Nogo Receptor Deletion and Multimodal Exercise Improve Distinct Aspects of Recovery in Cervical Spinal Cord Injury

Abstract

We tested the ability of two plasticity-promoting approaches to enhance recovery in a mouse model of incomplete spinal cord injury (SCI). Genetically, we reduced myelin-mediated inhibition of neural plasticity through Nogo66-receptor (NgR) gene deletion. Behaviorally, we utilized a novel multimodal exercise training paradigm. Adult mice of wild-type or NgR-null genotype were subjected to partial lateral hemisection (LHx) at C3-C4 with the intent of producing anatomically and functionally mild deficits. Exercise training or control treatment proceeded for 14 weeks. Behavioral outcomes were assessed prior to tract tracing and histological analysis. Genotype and training exerted differing effects on performance; training improved performance on a test related to the training regimen (task-specific benefit), whereas genotype also improved performance on more generalized behaviors (task-non-specific benefit). There were no significant histological differences across genotype or training assignment with regard to lesion size or axonal tract staining. Thus either NgR gene deletion or exercise training benefits mice with mild cervical spinal injury. In this lesion model, the effects of NgR deletion and training were not synergistic for the tasks assessed. Further work is required to optimize the interaction between pharmacological and physical interventions for SCI.

TrkB kinase activity is critical for recovery of respiratory function after cervical spinal cord hemisection

“…Spinal cord hemisection models to the cervical region have been limited (Anderson, et al, 2004, Blanco, et al, 2007, Harel, et al, 2010), and only a few previous studies report spinal cord hemisection to the C2 level in mice (Minor, et al, 2006, Seeds, et al, 2011). The C2SH model has been used extensively and validated across a range of species (c.f., Goshgarian, 2003).…”

Axonal regeneration induced by blockade of glial inhibitors coupled with activation of intrinsic neuronal growth pathways

“…Stroke recovery is greater with the NgR1 antagonist peptide, NEP1-40, and training, than with either intervention alone (Fang, et al, 2010). Motor deficits after cervical lateral hemisection of the spinal cord are lessened independently on different tasks by task-specific training versus NgR1 deletion (Harel, et al, 2010). However, an anti-Nogo antibody therapy was not synergistic with treadmill training in a partial spinal cord injury model (Maier, et al, 2009).…”

Degeneration of Phrenic Motor Neurons Induces Long-Term Diaphragm Deficits following Mid-Cervical Spinal Contusion in Mice

“…6 Other available animal models of SCI include crushtype lesions, 7 medullar compressions, 8 and surgical tract axotomies. [9][10][11][12][13] In particular, hemisection models at a high cervical level (C2) have been useful for studying the plasticity, recovery, and repair of descending innervation of the phrenic nucleus, and notably were used to characterize the crossed-phrenic pathway in both mice 13 and rats. 14 Rats have traditionally been the preferred species used in the SCI research community for conducting most types of studies.…”

“…15,16 Nevertheless, the development and widespread use of genetically modified animals, which are primarily in murine models, have paved the way for the manipulation of genes possibly relevant to the pathophysiology and treatment of SCI. 4,5,11,12,17 The first published study characterizing cervical (C5 level) contusion SCI in the mouse focused on assessment of forelimb motor function following several graded bilateral injuries at 30, 75, or 100 kD of impact force. 6 Using grip strength testing, a graded deficit was observed in forelimb grip force that was proportional to impact severity.…”