Biology subjects

Rybak, I. A.

Publications and source records attributed to Rybak, I. A..

At least 19 recordsLinked to original sources

bioRxiv2026

Speed-Dependent Turning Strategies in Quadrupedal Locomotion: Insights from Computational Modeling

Quadrupedal animals like mice navigate their environments through complex coordination of neural signals and biomechanical movements, enabling stable and directed locomotion. While many computational models simplify this process by assuming left-right symmetrical body movements and focusing on straight-line paths, real animals rely heavily on asymmetrical body movements to execute turns and adjust speed effectively. This study builds upon a previously developed model of quadrupedal locomotion proposed by Molkov et al., 2024) in which forward movement of the body was driven by central neural interactions, biomechanics, and proprioceptive feedback. We extended this model to comparatively investigate possible mechanisms of steering by introducing three distinct asymmetrical strategies-body bending, lateral force application, and lateral limb shifting as well as their combinations-to explore their potential involvement in turning performance. By simulating these strategies across a walking speed range, we measured and compared their impact on turning curvature the sharpness of the turn) and limb coordination. The latter was quantified through ratios of duty factors representing the relative time that a limb spent in contact with the ground compared to its counterpart on the opposite side. Our findings reveal that each strategy excels at different speeds: body bending allows sharp turns at low speeds, lateral force is most effective at medium speeds, and lateral shifting performs best at higher speeds. Our results suggest that animals select or combine turning strategies based on their locomotor speed or adjust speed to use a specific strategy. We also show that the forelimbs consistently play a primary role in steering, while the hindlimbs adjust propulsion and stability in ways that depend on the specific turning strategy. These results provide valuable insights into how spinal circuits and mechanical asymmetries work together to produce flexible, adaptive movement patterns, offering a robust framework for understanding locomotion in both biological organisms and robotic systems designed to mimic such behaviors.

systems biology↗

bioRxiv2025

Effect of Biceps Brachii Muscle Stimulation on Respiration before and after Cervical Spinal Cord Injury.

Cervical spinal cord injuries (SCI) often lead to respiratory impairments, significantly increasing morbidity and mortality in affected individuals. Limb muscle/afferent stimulation has been suggested as a potential approach to enhance breathing when supraspinal control over spinal respiratory circuits is compromised due to cervical SCI. Using a combination of intact, C2 Hemisected (C2Hx), and complete C1 Transected (C1Tx) rat models, we systematically evaluated the influence of forelimb muscle afferent input on phrenic motor output and respiratory patterns. Computational modeling was employed to replicate our experimental data and generate predictions. The developed computational model incorporates bilaterally located spinal and supraspinal respiratory circuits, allowing us to simulate their specific contributions to phrenic motor output under different conditions. In this study, we hypothesize that, in addition to supraspinal control, spinal circuits integrate limb sensory input to modulate the activity of phrenic motor neurons through local excitatory and inhibitory interneurons. These intraspinal pathways, normally suppressed by inhibition, can be recruited during movement to adapt breathing to motor demands. Our experimental and computational modeling results following biceps stimulation after C2Hx and C1Tx support this hypothesis, demonstrating that activation of limb afferent pathways can enhance phrenic motor output even after partial or complete loss of supraspinal drive. In the fully transected preparation, this effect required pharmacological disinhibition, confirming the presence of latent spinal pathways. This study provides the first evidence for functionally relevant intraspinal interactions between limb muscles and respiratory circuits and identifies a potential spinal mechanism that could be leveraged to promote breathing recovery after cervical SCI. Key PointsO_LIBiceps brachii electrical stimulation can increase breathing frequency and tidal volume in spontaneously breathing rats and variably induce transient increases or entrainment of phrenic nerve activity in intact rats under controlled ventilation. C_LIO_LIBiceps stimulation enhances ipsilateral phrenic activity in acute C2 hemisected (C2Hx) rats. C_LIO_LIBiceps stimulation drives bilateral phrenic output in C1 transected (C1Tx) rats under conditions of pharmacologically induced spinal disinhibition. C_LIO_LIA computational model incorporating bilateral brainstem and cervical spinal respiratory circuits is developed to simulate cervical spinal cord injuries (C2Hx and C1Tx) and to examine how biceps stimulation affects respiratory activity under different conditions. C_LIO_LIThese findings demonstrate a critical role for spinal circuits in locomotor-respiratory interactions. C_LI

neuroscience↗

bioRxiv2025

Mechanisms of adaptive interlimb coordination to sudden ground loss: a neuromusculoskeletal modeling study

Mammals exhibit robust walking across diverse environments, a capability largely attributed to central pattern generators (CPGs) in the spinal cord. Afferent feedback modulates CPG output and plays a critical role in adaptive locomotion, yet its specific contributions remain poorly understood. To investigate this, we used a neuromusculoskeletal model to simulate hindlimb locomotion in spinalized cats encountering a hole and experiencing a sudden loss of ground support, as described in prior experimental studies. The model couples a trunk-andhindlimb musculoskeletal system to a pair of two-level, half-center CPGs--one for each hindlimb. The model reproduced the observed adaptive interlimb coordination that allows cats to maintain walking after the sudden loss of ground support. Notably, the adaptive response emerged without re-optimizing parameters, which were tuned for steady walking in an environment without holes. Nullcline analysis based on dynamical systems theory revealed that afferent feedback mechanisms controlling the transitions between fast and slow neuronal dynamics facilitated adaptive interlimb coordination. These findings provide mechanistic insight into how spinal feedback circuits support robust locomotion through dynamic interactions between the nervous system, the musculoskeletal system, and the environment.

neuroscience↗

bioRxiv2025

Reorganization of spinal neural connectivity following recovery after thoracic spinal cord injury: insights from computational modelling

Rats exhibit significant recovery of locomotor function following incomplete spinal cord injuries, albeit with altered gait expression and reduced speed and stepping frequency. These changes likely result from and give insight into the reorganization within spared and injured spinal circuitry. Previously, we developed computational models of the mouse spinal locomotor circuitry controlling speed-dependent gait expression (Danner et al. 2017; Zhang et al. 2022). Here, we adapted these models to the rat and used the adapted model to explore potential circuit-level changes underlying altered gait expression observed after recovery from two different thoracic spinal cord injuries (lateral hemisection and contusion) that have roughly comparable levels of locomotor recovery (Danner et al., 2023). The model reproduced experimentally observed gait expression before injury and after recovery from lateral hemisection and contusion, and suggests two distinct, injury-specific routes to restored function. First, recovery after lateral hemisection required substantial functional restoration of damaged descending drive and long propriospinal connections, suggesting compensatory plasticity through formation of detour pathways. Second, recovery after a moderate midline contusion predominantly relied on reorganization of spared sublesional networks and altered control of supralesional cervical circuits, compensating for weakened propriospinal and descending pathways. Despite these differences, sensitivity analysis revealed that restored activation of sublesional lumbar rhythm-generating circuits and appropriately balanced lumbar commissural connectivity are the key determinants of post-injury gait expression, suggesting that injury symmetry shapes how the cord reorganizes, but effective recovery in both cases depends on re-engaging these lumbar networks, which makes them prime targets for therapeutic intervention.

neuroscience↗

bioRxiv2024

Properties of rhythmogenic currents in spinal Shox2 interneurons across postnatal development

Locomotor behaviors are performed by organisms throughout life, despite developmental changes in cellular properties, neural connectivity, and biomechanics. The basic rhythmic activity in the central nervous system that underlies locomotion is thought to be generated via a complex balance between network and intrinsic cellular properties. Within mature mammalian spinal locomotor circuitry, we have yet to determine which properties of spinal interneurons (INs) are critical to rhythmogenesis and how they change during development. Here, we combined whole cell patch clamp recordings, immunohistochemistry, and RNAscope targeting lumbar Shox2 INs in mice, which are known to be involved in locomotor rhythm generation. We focused on the properties of putatively rhythmogenic ionic currents and the expression of corresponding ion channels across postnatal time points in mice. We show that subsets of Shox2 INs display voltage-sensitive conductances, in addition to respective ion channels, which may contribute to or shape rhythmic bursting. Persistent inward currents, M-type potassium currents, slow afterhyperpolarization, and T-type calcium currents are enhanced with age. In contrast, the hyperpolarization-activated and A-type potassium currents were either found with low prevalence in subsets of neonatal, juvenile, and adult Shox2 INs or did not developmentally change. We show that Shox2 INs become more electrophysiologically diverse by juvenile and adult ages, when locomotor behavior is weight-bearing. These results suggest a developmental shift in the magnitude of rhythmogenic ionic currents and the expression of corresponding ion channels that may be important for mature, weight-bearing locomotor behavior.

neuroscience↗

bioRxiv2024

EFFECTS OF SPINAL TRANSECTION AND LOCOMOTOR SPEED ON MUSCLE SYNERGIES OF THE CAT HINDLIMB

It was suggested that during locomotion, the nervous system controls movement by activating groups of muscles, or muscle synergies. Analysis of muscle synergies can reveal the organization of spinal locomotor networks and how it depends on the state of the nervous system, such as before and after spinal cord injury, and on different locomotor conditions, including a change in speed. The goal of this study was to investigate the effects of spinal transection and locomotor speed on hindlimb muscle synergies and their time-dependent activity patterns in adult cats. EMG activities of 15 hindlimb muscles were recorded in 9 adult cats of either sex during tied-belt treadmill locomotion at speeds of 0.4, 0.7, and 1.0 m/s before and after recovery from a low thoracic spinal transection. We determined EMG burst groups using cluster analysis of EMG burst onset and offset times and muscle synergies using non-negative matrix factorization. We found five major EMG burst groups and five muscle synergies in each of six experimental conditions (2 states x 3 speeds). In each case, the synergies accounted for at least 90% of muscle EMG variance. Both spinal transection and locomotion speed modified subgroups of EMG burst groups and the composition and activation patterns of selected synergies. However, these changes did not modify the general organization of muscle synergies. Based on the obtained results, we propose an organization for a pattern formation network of a two-level central pattern generator that can be tested in neuromechanical simulations of spinal circuits controlling cat locomotion.

neuroscience↗

bioRxiv2024

Operation of spinal sensorimotor circuits controlling phase durations during tied-belt and split-belt locomotion after a lateral thoracic hemisection

Locomotion is controlled by spinal circuits that interact with supraspinal drives and sensory feedback from the limbs. These sensorimotor interactions are disrupted following spinal cord injury. The thoracic lateral hemisection represents an experimental model of an incomplete spinal cord injury, where connections between the brain and spinal cord are abolished on one side of the cord. To investigate the effects of such an injury on the operation of the spinal locomotor network, we used our computational model of cat locomotion recently published in eLife (Rybak et al., 2024) to investigate and predict changes in cycle and phase durations following a thoracic lateral hemisection during treadmill locomotion in tied-belt (equal left-right speeds) and split-belt (unequal left-right speeds) conditions. In our simulations, the "hemisection" was always applied to the right side. Based on our model, we hypothesized that following hemisection, the contralesional ("intact", left) side of the spinal network is mostly controlled by supraspinal drives, whereas the ipsilesional ("hemisected", right) side is mostly controlled by somatosensory feedback. We then compared the simulated results with those obtained during experiments in adult cats before and after a mid-thoracic lateral hemisection on the right side in the same locomotor conditions. Our experimental results confirmed many effects of hemisection on cat locomotion predicted by our simulations. We show that having the ipsilesional hindlimb step on the slow belt, but not the fast belt, during split-belt locomotion substantially reduces the effects of lateral hemisection. The model provides explanations for changes in temporal characteristics of hindlimb locomotion following hemisection based on altered interactions between spinal circuits, supraspinal drives, and somatosensory feedback.

neuroscience↗

bioRxiv2024

ROLE OF FORELIMB MORPHOLOGY IN MUSCLE SENSORIMOTOR FUNCTIONS DURING LOCOMOTION IN THE CAT

Previous studies established strong links between morphological characteristics of mammalian hindlimb muscles and their sensorimotor functions during locomotion. Less is known about the role of forelimb morphology in motor outputs and generation of sensory signals. Here, we measured morphological characteristics of 46 forelimb muscles from 6 cats. These characteristics included muscle attachments, physiological cross-sectional area (PCSA), fascicle length, etc. We also recorded full-body mechanics and EMG activity of forelimb muscles during level overground and treadmill locomotion in 7 and 16 adult cats of either sex, respectively. We computed forelimb muscle forces along with force- and length-dependent sensory signals mapped onto corresponding cervical spinal segments. We found that patterns of computed muscle forces and afferent activities were strongly affected by the muscles moment arm, PCSA, and fascicle length. Morphology of the shoulder muscles suggests distinct roles of the forelimbs in lateral force production and movements. Patterns of length-dependent sensory activity of muscles with long fibers (brachioradialis, extensor carpi radialis) closely matched patterns of overall forelimb length, whereas the activity pattern of biceps brachii matched forelimb orientation. We conclude that cat forelimb muscle morphology contributes substantially to locomotor function, particularly to control lateral stability and turning, rather than propulsion.

neuroscience↗

bioRxiv2024

Changes in intra- and interlimb reflexes from forelimb cutaneous afferents after staggered thoracic lateral hemisections during locomotion in cats

In quadrupeds, such as cats, cutaneous afferents from the forepaw dorsum signal external perturbations and send signals to spinal circuits to coordinate the activity in muscles of all four limbs. How these cutaneous reflex pathways from forelimb afferents are reorganized after an incomplete spinal cord injury is not clear. Using a staggered thoracic lateral hemisections paradigm, we investigated changes in intralimb and interlimb reflex pathways by electrically stimulating the left and right superficial radial nerves in seven adult cats and recording reflex responses in five forelimb and ten hindlimb muscles. After the first (right T5-T6) and second (left T10-T11) hemisections, forelimb-hindlimb coordination was altered and weakened. After the second hemisection, cats required balance assistance to perform quadrupedal locomotion. Short-, mid- and long- latency homonymous and crossed reflex responses in forelimb muscles and their phase modulation remained largely unaffected after staggered hemisections. The occurrence of homolateral and diagonal mid- and long-latency responses in hindlimb muscles evoked with left and right superficial radial nerve stimulation was significantly reduced at the first time point after the first hemisection, but partially recovered at the second time point with left superficial radial nerve stimulation. These responses were lost or reduced after the second hemisection. When present, all reflex responses, including homolateral and diagonal, maintained their phase-dependent modulation. Therefore, our results show a considerable loss in cutaneous reflex transmission from cervical to lumbar levels after incomplete spinal cord injury, albeit with preservation of phase modulation, likely affecting functional responses to external perturbations. Key pointsO_LICutaneous afferent inputs coordinate muscle activity in the four limbs during locomotion when the forepaw dorsum contacts an obstacle. C_LIO_LIThoracic spinal cord injury disrupts communication between spinal locomotor centers located at cervical and lumbar levels, impairing balance and limb coordination. C_LIO_LIWe investigated cutaneous reflexes from forelimb afferents during quadrupedal locomotion by electrically stimulating the superficial radial nerve bilaterally, before and after staggered lateral thoracic hemisections in cats. C_LIO_LIWe showed a loss/reduction of mid- and long-latency homolateral and diagonal reflex responses in hindlimb muscles early after the first hemisection that partially recovered with left superficial radial nerve stimulation, before being reduced after the second hemisection. C_LIO_LITargeting cutaneous reflex pathways from forelimb afferents projecting to the four limbs could help develop therapeutic approaches aimed at restoring transmission in ascending and descending spinal pathways. C_LI Figure Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=76 SRC="FIGDIR/small/590723v1_ufig1.gif" ALT="Figure 1"> View larger version (22K): org.highwire.dtl.DTLVardef@1ef94c1org.highwire.dtl.DTLVardef@f2ec5org.highwire.dtl.DTLVardef@c7c30aorg.highwire.dtl.DTLVardef@d5ce21_HPS_FORMAT_FIGEXP M_FIG C_FIG Contacting an obstacle during locomotion activates cutaneous afferents to maintain balance and coordinate all four limbs. Spinal cord injuries disrupt neural communications between spinal networks controlling the fore- and hindlimbs, impairing balance and limb coordination. Cutaneous reflex pathways can be used to develop therapeutic approaches for restoring ascending and descending transmission to facilitate locomotor recovery.

neuroscience↗

bioRxiv2024

Operation regimes of spinal circuits controlling locomotion and role of supraspinal drives and sensory feedback

Locomotion in mammals is directly controlled by the spinal neuronal network, operating under the control of supraspinal signals and somatosensory feedback that interact with each other. However, the functional architecture of the spinal locomotor network, its operation regimes, and the role of supraspinal and sensory feedback in different locomotor behaviors, including at different speeds, remain unclear. We developed a computational model of spinal locomotor circuits receiving supraspinal drives and limb sensory feedback that could reproduce multiple experimental data obtained in intact and spinal-transected cats during tied-belt and split-belt treadmill locomotion. We provide evidence that the spinal locomotor network operates in different regimes depending on locomotor speed. In an intact system, at slow speeds (< 0.4 m/s), the spinal network operates in a non-oscillating state-machine regime and requires sensory feedback or external inputs for phase transitions. Removing sensory feedback related to limb extension prevents locomotor oscillations at slow speeds. With increasing speed and supraspinal drives, the spinal network switches to a flexor-driven oscillatory regime and then to a classical half-center regime. Following spinal transection, the model predicts that the spinal network can only operate in the state-machine regime. Our results suggest that the spinal network operates in different regimes for slow exploratory and fast escape locomotor behaviors, making use of different control mechanisms.

neuroscience↗

bioRxiv2024

Forelimb movements contribute to hindlimb cutaneous reflexes during locomotion in cats

During quadrupedal locomotion, central circuits interacting with somatosensory feedback coordinate forelimb and hindlimb movements. How this is achieved is not clear. To determine if forelimb movements modulate hindlimb cutaneous reflexes involved in responding to an external perturbation, we stimulated the superficial peroneal nerve in six intact cats during quadrupedal locomotion and during hindlimb-only locomotion (with forelimbs standing on stationary platform) and in two spinal-transected cats during hindlimb-only locomotion. We compared cutaneous reflexes evoked in six ipsilateral and four contralateral hindlimb muscles. Results showed similar occurrence and phase-dependent modulation of short-latency inhibitory and excitatory responses during quadrupedal and hindlimb-only locomotion in intact cats. However, the depth of modulation was reduced in the ipsilateral semitendinosus during hindlimb-only locomotion. Additionally, longer-latency responses occurred less frequently in extensor muscles bilaterally during hindlimb-only locomotion while short-latency inhibitory and longer-latency excitatory responses occurred more frequently in the ipsilateral and contralateral sartorius anterior, respectively. After spinal transection, short-latency inhibitory and excitatory responses were similar to both intact conditions, while mid- or longer-excitatory responses were reduced or abolished. Our results suggest that the absence of forelimb movements suppresses inputs from supraspinal structures and/or cervical cord that normally contribute to longer-latency reflex responses in hindlimb extensor muscles. NEW & NOTEWORTHYDuring quadrupedal locomotion, the coordination of forelimb and hindlimb movements involves central circuits and somatosensory feedback. To demonstrate how forelimb movement affects hindlimb cutaneous reflexes during locomotion, we stimulated the superficial peroneal nerve in intact cats during quadrupedal and hindlimb-only locomotion, as well as in spinal-transected cats during hindlimb-only locomotion. We show that forelimb movement influences the modulation of hindlimb cutaneous reflexes, particularly the occurrence of long-latency reflex responses.

neuroscience↗

bioRxiv2023

Changes in intra- and interlimb reflexes from hindlimb cutaneous afferents after staggered thoracic lateral hemisections during locomotion in cats

When the foot dorsum contacts an obstacle during locomotion, cutaneous afferents signal central circuits to coordinate muscle activity in the four limbs. Spinal cord injury disrupts these interactions, impairing balance and interlimb coordination. We evoked cutaneous reflexes by electrically stimulating left and right superficial peroneal nerves before and after two thoracic lateral hemisections placed on opposite sides of the cord at 9-13 weeks interval in seven adult cats (4 males and 3 females). We recorded reflex responses in ten hindlimb and five forelimb muscles bilaterally. After the first (right T5-T6) and second (left T10-T11) hemisections, coordination of the fore- and hindlimbs was altered and/or became less consistent. After the second hemisection, cats required balance assistance to perform quadrupedal locomotion. Short-latency reflex responses in homonymous and crossed hindlimb muscles largely remained unaffected after staggered hemisections. However, mid- and long-latency homonymous and crossed responses in both hindlimbs occurred less frequently after staggered hemisections. In forelimb muscles, homolateral and diagonal mid- and long-latency response occurrence significantly decreased after the first and second hemisections. In all four limbs, however, when present, short-, mid- and long-latency responses maintained their phase-dependent modulation. We also observed reduced durations of short-latency inhibitory homonymous responses in left hindlimb extensors early after the first hemisection and delayed short-latency responses in the right ipsilesional hindlimb after the first hemisection. Therefore, changes in cutaneous reflex responses correlated with impaired balance/stability and interlimb coordination during locomotion after spinal cord injury. Restoring reflex transmission could be used as a biomarker to facilitate locomotor recovery. Key pointsO_LICutaneous afferent inputs coordinate muscle activity in the four limbs during locomotion when the foot dorsum contacts an obstacle. C_LIO_LIThoracic spinal cord injury disrupts communication between spinal locomotor centers located at cervical and lumbar levels, impairing balance and limb coordination. C_LIO_LIWe investigated cutaneous reflexes during quadrupedal locomotion by electrically stimulating the superficial peroneal nerve bilaterally, before and after staggered lateral thoracic hemisections of the spinal cord in cats. C_LIO_LIWe showed a loss/reduction of mid- and long-latency responses in all four limbs after staggered hemisections, which correlated with altered coordination of the fore- and hindlimbs and impaired balance. C_LIO_LITargeting cutaneous reflex pathways projecting to the four limbs could help develop therapeutic approaches aimed at restoring transmission in ascending and descending spinal pathways. C_LI

neuroscience↗

bioRxiv2023

Sensory Feedback and Central Neuronal Interactions in Mouse Locomotion

Locomotion is a complex process involving specific interactions between the central neural controller and the mechanical components of the system. The basic rhythmic activity generated by locomotor circuits in the spinal cord defines rhythmic limb movements and their central coordination. The operation of these circuits is modulated by sensory feedback from the limbs providing information about the state of the limbs and the body. However, the specific role and contribution of central interactions and sensory feedback in the control of locomotor gait and posture remain poorly understood. We use biomechanical data on quadrupedal locomotion in mice and recent findings on the organization of neural interactions within the spinal locomotor circuitry to create and analyze a tractable mathematical model of mouse locomotion. The model includes a simplified mechanical model of the mouse body with four limbs and a central controller composed of four rhythm generators, each operating as a state machine controlling the state of one limb. Feedback signals characterize the load and extension of each limb as well as postural stability (balance). We systematically investigate and compare several model versions and compare their behavior to existing experimental data on mouse locomotion. Our results highlight the specific roles of sensory feedback and some central propriospinal interactions between circuits controlling fore and hind limbs for speed-dependent gait expression. Our models suggest that postural imbalance feedback may be critically involved in the control of swing-to-stance transitions in each limb and the stabilization of walking direction.

systems biology↗

bioRxiv2023

Spinal sensorimotor circuits play a prominent role in hindlimb locomotor recovery after staggered thoracic lateral hemisections but cannot restore posture and interlimb coordination during quadrupedal locomotion in adult cats

Spinal sensorimotor circuits interact with supraspinal and peripheral inputs to generate quadrupedal locomotion. Ascending and descending spinal pathways ensure coordination between the fore-and hindlimbs. Spinal cord injury disrupts these pathways. To investigate the control of interlimb coordination and hindlimb locomotor recovery, we performed two lateral thoracic hemisections placed on opposite sides of the cord (right T5-T6 and left T10-T11) at an interval of approximately two months in eight adult cats. In three cats, we then made a complete spinal transection caudal to the second hemisection at T12-T13. We collected electromyography and kinematic data during quadrupedal and hindlimb-only locomotion before and after spinal lesions. We show that 1) cats spontaneously recover quadrupedal locomotion following staggered hemisections but require balance assistance after the second one, 2) coordination between the fore-and hindlimbs displays 2:1 patterns and becomes weaker and more variable after both hemisections, 3) left-right asymmetries in hindlimb stance and swing durations appear after the first hemisection and reverse after the second, and 4) support periods reorganize after staggered hemisections to favor support involving both forelimbs and diagonal limbs. Cats expressed hindlimb locomotion the day following spinal transection, indicating that lumbar sensorimotor circuits play a prominent role in hindlimb locomotor recovery after staggered hemisections. These results reflect a series of changes in spinal sensorimotor circuits that allow cats to maintain and recover some level of quadrupedal locomotor functionality with diminished motor commands from the brain and cervical cord, although the control of posture and interlimb coordination remains impaired. Significance StatementCoordinating the limbs during locomotion depends on pathways in the spinal cord. We used a spinal cord injury model that disrupts communication between the brain and spinal cord by sectioning half of the spinal cord on one side and then about two months later, half the spinal cord on the other side at different levels of the thoracic cord in cats. We show that despite a strong contribution from neural circuits located below the second spinal cord injury in the recovery of hindlimb locomotion, the coordination between the forelimbs and hindlimbs weakens and postural control is impaired. We can use our model to test approaches to restore the control of interlimb coordination and posture during locomotion after spinal cord injury.

neuroscience↗

bioRxiv2023

Spinal control of locomotion before and after spinal cord injury

Thoracic spinal cord injury affects long propriospinal neurons that interconnect the cervical and lumbar enlargements. These neurons are crucial for coordinating forelimb and hindlimb locomotor movements in a speed-dependent manner. However, recovery from spinal cord injury is usually studied over a very limited range of speeds that may not fully expose circuitry dysfunction. To overcome this limitation, we investigated overground locomotion in rats trained to move over an extended distance with a wide range of speeds both pre-injury and after recovery from thoracic hemisection or contusion injuries. In this experimental context, intact rats expressed a speed-dependent continuum of alternating (walk and trot) and non-alternating (canter, gallop, half-bound gallop, and bound) gaits. After a lateral hemisection injury, rats recovered the ability to locomote over a wide range of speeds but lost the ability to use the highest-speed gaits (half-bound gallop and bound) and predominantly used the limb contralateral to the injury as lead during canter and gallop. A moderate contusion injury caused a greater reduction in maximal speed, loss of all non-alternating gaits, and emergence of novel alternating gaits. These changes resulted from weak fore-hind coupling together with appropriate control of left-right alternation. After hemisection, animals expressed a subset of intact gaits with appropriate interlimb coordination even on the side of the injury, where the long propriospinal connections were severed. These observations highlight how investigating locomotion over the full range of speeds can reveal otherwise hidden aspects of spinal locomotor control and post-injury recovery.

neuroscience↗

bioRxiv2021

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

Speed-dependent interlimb coordination allows animals to maintain stable locomotion under different circumstances. We have previously demonstrated that a subset of spinal V3 neurons contributes to stable locomotion by mediating mutual excitation between left and right lumbar rhythm generators (RGs). Here, we expanded our investigation to the V3 neurons involved in ascending long propriospinal interactions (aLPNs). Using retrograde tracing, we revealed a subpopulation of lumbar V3 aLPNs with contralateral cervical projections. V3OFF mice, in which all V3 neurons were silenced, had a significantly reduced maximal locomotor speed, were unable to move using stable trot, gallop, or bound, and predominantly used lateral-sequence walk. To understand the functional roles of V3 aLPNs, we adapted our previous model of spinal circuitry controlling quadrupedal locomotion (Danner et al., 2017), by incorporating diagonal V3 aLPNs mediating inputs from each lumbar RG to the contralateral cervical RG. The updated model reproduces our experimental results and suggests that locally projecting V3 neurons, mediating left-right interactions within lumbar and cervical cords, promote left-right synchronization necessary for gallop and bound, whereas the V3 aLPNs promote synchronization between diagonal fore and hind RGs necessary for trot. The model proposes the organization of spinal circuits available for future experimental testing.

neuroscience↗

bioRxiv2020

Neural interactions in developing rhythmogenic spinal networks: Insights from computational modeling

The mechanisms involved in generation of rhythmic locomotor activity in the mammalian spinal cord remain poorly understood. These mechanisms supposedly rely on both intrinsic properties of constituting neurons and interactions between them. A subset of Shox2 neurons was found to contribute to generation of spinal locomotor activity, but the possible cellular basis for rhythmic bursting in these neurons remains unknown. Ha and Dougherty (2018) recently revealed the presence of bidirectional electrical coupling between Shox2 neurons in neonatal spinal cords, which can be critically involved in neuronal synchronization and generation of populational bursting. Gap junctional connections found between functionally-related Shox2 interneurons decrease with age, possibly being replaced by increasing interactions through chemical synapses. Here, we developed a computational model of a heterogeneous population of neurons sparsely connected by electrical or/and chemical synapses and investigated the dependence of frequency of populational bursting on the type and strength of neuronal interconnections. The model proposes a mechanistic explanation for emergence of a synchronized rhythmic activity in the neuronal population and provides insights into the mechanisms of the locomotor rhythm generation.

bioinformatics↗

bioRxiv2020

On the organization of the locomotor CPG: insights from split-belt locomotion and mathematical modeling

Rhythmic limb movements during locomotion are controlled by a 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 left-right 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 RGs (or an increase in locomotor speed) the rhythmogenic mechanism within 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. Key Point SummaryO_LILimb movements during locomotion are controlled by neural circuits located within the spinal cord. These circuits include rhythm generators (RGs) controlling each limb interacting through multiple commissural pathways. C_LIO_LIThe organization and operation of spinal RGs are not fully understood, and different competing concepts exists. We suggest that the operation of RGs is state-dependent, so that with an increase of external excitation the rhythmogenesis changes from "flexor-driven" oscillations to a "classical half-center" mechanism. C_LIO_LIA mathematical model of spinal circuits representing bilaterally-interacting RGs has been developed based on the above suggestion and used to interpret experimental data from intact and spinal cats walking on the ground or tied-belt treadmills (symmetric conditions) as well as on split-belt treadmills with different left and right belt speeds (asymmetric conditions). C_LIO_LIThe performed simulations and mathematical analysis of the model under different conditions provide new insights into operation of spinal circuits and limb coordination during locomotion. C_LI

neuroscience↗