This project combines electrophysiological and modeling approaches to study the organization and neuronal composition of the Central Pattern Generator (CPG) neural circuits in the mammalian spinal cord that coordinate rhythmic neural activity driving locomotion. This study will take a general approach that utilizes various spontaneous and evoked perturbations in the locomotor pattern (including deletions of motoneuron activity, spinal cord lesions and pharmacological manipulations) as probes to understand CPG organization and function. It is proposed that analysis of the influences of these perturbations on the rhythmic motor pattern and the activity of identified spinal interneurons will provide important insights on the spinal CPG organization and operation. These data will be used to develop a comprehensive computational model of the spinal locomotor CPG, and to refine and validate this model, so that it can reproduce both normal locomotor activity and the consequences of experimental perturbations. In turn, the model will serve as a computational framework to formulate predictions to guide subsequent experimental investigations. The project brings together two senior scientists with complementary and overlapping expertise in experimental (Dr. Harris-Warrick at Cornell University) and computational (Dr. Rybak at Drexel University) neuroscience. It has three interlocking objectives: 1) Explore alterations in behavior of, and synaptic drive to, motoneurons and genetically defined interneurons during spontaneous and evoked deletions in flexor and/or extensor rhythmic motor activity, to define the possible function of these interneurons in the locomotor CPG. 2) Explore the consequences of reducing CPG complexity by spinal cord hemisection and removal of spinal segments, and compare the behavior of identified interneurons in the reduced cord during deletions and after pharmacological blockade of synaptic inhibition. 3) Develop a comprehensive computational model of the neural circuits forming the locomotor CPG in the neonatal mouse spinal cord that includes genetically identified interneurons and suggests their roles in the generation of the locomotor pattern. Validate this model in simulations reproducing the specific transformations in motoneuron and interneuron activity and the entire locomotor pattern during experimental perturbations proposed in objectives 1 and 2.The model will be progressively developed by continuous interaction with the experimental studies, and will serve both as a testbed for working concepts on spinal cord organization and as a source of predictions for subsequent experimental validation.

Public Health Relevance

All vertebrates, including humans, have spinal CPGs that drive and coordinate locomotor movements. These CPGs survive upper spinal cord injuries, and are in principle capable of restoring locomotion after injury, as seen in rodents and cats. Better understanding ofthe organization and function of such CPGs will provide essential insights into future clinical strategies for restoration of locomotor function after spinal cord injury.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project (R01)
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Special Emphasis Panel (ZRG1)
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Chen, Daofen
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Cornell University
Other Basic Sciences
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United States
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Ausborn, Jessica; Snyder, Abigail C; Shevtsova, Natalia A et al. (2018) State-dependent rhythmogenesis and frequency control in a half-center locomotor CPG. J Neurophysiol 119:96-117
Danner, Simon M; Shevtsova, Natalia A; Frigon, Alain et al. (2017) Computational modeling of spinal circuits controlling limb coordination and gaits in quadrupeds. Elife 6:
Shevtsova, Natalia A; Rybak, Ilya A (2016) Organization of flexor-extensor interactions in the mammalian spinal cord: insights from computational modelling. J Physiol 594:6117-6131
Danner, Simon M; Wilshin, Simon D; Shevtsova, Natalia A et al. (2016) Central control of interlimb coordination and speed-dependent gait expression in quadrupeds. J Physiol 594:6947-6967
Shevtsova, Natalia A; Talpalar, Adolfo E; Markin, Sergey N et al. (2015) Organization of left-right coordination of neuronal activity in the mammalian spinal cord: Insights from computational modelling. J Physiol 593:2403-26
Rybak, Ilya A; Dougherty, Kimberly J; Shevtsova, Natalia A (2015) Organization of the Mammalian Locomotor CPG: Review of Computational Model and Circuit Architectures Based on Genetically Identified Spinal Interneurons(1,2,3). eNeuro 2:
Molkov, Yaroslav I; Bacak, Bartholomew J; Talpalar, Adolfo E et al. (2015) Mechanisms of left-right coordination in mammalian locomotor pattern generation circuits: a mathematical modeling view. PLoS Comput Biol 11:e1004270
Rybak, Ilya A; Molkov, Yaroslav I; Jasinski, Patrick E et al. (2014) Rhythmic bursting in the pre-Bötzinger complex: mechanisms and models. Prog Brain Res 209:1-23
Rybak, Ilya A; Shevtsova, Natalia A; Kiehn, Ole (2013) Modelling genetic reorganization in the mouse spinal cord affecting left-right coordination during locomotion. J Physiol 591:5491-508
Brocard, Frederic; Shevtsova, Natalia A; Bouhadfane, Mouloud et al. (2013) Activity-dependent changes in extracellular Ca2+ and K+ reveal pacemakers in the spinal locomotor-related network. Neuron 77:1047-54

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