NIH/NINDS R01 NS115900; 09/21/2020 - 06/30/2025
PI: Danner SM, Co-PI: Akay T
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Somatosensory feedback from the limbs is essential for locomotion and its recovery after spinal cord injury. To achieve stable locomotion, the spinal cord needs to process afferent feedback signals and properly adjust muscle activation and interlimb coordination. But the interactions of somatosensory feedback with the spinal circuitry during locomotion have yet to be understood on the same level of detail. In this project we propose to address this gap of knowledge by combing mouse genetics, in vivo electrophysiology, and behavioral analyses with computational modeling of spinal circuits and the musculoskeletal system. This multidisciplinary project will be performed in close interactive collaboration between two investigators with strong and complementary expertise in computational (Simon Danner, Drexel University, PI) and experimental studies of neural control of locomotion (Turgay Akay, Dalhousie University, Canada, Co-PI). The project has the following three aims: (1) Delineate the involvement of multiple spinal interneurons in the processing of sensory information and interlimb coordination by studying crossed reflexes at rest and during locomotion; (2) Design a predictive computational model of the spinal locomotor circuitry and its interactions with the mouse musculoskeletal system; (3) Integrate modeling and experimentation to uncover underlying neural mechanisms. The model will be used to derive informative predictions that will then be tested experimentally. In summary, the proposed multidisciplinary approach is based on state-of-art experimental and modeling methods and will provide important and novel insights into the neural organization of the spinal locomotor circuitry responsible for sensorimotor integration and interlimb coordination during locomotion that cannot be obtained by experimentation or modeling alone.
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NIH/NINDS R01 NS110550; 02/15/2020 - 01/31/2025
PIs: Rybak IA; Frigon A, Prilutsky BI
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Interlimb coordination is essential for maintaining balance when navigating in complex and/or changing environments. It involves complex dynamic interactions between neural circuits at different levels of the nervous system and biomechanical properties of the musculoskeletal system to allow animals to adjust locomotor speed and gait for goal-oriented behaviors. Interactions within the nervous system include those between the spinal circuits controlling each limb, supraspinal inputs and sensory feedback from the limbs. Despite their obvious importance, the mechanisms that control interlimb coordination and contribute to locomotor recovery following SCI and other neurological disorders remain poorly understood. To address this gap in knowledge, we will integrate multiple experimental and modeling approaches to investigate the neural and biomechanical mechanisms controlling interlimb coordination in a feline model before and after SCI disrupting neural communication between the brain and spinal cord and/or between the circuits controlling fore- and hindlimb movements.
The project will be performed in close interactive collaboration between three groups of investigators with strong and complementary expertise in the experimental study of cat locomotion, including SCI models (Alain Frigon, Universit de Sherbrooke, Canada), biomechanics of cat locomotion (Boris Prilutsky, Georgia Tech) and neural control of locomotion (Ilya Rybak, Drexel University). Results obtained from these studies will have an important theoretical impact on our understanding of how the limbs are coordinated during locomotion and how this coordination is altered and adjusted after disruption of spinal pathways between left-right or cervical-lumbar circuits. The results will identify neural pathways and biomechanical mechanisms that could be targeted to improve interlimb coordination in people with various movement disorders, such as SCI, stroke, and Parkinson's disease.
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NIH/NINDS R01 NS100928; 07/15/2017 - 05/31/2022
PI: Prilutsky BI; Co-PIs: Markin SN, Deliagina TG, Musienko PE
The overall goal of this project is to determine the contribution of motion-dependent afferent pathways, selected ascending and descending pathways in the spinocerebellar loop, and the central pattern generator (CPG) circuitry to the generation of the distinct kinematic and muscle synergies during normal walking and epidural stimulation(ES)-activated walking in cats with intact and partially transected spinal cord. This goal will be accomplished in experimental and neuromechanical computational studies performed in close collaboration among 4 research groups (Georgia Institute of Technology; Karolinska Institute, Sweden; Drexel University and Pavlov Institute of Physiology, Russia). We anticipate that this study will improve our understanding of how ES, sensory and supraspinal inputs, and CPG contribute to kinematic and muscle synergies during locomotion and thus will provide scientific basis for improvement of ES- stimulation therapies.
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NIH/NINDS R01 NS095366; 08/01/2015 - 07/31/2020
PIs: Dougherty KJ, Shevtsova NA
The overall goal of this collaborative project is to use state-of-the-art genetic, molecular and physiological studies of spinal neurons and neural circuits in combination with computational modeling to dissect the organization and operating mechanisms of the spinal locomotor central pattern generator (CPG). As demonstrated in rodents and cats, activation of the spinal locomotor CPG leads to the restoration of locomotion after upper spinal cord injury. The proposed study will provide an important theoretical basis for the future development of new, effective methods for restoring locomotor function after spinal cord injury and various degenerative disorders affecting normal locomotion.The central issues addressed in this study include understanding the rhythm-generating mechanisms operating in the spinal cord as well as the organization of flexor-extensor interactions.
We propose to:
- Investigate recently identified spinal interneurons that are considered to belong to rhythm-generating circuits
- Identify their connectivity pattern
- Determine the functional links between these neurons and other key components in the spinal locomotor CPG
The project brings together two laboratories with complementary expertise in experimental and computational neuroscience to:
- Specific aim 1: Determine and investigate the cellular basis of rhythmic bursting in Shox2 neurons and their mutual interactions. Investigate potential differences between these neurons with flexor- versus extensor-related activity.
- Specific aim 2: Investigate inhibitory interactions between the flexor- and extensor-related rhythm-generating neurons and the role of genetically-identified V2b and V1 neurons in these interactions.
- Specific aim 3: Investigate properties of neuronal and network organization leading to the frequency-dependent flexor-extensor asymmetry and study interactions between flexor-extensor and left-right coordinating networks.
The model will be progressively developed by continuous interaction with the experimental studies and will serve both as a testbed for working concepts on the organization of the rhythm generating circuits in the spinal cord and as a source of predictions for subsequent experimental validation.
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NIH/NINDS R01 NS090919; 09/15/2014 - 07/31/2020
PIs: Rybak IA, Goulding M, Kiehn O
The overall goal of this project is to dissect the organization of the spinal CPG with focus on the organization of flexor-extensor alternating and left-right coordinating circuits. All work will be done on identifiable classes of spinal interneurons labeled by genetic markers in transgenic mice and/or classified by anatomic or electrophysiological labeling needed to obtain a unified picture of the CPG organization. We propose to identify the functional connectome and the interactions between these fundamental components of the CPG. The experiments performed will use a combination of electrophysiological, imaging, and molecular biology techniques complemented with advanced computer modeling.
The three PIs involved in this project have strong background and experience in spinal cord studies and unique expertise in physiological, genetic and molecular methods (Martyn Goulding and Ole Kiehn) and computational modeling (Ilya Rybak). The specific aims of the project include:
- Investigation of activity patterns and connectivity of the genetically identified spinal interneurons responsible for left-right coordination during locomotion (aim 1)
- Investigation of the genetically identified spinal interneurons and their connectivity responsible for flexor-extensor alternation and their interactions with the circuits providing left-right coordination (aim 2)
- Development of a comprehensive computational model of spinal cord circuits (aim 3)
The proposed multidisciplinary approach based on the state-of-art methods and close collaboration between the three leading labs will investigate and analyze the specific contributions of left-right and flexor-extensor coordinating neuronal circuits and their interactions to the generation and control of the locomotor pattern and provide important insights into the neural organization of the mammalian spinal cord, leading to new strategies to treat spinal cord injury and degeneration spinal cord disorders.
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PIs: Harris-Warrick RM, Rybak IA
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 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:
- 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.
- 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.
- 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.
Better understanding of the organization and function of the spinal CPG will provide essential insights into future clinical strategies for restoration of locomotor function after spinal cord injury.
Computational modeling of the primate motor control system for subsequent simulation studies of Huntington's disease
CHDI Foundation; 10/01/2014 - 09/30/2017
PI: Rybak, IA
This project represents the first steps towards the ultimate goal of creating a comprehensive multi-level, multi-scale neural model of the motor control system. The model will ultimately serve as a test bed for studying motor dysfunctions associated with and/or resulted from Huntington's disease (HD). We will take a multi-resolution modeling approach in which more detailed cellular and network neuron models (representing various CNS regions) will be sequentially incorporated into a larger systems-level model that produces simulated movements. The initial low-resolution systems-level model will describe system interactions between the major brain structures (nuclei, represented as model compartments) involved in planning, learning, and control of individual and successive arm reaching movements.
We will consider (simulate and investigate) multiple interrelated motor/behavioral processes involving the basal ganglia (BG) including goal-directed reaching movements, decision-making between competing motor strategies, and motor task execution. The resultant model will provide a test bed for subsequent simulations of sequential reaching-related motor dysfunctions associated with HD, as well as for predictions of the possible effects of HD treatments at various functional levels.
PIs: Rybak IA, Ben-Tal A, Dick TE, Paton JFR, Smith JC
The specific aims of this multi-institutional project are:
- Develop a Physiome-type, predictive, multiscale computational model of neural control of breathing that links multiple physiological mechanisms and processes involved in the vital function of breathing but operating at different scales of functional and structural organization
- Validate this model in a series of complementary experimental investigations
- Use the model as a computational framework for formulating predictions about possible sources and mechanisms of respiratory pattern alteration associated with heart failure
The project brings together a multidisciplinary team of scientists with long standing collaboration and complementary expertise in respiration physiology, neuroscience and translational medical studies (Thomas E. Dick, Case Western Reserve University;Julian F.R. Paton, University of Bristol, UK; Robert F. Rogers, Drexel University; Jeffrey C. Smith, NINDS, NIH, intramural), mathematics, system analysis and bioengineering (Alona Ben-Tal, Massey University, NZ), and computational neuroscience and neural control (Ilya A. Rybak, Drexel University). The end result of our proposed cross-disciplinary modeling and experimental studies will be the development and implementation of a new, fully operational, multiscale model of the integrated neurophysiological control system for breathing based on the current state of physiological knowledge. This model can then be used as a computational framework for formulating predictions about possible neural mechanisms of respiratory diseases and suggesting possible treatments.
NIH/NIBIB R01 EB012855
PIs: Lemay MA, Markin SN, Prilutsky BI
NIH/NHLBI R33 HL087379
PI: Rybak IA
NIH/NINDS R01 NS057815
PIs: Rybak IA, Smith, Paton JFR
NIH/NINDS; R01 NS048844
PIs: Rybak IA, McCrea DA, Prilutsky BI, Lemay MA
Modeling state-dependent neural mechanisms for generation of the respiratory rhythm and pattern
NIH/NINDS Research Contract
PI: Rybak IA
NIH/NINDS R01 NS046062
PIs: Lindsey BG, Rybak IA, Orem J, Dick TE, Solomon IC
The PreBotzinger circuit and respiratory rhythm generation
NIH/NHLBI R01 HL072415
PIs: McCrimmon DR, Rybak IA (Drexel subcontract)
Closed-loop brain-machine interface for augmenting motor performance
PIs: Nicolelis M, Chapin JK, Rybak IA (Drexel subcontract)
Development of biomimetic CPG-based neural controller for bipedal robot locomotion
PI: Rybak IA
PI: Rybak IA
Computational modeling of spinal cord neural circuitry for limb control during locomotion
PI: Rybak IA
Development of biomimetic robots and sensors using hybrid brain-machine technology
PI: Chapin JK, Rybak IA (Drexel subcontract)
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