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.

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.

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.

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.

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

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 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. The V3 neurons are known to be involved in interlimb coordination. We previously modeled the locomotor spinal circuitry controlling interlimb coordination (Danner et al.

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

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.

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 suggested to contribute to generation of spinal locomotor activity, but the possible cellular basis for rhythmic bursting in these neurons remains unknown.

Spinal V3 Interneurons and Left-Right Coordination in Mammalian Locomotion.

Commissural interneurons (CINs) mediate interactions between rhythm-generating locomotor circuits located on each side of the spinal cord and are necessary for left-right limb coordination during locomotion. While glutamatergic V3 CINs have been implicated in left-right coordination, their functional connectivity remains elusive. Here, we addressed this issue by combining experimental and modeling approaches.

Modulation of Respiratory System by Limb Muscle Afferents in Intact and Injured Spinal Cord.

Breathing constantly adapts to environmental, metabolic or behavioral changes by responding to different sensory information, including afferent feedback from muscles. Importantly, not just respiratory muscle feedback influences respiratory activity. Afferent sensory information from rhythmically moving limbs has also been shown to play an essential role in the breathing.

Computational modeling of brainstem circuits controlling locomotor frequency and gait.

A series of recent studies identified key structures in the mesencephalic locomotor region and the caudal brainstem of mice involved in the initiation and control of slow (exploratory) and fast (escape-type) locomotion and gait. However, the interactions of these brainstem centers with each other and with the spinal locomotor circuits are poorly understood. Previously we suggested that commissural and long propriospinal interneurons are the main targets for brainstem inputs adjusting gait (Danner et al.

Computational modeling of spinal circuits controlling limb coordination and gaits in quadrupeds.

Interactions between cervical and lumbar spinal circuits are mediated by long propriospinal neurons (LPNs). Ablation of descending LPNs in mice disturbs left-right coordination at high speeds without affecting fore-hind alternation. We developed a computational model of spinal circuits consisting of four rhythm generators coupled by commissural interneurons (CINs), providing left-right interactions, and LPNs, mediating homolateral and diagonal interactions.

State-dependent rhythmogenesis and frequency control in a half-center locomotor CPG.

The spinal locomotor central pattern generator (CPG) generates rhythmic activity with alternating flexion and extension phases. This rhythmic pattern is likely to result from inhibitory interactions between neural populations representing flexor and extensor half-centers. However, it is unclear whether the flexor-extensor CPG has a quasi-symmetric organization with both half-centers critically involved in rhythm generation, features an asymmetric organization with flexor-driven rhythmogenesis, or comprises a pair of intrinsically rhythmic half-centers.

Organization of flexor-extensor interactions in the mammalian spinal cord: insights from computational modelling.

Key Points: Alternation of flexor and extensor activity in the mammalian spinal cord is mediated by two classes of genetically identified inhibitory interneurons, V1 and V2b. The V1 interneurons are essential for high-speed locomotor activity. They secure flexor-extensor alternations in the intact cord but lose this function after hemisection, suggesting that they are activated by inputs from the contralateral side of the cord.

Central control of interlimb coordination and speed-dependent gait expression in quadrupeds.

Key Points: Quadrupeds express different gaits depending on speed of locomotion. Central pattern generators (one per limb) within the spinal cord generate locomotor oscillations and control limb movements. Neural interactions between these generators define interlimb coordination and gait.

Organization of the Mammalian Locomotor CPG: Review of Computational Model and Circuit Architectures Based on Genetically Identified Spinal Interneurons(1,2,3).

The organization of neural circuits that form the locomotor central pattern generator (CPG) and provide flexor-extensor and left-right coordination of neuronal activity remains largely unknown. However, significant progress has been made in the molecular/genetic identification of several types of spinal interneurons, including V0 (V0D and V0V subtypes), V1, V2a, V2b, V3, and Shox2, among others. The possible functional roles of these interneurons can be suggested from changes in the locomotor pattern generated in mutant mice lacking particular neuron types.

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

Key Points: 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 V0D and excitatory V0V CINs and ipsilaterally projecting excitatory V2a interneurons were shown to secure left-right alternation at different locomotor speeds. 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 V0D , V2a-V0V and V3 neuron populations.

A closed-loop model of the respiratory system: focus on hypercapnia and active expiration.

Breathing is a vital process providing the exchange of gases between the lungs and atmosphere. During quiet breathing, pumping air from the lungs is mostly performed by contraction of the diaphragm during inspiration, and muscle contraction during expiration does not play a significant role in ventilation. In contrast, during intense exercise or severe hypercapnia forced or active expiration occurs in which the abdominal "expiratory" muscles become actively involved in breathing.

Effects of glycinergic inhibition failure on respiratory rhythm and pattern generation.

Inhibitory interactions between neurons of the respiratory network are involved in rhythm generation and pattern formation. Using a computational model of brainstem respiratory networks, we investigated the possible effects of suppressing glycinergic inhibition on the activity of different respiratory neuron types. Our study revealed that progressive suppression of glycinergic inhibition affected all neurons of the network and disturbed neural circuits involved in termination of inspiration.

Rhythmic bursting in the pre-Bötzinger complex: mechanisms and models.

The pre-Bötzinger complex (pre-BötC), a neural structure involved in respiratory rhythm generation, can generate rhythmic bursting activity in vitro that persists after blockade of synaptic inhibition. Experimental studies have identified two mechanisms potentially involved in this activity: one based on the persistent sodium current (INaP) and the other involving calcium (ICa) and/or calcium-activated nonspecific cation (ICAN) currents. In this modeling study, we investigated bursting generated in single neurons and excitatory neural populations with randomly distributed conductances of INaP and ICa.

Modelling genetic reorganization in the mouse spinal cord affecting left-right coordination during locomotion.

The spinal neural circuit contains inhibitory (CINi) and excitatory (CINe) commissural interneurons with axons crossing the mid-line. Direction of these axons to the other side of the cord is controlled by axon guidance molecules, such as Netrin-1 and DCC. The cord also contains glutamatergic interneurons, whose axon guidance involves the EphA4 receptor.

Activity-dependent changes in extracellular Ca2+ and K+ reveal pacemakers in the spinal locomotor-related network.

Changes in the extracellular ionic concentrations occur as a natural consequence of firing activity in large populations of neurons. The extent to which these changes alter the properties of individual neurons and the operation of neuronal networks remains unknown. Here, we show that the locomotor-like activity in the isolated neonatal rodent spinal cord reduces the extracellular calcium ([Ca(2+)]o) to 0.

Sodium and calcium mechanisms of rhythmic bursting in excitatory neural networks of the pre-Bötzinger complex: a computational modelling study.

The neural mechanisms generating rhythmic bursting activity in the mammalian brainstem, particularly in the pre-Bötzinger complex (pre-BötC), which is involved in respiratory rhythm generation, and in the spinal cord (e.g. locomotor rhythmic activity) that persist after blockade of synaptic inhibition remain poorly understood.