Mechanisms of locomotor recovery after SCI in cats

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Transplants of nerve growth promoting factors into the injured spinal cord promote the recovery of locomotion in animal models of spinal cord injury. We suspect that this recovery may be mostly due to the effects of those factors on the spinal cord circuitry responsible for the treadmill entrained locomotion that can be observed in spinalized animals and humans. Our long-term goals are to maximize the locomotor recovery obtainable after spinal cord injury using combination therapies combining regenerative grafts, sensorimotor training, and electrical stimulation of the lumbar locomotor circuitry. The aims of this project are to establish: 1) whether growth from supraspinal centers is necessary to obtain the locomotor recovery provided by transplant of the growth factors, 2) whether the lumbar circuitry of locomotion can be activated by transplants in a sub-chronic or chronic model of injury, and 3) whether the effects of spinal transplants on the locomotor circuitry are similar in their actions to the effects obtained with locomotor training. In Aims 1 & 2, the locomotor recovery provided by the transplant of neurotrophins producing cells will be evaluated via kinematic analyses of treadmill locomotion in a mammalian model of spinal cord injury, and nerve growth will be measured using histological methods. Aim 1 will use an impermeable membrane to block the possibility of supraspinal axonal growth through the injury. In Aim 2, grafting will occur after a delay of 2 or 6 weeks following the spinal transection. In Aim 3, the modifications to the spinal circuitry will be evaluated via stimulation of selected afferent pathways in groups of animals receiving the neurotrophins producing transplants or locomotor training, and using a recently introduced computational model of the mammalian locomotor neural circuitry combined with a musculo-skeletal model of the hindlimbs. The results of this project will provide significant insight into the spinal mechanisms responsible for the control of locomotion and will constitute an important step towards the development of effective methods for the restoration of locomotor function after spinal cord injury.