Multiple Rhythm-Generating Circuits Act in Tandem with Pacemaker Properties to Control the Start and Speed of Locomotion

Song, Jianren; Pallucchi, Irene; Ausborn, Jessica; Ampatzis, Konstantinos; Bertuzzi, Maria; Fontanel, Pierre; Picton, Laurence D.; Manira, Abdeljabbar El

doi:10.1016/j.neuron.2019.12.030

Cited by 59 publications

(66 citation statements)

References 90 publications

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“…The immediate assumption was that the locomotor rhythm may emerge from neurons incorporating I NaP as a "pacemaker" current. In line with this concept, inhibition of I NaP abolishes locomotor-like activity in rodents [3,[9][10][11] and salamanders [12] and disrupts locomotion in zebrafish [8,13] and Xenopus laevis tadpoles [14]. Altogether, a picture emerges that the locomotor rhythm arises from a dynamic interplay between circuit-based activity and pacemaker burst-generating mechanisms with a critical role of I NaP for the initiation of bursts [4,10].…”

Section: Introductionmentioning

confidence: 74%

“…The rhythm-generating network is a set of pacemaker cells endowed with intrinsic bursting activity in a frequency range similar to stepping rhythms [3,4]. In exploring the ionic basis for rhythmogenesis, we identified the persistent sodium current (I NaP ) as a critical current in burst-generating mechanism [5][6][7][8]. The immediate assumption was that the locomotor rhythm may emerge from neurons incorporating I NaP as a "pacemaker" current.…”

Section: Introductionmentioning

confidence: 99%

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The M-current works in tandem with the persistent sodium current to set the speed of locomotion

et al. 2020

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The central pattern generator (CPG) for locomotion is a set of pacemaker neurons endowed with inherent bursting driven by the persistent sodium current (INaP). How they proceed to regulate the locomotor rhythm remained unknown. Here, in neonatal rodents, we identified a persistent potassium current critical in regulating pacemakers and locomotion speed. This current recapitulates features of the M-current (IM): a subthreshold noninactivating outward current blocked by 10,10-bis(4-pyridinylmethyl)-9(10H)-anthracenone dihydrochloride (XE991) and enhanced by N-(2-chloro-5-pyrimidinyl)-3,4-difluorobenzamide (ICA73). Immunostaining and mutant mice highlight an important role of Kv7.2-containing channels in mediating IM. Pharmacological modulation of IM regulates the emergence and the frequency regime of both pacemaker and CPG activities and controls the speed of locomotion. Computational models captured these results and showed how an interplay between IM and INaP endows the locomotor CPG with rhythmogenic properties. Overall, this study provides fundamental insights into how IM and INaP work in tandem to set the speed of locomotion.

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Section: Introductionmentioning

confidence: 74%

Section: Introductionmentioning

confidence: 99%

The M-current works in tandem with the persistent sodium current to set the speed of locomotion

et al. 2020

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“…A servomechanism for efficient locomotor behavior Next we examined whether the movement-encoded inhibitory feedback signal from ILP neurons is integrated in the central locomotor network. Our analysis focused on three core components of the zebrafish locomotor network: motor neurons (Ampatzis et al, 2013;Gabriel et al, 2011;Song et al, 2016), rhythm-generating excitatory V2a interneurons (Ampatzis et al, 2014;Ausborn et al, 2012;Ljunggren et al, 2014;Eklö f-Ljunggren et al, 2012;Song et al, 2018Song et al, , 2020, and left-right-coordinating inhibitory V0d interneurons (Satou et al, 2020), which were recorded during movement-induced activation of ILP neurons in the isolated spinal cord. In motor neurons, no response was induced by bending of the spinal cord in either direction ( Figure 7A).…”

Section: Ll Open Accessmentioning

confidence: 99%

A spinal organ of proprioception for integrated motor action feedback

Picton

Bertuzzi

Pallucchi

et al. 2021

Neuron

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“…Persistent Na + (INaP) and calcium (ICaL) currents mediate endogenous bursting properties and contribute to the generation of rhythmic behaviours in a variety of systems (Brocard et al, 2013;Del Negro, 2005;Song et al, 2020;Tazerart et al, 2008;Zhong et al, 2007). In our model, INaP contributed to the initiation of bursts and supported the burst phase of individual fast bursts.…”

Section: Persistent Na + Current Contributes To Episodic Bursting Rhymentioning

confidence: 91%

“…Recruitment of neural ensembles or modules may also generate different patterns of rhythmic activity. Orderly recruitment of discrete motor modules in the zebrafish permit speed control (Gabriel et al, 2011;Jha and Thirumalai, 2020;McLean et al, 2007;Song et al, 2020). The emergence of more complex locomotor behaviours during development coincides with the integration of newly born populations of hindbrain V2a interneurons with intrinsic properties and modular synaptic connectivity to accommodate specific locomotor behaviours (Pujala and Koyama, 2019).…”

Section: Caveats Limitations Future Directions and New Questionsmentioning

confidence: 99%

Contributions of h- and Na⁺/K⁺ pump currents to the generation of episodic and continuous rhythmic activities

Sharples

Parker

Vargas

et al. 2020

Preprint

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Developing spinal motor networks produce a diverse array of outputs, including episodic and continuous patterns of rhythmic activity. Variation in excitability state and neuromodulatory tone can facilitate transitions between episodic and continuous rhythms; however, the intrinsic mechanisms that govern these rhythms and transitions are poorly understood. Here, we tested the capacity of a single central pattern generator (CPG) circuit with tunable properties to generate multiple outputs. To address this, we deployed a computational model composed of an inhibitory half-centre oscillator. We tested the contributions of key properties predicted by the model to the generation of an episodic rhythm produced by isolated spinal cords of the newborn mouse. The model was capable of reproducing the diverse state-dependent rhythms evoked by dopamine in the neonatal mouse spinal cord. In the model, episodic bursting depended predominantly on the endogenous oscillatory properties of neurons, with persistent Na+(INaP), Na+-K+ ATPase pump (IPump), and hyperpolarization-activated currents (Ih) playing key roles. Modulation of all three currents produced transitions between episodic and continuous rhythms and silence. Pharmacological manipulation of these properties in vitro led to consistent changes in spinally generated rhythmic outputs elicited by dopamine. The model also showed multistable zones within a narrow range of parameter space for IPump and Ih, where switches between rhythms were rapidly triggered by brief but specific perturbations. Outside of those zones, brief perturbations could reset episodic and continuous rhythmicity generated by the model. Our modelling and experimental results provide insight into mechanisms that govern the generation of multiple patterns of rhythmicity by a single CPG. We propose that neuromodulators alter circuit properties to position the network within regions of state-space that favour stable outputs or, in the case of multistable zones, facilitate rapid transitions between states.Significance statementThe ability of a single CPG to produce and transition between multiple rhythmic patterns of activity is poorly understood. We deployed a complementary computational half-centre oscillator model and an isolated spinal cord experimental model to identify key currents whose interaction produced episodic and continuous rhythmic activity. Combined, our experimental and modelling approaches suggest mechanisms that govern generating and transitioning between diverse rhythms in mammalian spinal networks. This work sheds light on the ability of a single CPG to produce episodic bouts often observed in behavioural contexts.

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Multiple Rhythm-Generating Circuits Act in Tandem with Pacemaker Properties to Control the Start and Speed of Locomotion

Cited by 59 publications

References 90 publications

The M-current works in tandem with the persistent sodium current to set the speed of locomotion

The M-current works in tandem with the persistent sodium current to set the speed of locomotion

A spinal organ of proprioception for integrated motor action feedback

Contributions of h- and Na⁺/K⁺ pump currents to the generation of episodic and continuous rhythmic activities

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Multiple Rhythm-Generating Circuits Act in Tandem with Pacemaker Properties to Control the Start and Speed of Locomotion

Cited by 59 publications

References 90 publications

The M-current works in tandem with the persistent sodium current to set the speed of locomotion

The M-current works in tandem with the persistent sodium current to set the speed of locomotion

A spinal organ of proprioception for integrated motor action feedback

Contributions of h- and Na+/K+ pump currents to the generation of episodic and continuous rhythmic activities

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Contributions of h- and Na⁺/K⁺ pump currents to the generation of episodic and continuous rhythmic activities