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Neuronal Control of Locomotion

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Neurobiology".

Deadline for manuscript submissions: closed (28 February 2022) | Viewed by 45317

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Assoc. Prof. Turgay Akay

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Brain Repair Center, Atlantic Mobility Action Project, Department of Medical Neuroscience, Dalhousie University, Halifax, NS, Canada
Interests: Motor Control; Neuroscience; Locomotion; Central Pattern Generation; Proprioception; Reflexes

Special Issue Information

Dear Colleagues,

One of the main areas of Neuroscience research is understanding how the nervous system generates and controls movement. Research that aims to understand locomotion, defined as the movement of an organism from one place to another, has been one of the main areas contributing to this understanding. During locomotion, patterned and rhythmic contractions of multiple muscles underlie the coordinated movement of the body or limbs to provide posture and propulsion. These patterned contractions of muscles are controlled by the activities of motor neuron pools located within the central nervous system (CNS). It is generally accepted that at least some aspects of this patterned motor neuron activation are controlled by the action of a pre-motor network of interneurons within CNS, the central pattern generator (CPG). Moreover, the activity of the CPG is constantly modified by the sensory feedback from the periphery that provides the CPG with the information regarding the terrain, the body, and equilibrium. Despite the large volume of information that we have accumulated over the last century, core aspects of the neuronal mechanisms that control locomotion remain obscure. Advances in developmental and molecular biology, combined with new neuroscience methods for recording locomotor activity, have provided us with new opportunities to better our understanding.

The purpose of this Special Issue is to highlight different aspects of the neuronal control of locomotion using different approaches, including molecular biology, neuroscience, biomechanics, and computational approaches, on different model systems.

Assoc. Prof. Turgay Akay
Guest Editor

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Keywords

locomotion
neuroscience
molecular biology
genetics
gene delivery
motion analysis
in vivo electrophysiology
in vitro electrophysiology
central pattern generators
sensory feedback

Published Papers (12 papers)

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Research

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21 pages, 5897 KiB

Open AccessArticle

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

by Natalia A. Shevtsova, Erik Z. Li, Shayna Singh, Kimberly J. Dougherty and Ilya A. Rybak

Int. J. Mol. Sci. 2022, 23(10), 5541; https://doi.org/10.3390/ijms23105541 - 16 May 2022

Cited by 3 | Viewed by 1502

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. Full article

(This article belongs to the Special Issue Neuronal Control of Locomotion)

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25 pages, 4101 KiB

Open AccessArticle

Unusual Quadrupedal Locomotion in Rat during Recovery from Lumbar Spinal Blockade of 5-HT₇ Receptors

by Urszula Sławińska, Henryk Majczyński, Anna Kwaśniewska, Krzysztof Miazga, Anna M. Cabaj, Marek Bekisz, Larry M. Jordan and Małgorzata Zawadzka

Int. J. Mol. Sci. 2021, 22(11), 6007; https://doi.org/10.3390/ijms22116007 - 02 Jun 2021

Cited by 4 | Viewed by 2763

Abstract

Coordination of four-limb movements during quadrupedal locomotion is controlled by supraspinal monoaminergic descending pathways, among which serotoninergic ones play a crucial role. Here we investigated the locomotor pattern during recovery from blockade of 5-HT₇ or 5-HT_2A receptors after intrathecal application of SB269970 or cyproheptadine in adult rats with chronic intrathecal cannula implanted in the lumbar spinal cord. The interlimb coordination was investigated based on electromyographic activity recorded from selected fore- and hindlimb muscles during rat locomotion on a treadmill. In the time of recovery after hindlimb transient paralysis, we noticed a presence of an unusual pattern of quadrupedal locomotion characterized by a doubling of forelimb stepping in relation to unaffected hindlimb stepping (2FL-1HL) after blockade of 5-HT₇ receptors but not after blockade of 5-HT_2A receptors. The 2FL-1HL pattern, although transient, was observed as a stable form of fore-hindlimb coupling during quadrupedal locomotion. We suggest that modulation of the 5-HT₇ receptors on interneurons located in lamina VII with ascending projections to the forelimb spinal network can be responsible for the 2FL-1HL locomotor pattern. In support, our immunohistochemical analysis of the lumbar spinal cord demonstrated the presence of the 5-HT₇ immunoreactive cells in the lamina VII, which were rarely 5-HT_2A immunoreactive. Full article

(This article belongs to the Special Issue Neuronal Control of Locomotion)

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24 pages, 12693 KiB

Open AccessArticle

Noradrenergic Components of Locomotor Recovery Induced by Intraspinal Grafting of the Embryonic Brainstem in Adult Paraplegic Rats

by Anna Kwaśniewska, Krzysztof Miazga, Henryk Majczyński, Larry M. Jordan, Małgorzata Zawadzka and Urszula Sławińska

Int. J. Mol. Sci. 2020, 21(15), 5520; https://doi.org/10.3390/ijms21155520 - 01 Aug 2020

Cited by 5 | Viewed by 2419

Abstract

Intraspinal grafting of serotonergic (5-HT) neurons was shown to restore plantar stepping in paraplegic rats. Here we asked whether neurons of other phenotypes contribute to the recovery. The experiments were performed on adult rats after spinal cord total transection. Grafts were injected into the sub-lesional spinal cord. Two months later, locomotor performance was tested with electromyographic recordings from hindlimb muscles. The role of noradrenergic (NA) innervation was investigated during locomotor performance of spinal grafted and non-grafted rats using intraperitoneal application of α₂ adrenergic receptor agonist (clonidine) or antagonist (yohimbine). Morphological analysis of the host spinal cords demonstrated the presence of tyrosine hydroxylase positive (NA) neurons in addition to 5-HT neurons. 5-HT fibers innervated caudal spinal cord areas in the dorsal and ventral horns, central canal, and intermediolateral zone, while the NA fiber distribution was limited to the central canal and intermediolateral zone. 5-HT and NA neurons were surrounded by each other’s axons. Locomotor abilities of the spinal grafted rats, but not in control spinal rats, were facilitated by yohimbine and suppressed by clonidine. Thus, noradrenergic innervation, in addition to 5-HT innervation, plays a potent role in hindlimb movement enhanced by intraspinal grafting of brainstem embryonic tissue in paraplegic rats. Full article

(This article belongs to the Special Issue Neuronal Control of Locomotion)

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Review

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17 pages, 2417 KiB

Open AccessReview

Cholinergic Modulation of Locomotor Circuits in Vertebrates

by Didier Le Ray, Sandrine S. Bertrand and Réjean Dubuc

Int. J. Mol. Sci. 2022, 23(18), 10738; https://doi.org/10.3390/ijms231810738 - 14 Sep 2022

Cited by 8 | Viewed by 2270

Abstract

Locomotion is a basic motor act essential for survival. Amongst other things, it allows animals to move in their environment to seek food, escape predators, or seek mates for reproduction. The neural mechanisms involved in the control of locomotion have been examined in many vertebrate species and a clearer picture is progressively emerging. The basic muscle synergies responsible for propulsion are generated by neural networks located in the spinal cord. In turn, descending supraspinal inputs are responsible for starting, maintaining, and stopping locomotion as well as for steering and controlling speed. Several neurotransmitter systems play a crucial role in modulating the neural activity during locomotion. For instance, cholinergic inputs act both at the spinal and supraspinal levels and the underlying mechanisms are the focus of the present review. Much information gained on supraspinal cholinergic modulation of locomotion was obtained from the lamprey model. Nicotinic cholinergic inputs increase the level of excitation of brainstem descending command neurons, the reticulospinal neurons (RSNs), whereas muscarinic inputs activate a select group of hindbrain neurons that project to the RSNs to boost their level of excitation. Muscarinic inputs also reduce the transmission of sensory inputs in the brainstem, a phenomenon that could help in sustaining goal directed locomotion. In the spinal cord, intrinsic cholinergic inputs strongly modulate the activity of interneurons and motoneurons to control the locomotor output. Altogether, the present review underlines the importance of the cholinergic inputs in the modulation of locomotor activity in vertebrates. Full article

(This article belongs to the Special Issue Neuronal Control of Locomotion)

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26 pages, 3017 KiB

Open AccessReview

Role of DSCAM in the Development of Neural Control of Movement and Locomotion

by Maxime Lemieux, Louise Thiry, Olivier D. Laflamme and Frédéric Bretzner

Int. J. Mol. Sci. 2021, 22(16), 8511; https://doi.org/10.3390/ijms22168511 - 07 Aug 2021

Cited by 4 | Viewed by 3238

Abstract

Locomotion results in an alternance of flexor and extensor muscles between left and right limbs generated by motoneurons that are controlled by the spinal interneuronal circuit. This spinal locomotor circuit is modulated by sensory afferents, which relay proprioceptive and cutaneous inputs that inform the spatial position of limbs in space and potential contacts with our environment respectively, but also by supraspinal descending commands of the brain that allow us to navigate in complex environments, avoid obstacles, chase prey, or flee predators. Although signaling pathways are important in the establishment and maintenance of motor circuits, the role of DSCAM, a cell adherence molecule associated with Down syndrome, has only recently been investigated in the context of motor control and locomotion in the rodent. DSCAM is known to be involved in lamination and delamination, synaptic targeting, axonal guidance, dendritic and cell tiling, axonal fasciculation and branching, programmed cell death, and synaptogenesis, all of which can impact the establishment of motor circuits during development, but also their maintenance through adulthood. We discuss herein how DSCAM is important for proper motor coordination, especially for breathing and locomotion. Full article

(This article belongs to the Special Issue Neuronal Control of Locomotion)

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12 pages, 1042 KiB

Open AccessReview

The Temporal Mechanisms Guiding Interneuron Differentiation in the Spinal Cord

by Dylan Deska-Gauthier and Ying Zhang

Int. J. Mol. Sci. 2021, 22(15), 8025; https://doi.org/10.3390/ijms22158025 - 27 Jul 2021

Cited by 2 | Viewed by 2254

Abstract

Neurogenesis timing is an essential developmental mechanism for neuronal diversity and organization throughout the central nervous system. In the mouse spinal cord, growing evidence is beginning to reveal that neurogenesis timing acts in tandem with spatial molecular controls to diversify molecularly and functionally distinct post-mitotic interneuron subpopulations. Particularly, in some cases, this temporal ordering of interneuron differentiation has been shown to instruct specific sensorimotor circuit wirings. In zebrafish, in vivo preparations have revealed that sequential neurogenesis waves of interneurons and motor neurons form speed-dependent locomotor circuits throughout the spinal cord and brainstem. In the present review, we discuss temporal principals of interneuron diversity taken from both mouse and zebrafish systems highlighting how each can lend illuminating insights to the other. Moving forward, it is important to combine the collective knowledge from different systems to eventually understand how temporally regulated subpopulation function differentially across speed- and/or state-dependent sensorimotor movement tasks. Full article

(This article belongs to the Special Issue Neuronal Control of Locomotion)

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15 pages, 981 KiB

Open AccessReview

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

by Jessica Ausborn, Natalia A. Shevtsova and Simon M. Danner

Int. J. Mol. Sci. 2021, 22(13), 6835; https://doi.org/10.3390/ijms22136835 - 25 Jun 2021

Cited by 7 | Viewed by 3426

Abstract

Neuronal circuits in the spinal cord are essential for the control of locomotion. They integrate supraspinal commands and afferent feedback signals to produce coordinated rhythmic muscle activations necessary for stable locomotion. For several decades, computational modeling has complemented experimental studies by providing a mechanistic rationale for experimental observations and by deriving experimentally testable predictions. This symbiotic relationship between experimental and computational approaches has resulted in numerous fundamental insights. With recent advances in molecular and genetic methods, it has become possible to manipulate specific constituent elements of the spinal circuitry and relate them to locomotor behavior. This has led to computational modeling studies investigating mechanisms at the level of genetically defined neuronal populations and their interactions. We review literature on the spinal locomotor circuitry from a computational perspective. By reviewing examples leading up to and in the age of molecular genetics, we demonstrate the importance of computational modeling and its interactions with experiments. Moving forward, neuromechanical models with neuronal circuitry modeled at the level of genetically defined neuronal populations will be required to further unravel the mechanisms by which neuronal interactions lead to locomotor behavior. Full article

(This article belongs to the Special Issue Neuronal Control of Locomotion)

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12 pages, 1461 KiB

Open AccessReview

The CPGs for Limbed Locomotion–Facts and Fiction

by Sten Grillner and Alexander Kozlov

Int. J. Mol. Sci. 2021, 22(11), 5882; https://doi.org/10.3390/ijms22115882 - 30 May 2021

Cited by 28 | Viewed by 4451

Abstract

The neuronal networks that generate locomotion are well understood in swimming animals such as the lamprey, zebrafish and tadpole. The networks controlling locomotion in tetrapods remain, however, still enigmatic with an intricate motor pattern required for the control of the entire limb during the support, lift off, and flexion phase, and most demandingly when the limb makes contact with ground again. It is clear that the inhibition that occurs between bursts in each step cycle is produced by V2b and V1 interneurons, and that a deletion of these interneurons leads to synchronous flexor–extensor bursting. The ability to generate rhythmic bursting is distributed over all segments comprising part of the central pattern generator network (CPG). It is unclear how the rhythmic bursting is generated; however, Shox2, V2a and HB9 interneurons do contribute. To deduce a possible organization of the locomotor CPG, simulations have been elaborated. The motor pattern has been simulated in considerable detail with a network composed of unit burst generators; one for each group of close synergistic muscle groups at each joint. This unit burst generator model can reproduce the complex burst pattern with a constant flexion phase and a shortened extensor phase as the speed increases. Moreover, the unit burst generator model is versatile and can generate both forward and backward locomotion. Full article

(This article belongs to the Special Issue Neuronal Control of Locomotion)

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17 pages, 665 KiB

Open AccessReview

Spinal Inhibitory Interneurons: Gatekeepers of Sensorimotor Pathways

by Nicholas J. Stachowski and Kimberly J. Dougherty

Int. J. Mol. Sci. 2021, 22(5), 2667; https://doi.org/10.3390/ijms22052667 - 06 Mar 2021

Cited by 19 | Viewed by 6275

Abstract

The ability to sense and move within an environment are complex functions necessary for the survival of nearly all species. The spinal cord is both the initial entry site for peripheral information and the final output site for motor response, placing spinal circuits as paramount in mediating sensory responses and coordinating movement. This is partly accomplished through the activation of complex spinal microcircuits that gate afferent signals to filter extraneous stimuli from various sensory modalities and determine which signals are transmitted to higher order structures in the CNS and to spinal motor pathways. A mechanistic understanding of how inhibitory interneurons are organized and employed within the spinal cord will provide potential access points for therapeutics targeting inhibitory deficits underlying various pathologies including sensory and movement disorders. Recent studies using transgenic manipulations, neurochemical profiling, and single-cell transcriptomics have identified distinct populations of inhibitory interneurons which express an array of genetic and/or neurochemical markers that constitute functional microcircuits. In this review, we provide an overview of identified neural components that make up inhibitory microcircuits within the dorsal and ventral spinal cord and highlight the importance of inhibitory control of sensorimotor pathways at the spinal level. Full article

(This article belongs to the Special Issue Neuronal Control of Locomotion)

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14 pages, 6153 KiB

Open AccessReview

The Effects of Mechanical Scale on Neural Control and the Regulation of Joint Stability

by Gil Serrancolí, Cristiano Alessandro and Matthew C. Tresch

Int. J. Mol. Sci. 2021, 22(4), 2018; https://doi.org/10.3390/ijms22042018 - 18 Feb 2021

Cited by 2 | Viewed by 1948

Abstract

Recent work has demonstrated how the size of an animal can affect neural control strategies, showing that passive viscoelastic limb properties have a significant role in determining limb movements in small animals but are less important in large animals. We extend that work to consider effects of mechanical scaling on the maintenance of joint integrity; i.e., the prevention of aberrant contact forces within joints that might lead to joint dislocation or cartilage degradation. We first performed a literature review to evaluate how properties of ligaments responsible for joint integrity scale with animal size. Although we found that the cross-sectional area of the anterior cruciate ligament generally scaled with animal size, as expected, the effects of scale on the ligament’s mechanical properties were less clear, suggesting potential adaptations in passive contributions to the maintenance of joint integrity across species. We then analyzed how the neural control of joint stability is altered by body scale. We show how neural control strategies change across mechanical scales, how this scaling is affected by passive muscle properties and the cost function used to specify muscle activations, and the consequences of scaling on internal joint contact forces. This work provides insights into how scale affects the regulation of joint integrity by both passive and active processes and provides directions for studies examining how this regulation might be accomplished by neural systems. Full article

(This article belongs to the Special Issue Neuronal Control of Locomotion)

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18 pages, 1224 KiB

Open AccessReview

Relative Contribution of Proprioceptive and Vestibular Sensory Systems to Locomotion: Opportunities for Discovery in the Age of Molecular Science

by Turgay Akay and Andrew J. Murray

Int. J. Mol. Sci. 2021, 22(3), 1467; https://doi.org/10.3390/ijms22031467 - 02 Feb 2021

Cited by 19 | Viewed by 10553

Abstract

Locomotion is a fundamental animal behavior required for survival and has been the subject of neuroscience research for centuries. In terrestrial mammals, the rhythmic and coordinated leg movements during locomotion are controlled by a combination of interconnected neurons in the spinal cord, referred as to the central pattern generator, and sensory feedback from the segmental somatosensory system and supraspinal centers such as the vestibular system. How segmental somatosensory and the vestibular systems work in parallel to enable terrestrial mammals to locomote in a natural environment is still relatively obscure. In this review, we first briefly describe what is known about how the two sensory systems control locomotion and use this information to formulate a hypothesis that the weight of the role of segmental feedback is less important at slower speeds but increases at higher speeds, whereas the weight of the role of vestibular system has the opposite relation. The new avenues presented by the latest developments in molecular sciences using the mouse as the model system allow the direct testing of the hypothesis. Full article

(This article belongs to the Special Issue Neuronal Control of Locomotion)

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12 pages, 271 KiB

Open AccessReview

Recent Insights into the Rhythmogenic Core of the Locomotor CPG

by Vladimir Rancic and Simon Gosgnach

Int. J. Mol. Sci. 2021, 22(3), 1394; https://doi.org/10.3390/ijms22031394 - 30 Jan 2021

Cited by 17 | Viewed by 2675

Abstract

In order for locomotion to occur, a complex pattern of muscle activation is required. For more than a century, it has been known that the timing and pattern of stepping movements in mammals are generated by neural networks known as central pattern generators (CPGs), which comprise multiple interneuron cell types located entirely within the spinal cord. A genetic approach has recently been successful in identifying several populations of spinal neurons that make up this neural network, as well as the specific role they play during stepping. In spite of this progress, the identity of the neurons responsible for generating the locomotor rhythm and the manner in which they are interconnected have yet to be deciphered. In this review, we summarize key features considered to be expressed by locomotor rhythm-generating neurons and describe the different genetically defined classes of interneurons which have been proposed to be involved. Full article

(This article belongs to the Special Issue Neuronal Control of Locomotion)

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