Promoting the rewiring of lesioned motor tracts following a spinal cord injury is a promising strategy to restore motor function. For instance, axonal collaterals may connect to spared, lesion-bridging neurons, thereby establishing a detour for descending signals and thus promoting functional recovery. In our rat model of cervical spinal cord injury, we attempted to promote targeted rewiring of the unilaterally injured corticospinal tract (CST) via the spared reticulospinal tract (RtST). To promote new connections between the two tracts in the brainstem, we administered viral vectors producing two neurotrophins. Brain-derived neurotrophic factor (BDNF), a known promotor of collateral growth, was expressed in the motor cortex, and neurotrophin 3 (NT-3), which has chemoattractive properties, was expressed in the reticular formation. Because rehabilitative training has proven to be beneficial in promoting functionally meaningful plasticity following injury, we added training in a skilled reaching task. Different neurotrophin or control treatments with or without training were evaluated. As hypothesized, improvements of motor performance with the injured forelimb following neurotrophin treatment alone were absent or modest compared to untreated controls. In contrast, we found a significant synergistic effect on performance when BDNF treatment was combined with training. The mechanism of this recovery remains unidentified, as histological analyses of CST and RtST collateral projections did not reveal differences among treatment groups. In conclusion, we demonstrate that following a cervical spinal lesion, rehabilitative training is necessary to translate effects of BDNF into functional recovery by mechanisms which are likely independent of collateral sprouting of the CST or RtST into the gray matter.
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