Grant: Project Grant

The many neurons in the spinal cord are the building blocks of spinal neuronal circuits that generate basic functions such as walking, integrating commands from the brain and sensory feedback from skin and muscle to generate walking. After a spinal cord injury (SCI), descending commands from the brain are disrupted, and sensory inputs become more important for motor function. Indeed, intensive rehabilitation training, like treadmill training of walking, activates sensory afferents to drive residual spinal circuits to promote recovery, and emerging locomotor therapies like epidural spinal cord stimulation have been shown to function by activating sensory afferents. It is therefore essential that we understand how sensory feedback drives walking after a SCI. This project thus examines the roles of spinal neurons called V3 neurons after SCI, since V3 neurons receive sensory input and connect to spinal circuits for walking. Using mouse models of SCI, we will test the hypothesis that sensory feedback activates V3 neurons that in turn drive excitatory neuron circuits to initiate walking after SCI, and thus activating V3 neurons (either by genetic approaches or sensory stimulation) provides a novel target to improve recovery. However, our preliminary results suggest that V3 neurons also connect to GABAergic inhibitory neurons that suppress walking excessively after SCI, which may limit the utility of V3 neurons in restoring walking. Fortunately, this activation of inhibitory circuits can be reduced using clinically applicable drugs that block GABAA receptors. We thus hypothesize that V3 activation combined with selective GABAA receptor blockers and daily treadmill training will lead to marked improvements in walking after SCI, exceeding the outcomes of epidural stimulation and training alone. In summary, activating V3 neurons while also inhibiting specific GABAA receptors promises to be a practical new approach to rehabilitation in SCI.