Functional recovery in T13-L1 hemisected rats resulting from peripheral nerve rerouting: role of central neuroplasticity.

BACKGROUND: Functional improvements after spinal cord injury (SCI) have been reported anecdotally following neurotization, in other words, rerouting nerves proximal to injured cord segments to distal neuromuscular targets, although the underlying mechanisms remain largely unknown. AIM: To test our hypothesis that neurotization-mediated recovery is primarily attributable to CNS neuroplasticity that therefore manifests optimal response during particular therapeutic windows, we anastomosed the T12 intercostal nerve to the ipsilateral L3 nerve root 1-4 weeks after T13-L1 midline hemisection in rats. RESULTS: While axonal tracing and electromyography revealed limited reinnervation in the target muscles, neurobehavioral function, as assessed by locomotion, extensor postural thrust and sciatic functional index of SCI rats receiving neurotization 7-10 days postinjury (n = 11), recovered to levels close to non-SCI controls with neurotization only (n = 3), beginning 3-5 weeks postanastomosis. Conversely, hindlimb deficits were unchanged in hemisected controls with sham neurotization (n = 7) or 4 weeks-delayed neurotization (n = 3) and in rats that had undergone T13-L1 transection plus bilateral anastomoses (n = 6). CONCLUSION: Neurotized SCI animals demonstrated multiparameters of neural reorganization in the distal lumbar cord, including enhanced proliferation of endogenous neural stem cells, increased immunoreactivity of serotonin and synaptophysin, and neurite growth/sprouting, suggesting that anastomosing functional nerves with the nerve stump emerging distal to the hemisection stimulates neuroplasticity in the dysfunctional spinal cord. Our conclusion is validated by the fact that severance of the T13-L1 contralateral cord abolished the postanastomosis functional recovery. Neurotization and its neuroplastic sequelae need to be explored further to optimize clinical strategies of post-SCI functional repair.

Respiratory abnormalities resulting from midcervical spinal cord injury and their reversal by serotonin 1A agonists in conscious rats.

Respiratory dysfunction after cervical spinal cord injury (SCI) has not been examined experimentally using conscious animals, although clinical SCI most frequently occurs in midcervical segments. Here, we report a C5 hemicontusion SCI model in rats with abnormalities that emulate human post-SCI pathophysiology, including spontaneous recovery processes. Post-C5 SCI rats demonstrated deficits in minute ventilation (Ve) responses to a 7% CO2 challenge that correlated significantly with lesion severities (no injury or 12.5, 25, or 50 mm x 10 g weight drop; New York University impactor; p < 0.001) and ipsilateral motor neuron loss (p = 0.016). Importantly, C5 SCI resulted in at least 4 weeks of respiratory abnormalities that ultimately recovered afterward. Because serotonin is involved in respiration-related neuroplasticity, we investigated the impact of activating 5-HT1A receptors on post-C5 SCI respiratory dysfunction. Treatment with the 5-HT1A agonist 8-hydroxy-2-(di-n-propylmino)tetralin (8-OH DPAT) (250 microg/kg, i.p.) restored hypercapnic Ve at 2 and 4 weeks after injury (i.e., approximately 39.2% increase vs post-SCI baseline; p < or = 0.033). Improvements in hypercapnic Ve response after single administration of 8-OH DPAT were dose dependent and lasted for approximately 4 h(p < or = 0.038 and p < or = 0.024, respectively). Treatment with another 5-HT1A receptor agonist, buspirone (1.5 mg/kg, i.p.), replicated the results, whereas pretreatment with a 5-HT1A-specific antagonist, 4-iodo-N-[2-[4(methoxyphenyl)-1-piperazinyl]ethyl]-N-2-pyridinyl-benzamide (3 mg/kg, i.p.) given 20 min before 8-OH DPAT negated the effect of 8-OH DPAT. These results imply a potential clinical use of 5-HT1A agonists for post-SCI respiratory disorders.