Mechanisms of Activity-Dependent Plasticity After Spinal Cord Injury and the Role of Proprioceptive Stimulation.

摘要

Recovery following spinal cord injury (SO) is attributable to the innate plasticity of the nervous system and retention of spinal circuits involved in locomotion and other behaviors. Repetitive patterned activity in the form of exercise improves this recovery by increasing local neurotrophic factor levels and axon sprouting in the spinal cord and by minimizing possible adverse effects of spinal cord plasticity. To better understand the underlying features of activity-dependent plasticity, we analyzed molecular changes in the spinal cord resulting from a passive exercise regimen. In doing so, we paid special attention to the role of the sensory system in modulating the molecular response and reflex activity of neurons below the level of injury.;First, we examined changes in mRNA expression following injury and exercise in cells of the motor system and proprioceptive sensory system, with emphasis on genes associated with the injury response and with neurotrophic factors because of their ability to modify neural circuits. Exercise increased the expression of genes associated with survival and reduced those associated with apoptosis. Exercise increased expression of the neurotrophic factors, but only in cells of the motor system.;To determine if sensory input was necessary for reflex normalization seen with exercise after SCI, we used pyridoxine (toxic to large, sensory neurons) to block proprioceptive sensory input. Hyperactive reflexes associated with SCI were not normalized in exercised animals treated with pyridoxine, demonstrating a critical role of proprioceptive stimulation in modulation of the H-reflex. Further, immunohistochemical analysis of synaptic elements below the level of the injury indicated no change with exercise after pyridoxine administration.;Next, we examined the role of sensory stimulation in molecular changes observed with exercise. We analyzed gene expression in motoneurons, after SCI and exercise, in animals lacking either proprioceptive sensory stimulation or all sensory stimulation caudal to the injury. Exercise failed to increase expression of neurotrophic factors in motoneurons in either state of sensory loss. Overall these results demonstrate possible molecular mechanisms and the critical role of proprioceptive input in activity-dependent plasticity.