Spinal cord regeneration requires injured neurons to survive, re-grow axons, and reconnect with appropriate targets. Since many of these events are related to what must occur during spinal cord development, it may be helpful to use developmental strategies in order to restore locomotor function following spinal cord injury (SCI). Numerous studies have focused on anti-inflammatory steroids and glutamate antagonists, to minimize neuronal death, and inhibitory factors such as myelin-associated glycoprotein (MAG) and Nogo-A, to overcome the inhibition of axon growth; but less research has addressed the problem of reestablishing functional and appropriate synaptic connections. In addition to the obvious need to reestablish appropriate connections to mediate coordinated locomotion, it is important not to promote random growth and connections because maladaptive function could arise resulting in neuropathic pain, for example. Developmental studies have implicated cellular depolarization (activity) as an important process in establishing appropriate locomotor function during fetal development. The formation of spinal locomotor networks, initial synaptogenesis, refinement of connectivity, cell survival, as well as maturation of muscle targets are all thought to depend, at least in part, on activity. Therefore, the overall aim of this pilot project is to define mechanistically how cellular activity affects SCI recovery. The two major goals of this proposal are: (L) to develop a novel genetically-modified mouse line in which the activity of motor neurons can be switched ON and OFF, and (2.) to use genetic and pharmacological approaches in mice recovering from mild contusive SCI to precisely define the role of activity in reestablishing, locomotor function. These studies should define how activity influences SCI recovery, and may provide insight into desirable cellular and molecular targets for pharmacalogical agents that promote the reformation of functional locomotor circuitry following SCI.
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