The long term objectives of this study are to define effective interventions to the cascade of structural, biochemical and functional alterations that occur in myofibers following a severe spinal cord injury (SCI) and to determine if the maintenance of the mass and biochemical features of muscles by different therapies can expand functional capabilities following SCI. The present proposal focuses on defining the potential for activity dependent plasticity within the adult rat spinal cord and hind limb muscles and on determining how structural changes in response to an intervention can translate into functional repair.
The Specific Aims address the hypothesis that motor-assisted cycling exercise of paralyzed hind limbs, alone or in combination with a fetal tissue transplant, leads to structural and functional changes in the spinal cord caudal to a complete transection lesion which in turn affect muscle structure and function.
Aim I will use an established SCI and hind limb exercise model to address the potential for plasticity of motoneuron properties and spinal cord circuitry caudal to the lesion site. The importance of sensory input to the spinal cord for plasticity will be determined by deafferentation of the caudal spinal cord followed by exercise of the hind limbs.
The second Aim will test whether the degree of sensory and motor stimulation that occurs during hind limb exercise can promote and/or guide regenerative axonal growth through a fetal spinal cord tissue transplant. Experiments of Aim III will define the interactive effects of exercise and transplantation on the size, metabolic capacity and contractile features of paralyzed hind limb muscles. Behavioral (overground locomotion) and physiological (H-reflex) measures of muscle activity will be combined with a molecular (cDNA arrays) analysis of changes in gene expression post-injury/intervention to provide a comprehensive view of the benefits of a combined therapy approach. We also will determine if beneficial effects of exercise and transplantation can be attained if interventions are delayed for 1 month after SCI. This study will begin to identify the morphological basis for physiological evidence of activity dependent plasticity within the spinal cord and hind limb muscles. Important information about reorganization within the spinal cord and in affected muscles after injury/intervention will be collected. These experiments have direct relevance to the design and implementation of treatment programs for spinal cord injured individuals.
| Beaumont, Eric; Houle, John D; Peterson, Charlotte A et al. (2004) Passive exercise and fetal spinal cord transplant both help to restore motoneuronal properties after spinal cord transection in rats. Muscle Nerve 29:234-42 |
| Dupont-Versteegden, Esther E; Houle, John D; Dennis, Richard A et al. (2004) Exercise-induced gene expression in soleus muscle is dependent on time after spinal cord injury in rats. Muscle Nerve 29:73-81 |
| Houle, John D; Tessler, Alan (2003) Repair of chronic spinal cord injury. Exp Neurol 182:247-60 |
| Dupont-Versteegden, Esther E; Knox, Micheal; Gurley, Cathy M et al. (2002) Maintenance of muscle mass is not dependent on the calcineurin-NFAT pathway. Am J Physiol Cell Physiol 282:C1387-95 |
