, are lacking. Here we show, using intersectional mouse genetics, that ablation of a group of transcriptionally defined commissural neurons--the V0 population--leads to a quadrupedal hopping at all frequencies of locomotion. The selective ablation of inhibitory V0 neurons leads to a lack of left-right pattern at low frequencies, mixed coordination at medium frequencies, and alternation at high locomotor frequencies. When ablation is targeted to excitatory V0 neurons, left-right alternation is present at low frequencies, and hopping is restricted to medium and high locomotor frequencies. Therefore, the intrinsic logic of the central control of locomotion incorporates a modular organization, with two subgroups of V0 neurons required for the existence of left-right alternating modes at different speeds of locomotion. The two molecularly distinct sets of commissural neurons may constrain species-related naturally occurring frequency-dependent coordination and be involved in the evolution of different gaits.
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TL;DR: The emergent themes from this research are that the locomotor networks have a modular organization with distinct transmitter and molecular codes and that their organization is reconfigured with changes to the speed of locomotion or changes in gait.
Abstract: In vertebrates, assemblies of neurons in the spinal cord generate the precise timing and patterning of locomotor movements. In this Review, Ole Kiehn examines the organization and operation of these spinal locomotor networks in limbed and non-limbed animals.
542 citations
TL;DR: This work aims at covering all main aspects of this complex behavior - from the operation of the microcircuits in the spinal cord to the systems and behavioral levels and extend from mammalian locomotion to the basic undulatory movements of lamprey and fish.
Abstract: The vertebrate control of locomotion involves all levels of the nervous system from cortex to the spinal cord. Here, we aim to cover all main aspects of this complex behavior, from the operation of...
257 citations
TL;DR: This work identifies an ipsilaterally projecting excitatory interneuron population, marked by the expression of Shox2 that overlaps partially with V2a interneurons, that appears to participate in the rhythm-generating kernel for spinal locomotion.
202 citations
Cites background from "Dual-mode operation of neuronal net..."
...The most likely explanation for this is that the Shox2+ non-V2a INs and the Shox2off V2a INs drive commissural pathways active at different speeds of locomotion (Figure 8B; see also Talpalar et al., 2013)....
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TL;DR: The V2a "stop neurons" represent a glutamatergic descending pathway that favors immobility and may thus help control the episodic nature of locomotion.
198 citations
Cites background or methods from "Dual-mode operation of neuronal net..."
...Three to four weeks following viral transfection, locomotion was tested when animals were moving in a linear corridor (Bellardita and Kiehn, 2015; Talpalar et al., 2013)....
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...…activity, we bath-applied the minimal concentrations of neuroactive substances N-methyl-D-aspartate (NMDA) (5–7 mM) and serotonin (5-HT) (8–10 mM) sufficient to induce slow and intermediate frequency, locomotor-like activity (up to 0.45 Hz; Talpalar et al., 2013; Talpalar and Kiehn, 2010)....
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...To test for the possibility that the role of descending V2a neurons may be revealed during ongoing locomotor-like activity, we bath-applied the minimal concentrations of neuroactive substances N-methyl-D-aspartate (NMDA) (5–7 mM) and serotonin (5-HT) (8–10 mM) sufficient to induce slow and intermediate frequency, locomotor-like activity (up to 0.45 Hz; Talpalar et al., 2013; Talpalar and Kiehn, 2010)....
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...…experimental interferences were previously shown to reliably forecast the consequences on limbed locomotion at later developmental stages (Andersson et al., 2012; Bellardita andKiehn, 2015; Crone et al., 2008; Crone et al., 2009; Kullander et al., 2003; Talpalar et al., 2013; Zhang et al., 2014)....
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...Activities recorded in the in vitro rodent preparations at early postnatal stages and their perturbations following experimental interferences were previously shown to reliably forecast the consequences on limbed locomotion at later developmental stages (Andersson et al., 2012; Bellardita andKiehn, 2015; Crone et al., 2008; Crone et al., 2009; Kullander et al., 2003; Talpalar et al., 2013; Zhang et al., 2014)....
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TL;DR: This work shows that the production of an alternating flexor-extensor motor rhythm depends on the composite activities of two classes of ventrally located inhibitory neurons, V1 and V2b interneurons (INs).
185 citations
Cites background from "Dual-mode operation of neuronal net..."
...…INs are largely responsible for this facet of motor coordination, as the inactivation of other inhibitory neuron populations, including V0 INs and Lbx1-derived inhibitory neuron cell types, does not alter flexor-extensor phasing (Lanuza et al., 2004; Talpalar et al., 2013; M.G., unpublished data)....
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References
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TL;DR: A map of GFP distribution in the knock‐in mouse brain is constructed and many medium‐sized spherical somata emitting intense GFP fluorescence were observed in layer I, in accord with unidentified GFP‐positive cells.
Abstract: Gamma-aminobutyric acid (GABA)ergic neurons in the central nervous system regulate the activity of other neurons and play a crucial role in information processing. To assist an advance in the research of GABAergic neurons, here we produced two lines of glutamic acid decarboxylase-green fluorescence protein (GAD67-GFP) knock-in mouse. The distribution pattern of GFP-positive somata was the same as that of the GAD67 in situ hybridization signal in the central nervous system. We encountered neither any apparent ectopic GFP expression in GAD67-negative cells nor any apparent lack of GFP expression in GAD67-positive neurons in the two GAD67-GFP knock-in mouse lines. The timing of GFP expression also paralleled that of GAD67 expression. Hence, we constructed a map of GFP distribution in the knock-in mouse brain. Moreover, we used the knock-in mice to investigate the colocalization of GFP with NeuN, calretinin (CR), parvalbumin (PV), and somatostatin (SS) in the frontal motor cortex. The proportion of GFP-positive cells among NeuN-positive cells (neocortical neurons) was approximately 19.5%. All the CR-, PV-, and SS-positive cells appeared positive for GFP. The CR-, PV, and SS-positive cells emitted GFP fluorescence at various intensities characteristics to them. The proportions of CR-, PV-, and SS-positive cells among GFP-positive cells were 13.9%, 40.1%, and 23.4%, respectively. Thus, the three subtypes of GABAergic neurons accounted for 77.4% of the GFP-positive cells. They accounted for 6.5% in layer I. In accord with unidentified GFP-positive cells, many medium-sized spherical somata emitting intense GFP fluorescence were observed in layer I.
1,214 citations
TL;DR: New advances in understanding the mammalian CPGs are discussed with a focus on experiments that address the overall network structure as well as the identification of CPG neurons.
Abstract: Intrinsic spinal networks, known as central pattern generators (CPGs), control the timing and pattern of the muscle activity underlying locomotion in mammals. This review discusses new advances in understanding the mammalian CPGs with a focus on experiments that address the overall network structure as well as the identification of CPG neurons. I address the identification of excitatory CPG neurons and their role in rhythm generation, the organization of flexor-extensor networks, and the diverse role of commissural interneurons in coordinating left-right movements. Molecular and genetic approaches that have the potential to elucidate the function of populations of CPG interneurons are also discussed.
842 citations
TL;DR: This work has shown that in one vertebrate model system, the lamprey, it has been possible to make the connection between different subtypes of ion channels and transmitters and their roles at the cellular and network levels, and it is therefore possible to link the role of certain genes or molecules to motor behaviour in this system.
Abstract: The vertebrate motor system is equipped with a number of neuronal networks that underlie different patterns of behaviour, from simple protective reflexes to complex movements. The current challenge is to understand the intrinsic function of these networks: that is, the cellular basis of motor behaviour. In one vertebrate model system, the lamprey, it has been possible to make the connection between different subtypes of ion channels and transmitters and their roles at the cellular and network levels. It is therefore possible to link the role of certain genes or molecules to motor behaviour in this system.
833 citations
TL;DR: The advent of novel molecular and genetic techniques coupled with recent advances in knowledge of spinal cord development means that a comprehensive understanding of how the motor circuitry is organized and operates may be within the authors' grasp.
Abstract: Neurobiologists have long sought to understand how circuits in the nervous system are organized to generate the precise neural outputs that underlie particular behaviours. The motor circuits in the spinal cord that control locomotion, commonly referred to as central pattern generator networks, provide an experimentally tractable model system for investigating how moderately complex ensembles of neurons generate select motor behaviours. The advent of novel molecular and genetic techniques coupled with recent advances in our knowledge of spinal cord development means that a comprehensive understanding of how the motor circuitry is organized and operates may be within our grasp.
719 citations
TL;DR: The ability to generate fast and regular rhythmic activity decreased in the caudal direction, but the rhythm-generating network was found to be distributed over the entire lumbar region and to extend into the caUDal thoracic region.
Abstract: The isolated spinal cord of the newborn rat contains networks that are able to create a patterned motor output resembling normal locomotor movements. In this study, we sought to localize the regions of primary importance for rhythm and pattern generation using specific mechanical lesions. We used ventral root recordings to monitor neuronal activity and tested the ability of various isolated parts of the caudal thoracic-lumbar cord to generate rhythmic bursting in a combination of 5-HT and NMDA. In addition, pathways mediating left/right and rostrocaudal burst alternation were localized. We found that the isolated ventral third of the spinal cord can generate normally coordinated rhythmic activity, whereas lateral fragments resulting from sagittal sections showed little or no rhythmogenic capability compared with intact control preparations. The ability to generate fast and regular rhythmic activity decreased in the caudal direction, but the rhythm-generating network was found to be distributed over the entire lumbar region and to extend into the caudal thoracic region. The pathways mediating left/right alternation exist primarily in the ventral commissure. As with the rhythmogenic ability, these pathways were distributed along the lumbar enlargement. Both lateral and ventral funiculi were sufficient to coordinate activity in the rostral and caudal regions. We conclude that the networks organizing locomotor-related activity in the spinal cord of the newborn rat are distributed.
526 citations