Dataset Information

The effects of mouse strain and age on a model of unilateral cervical contusion spinal cord injury.

ABSTRACT: There are approximately 1.2 million people currently living with spinal cord injury (SCI), with a majority of cases at the cervical level and half involving incomplete injuries. Yet, as most preclinical research has been focused on bilateral thoracic models, there remains a disconnect between bench and bedside that limits translational success. Here, we profile a clinically relevant model of unilateral cervical contusion injury in the mouse (30kD with 0, 2, 5, or 10 second dwell time). We demonstrate sustained behavioral deficits in performance on grip strength, cylinder reaching, horizontal ladderbeam and CatWalk automated gait analysis tasks. Beyond highlighting reliable parameters for injury assessment, we also explored the effect of mouse strain and age on injury outcome, including evaluation of constitutively immunodeficient mice relevant for neurotransplantation and cellular therapy testing. Comparison of C57Bl/6 and immunodeficient Rag2gamma(c)-/- as well as Agouti SCIDxRag2Gamma(c)-/- hybrid mouse strains revealed fine differences in post-injury ipsilateral grip strength as well as total number of rearings on the cylinder task. Differences in post-SCI contralateral forepaw duty cycle and regularity index as measured by CatWalk gait analysis between the two immunodeficient strains were also observed. Further, assessment of young (3-4 months old) and aging (16-17 months old) Rag2gamma(c)-/- mice identified age-related pre-injury differences in strength and rearing that were largely masked following cervical contusion injury; observations that may help interpret previous results in aged rodents as well as human clinical trials. Collectively, the work provides useful insight for experimental design and analysis of future pre-clinical studies in a translational unilateral cervical contusion injury model.

SUBMITTER: Nishi RA

PROVIDER: S-EPMC7295191 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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The effects of mouse strain and age on a model of unilateral cervical contusion spinal cord injury.

Nishi Rebecca A RA Badner Anna A Hooshmand Mitra J MJ Creasman Dana A DA Liu Hongli H Anderson Aileen J AJ

PloS one 20200615 6

There are approximately 1.2 million people currently living with spinal cord injury (SCI), with a majority of cases at the cervical level and half involving incomplete injuries. Yet, as most preclinical research has been focused on bilateral thoracic models, there remains a disconnect between bench and bedside that limits translational success. Here, we profile a clinically relevant model of unilateral cervical contusion injury in the mouse (30kD with 0, 2, 5, or 10 second dwell time). We demons ...[more]

PMID: 32542053

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Project description:Contusion-type cervical spinal cord injury (SCI) is one of the most common forms of SCI observed in patients. In particular, injuries targeting the C3-C5 region affect the pool of phrenic motor neurons (PhMNs) that innervates the diaphragm, resulting in significant and often chronic respiratory dysfunction. Using a previously described rat model of unilateral midcervical C4 contusion with the Infinite Horizon Impactor, we have characterized the early time course of PhMN degeneration and consequent respiratory deficits following injury, as this knowledge is important for designing relevant treatment strategies targeting protection and plasticity of PhMN circuitry. PhMN loss (48% of the ipsilateral pool) occurred almost entirely during the first 24 h post-injury, resulting in persistent phrenic nerve axonal degeneration and denervation at the diaphragm neuromuscular junction (NMJ). Reduced diaphragm compound muscle action potential amplitudes following phrenic nerve stimulation were observed as early as the first day post-injury (30% of pre-injury maximum amplitude), with slow functional improvement over time that was associated with partial reinnervation at the diaphragm NMJ. Consistent with ipsilateral diaphragmatic compromise, the injury resulted in rapid, yet only transient, changes in overall ventilatory parameters measured via whole-body plethysmography, including increased respiratory rate, decreased tidal volume, and decreased peak inspiratory flow. Despite significant ipsilateral PhMN loss, the respiratory system has the capacity to quickly compensate for partially impaired hemidiaphragm function, suggesting that C4 hemicontusion in rats is a model of SCI that manifests subacute respiratory abnormalities. Collectively, these findings demonstrate significant and persistent diaphragm compromise in a clinically relevant model of midcervical contusion SCI; however, the therapeutic window for PhMN protection is restricted to early time points post-injury. On the contrary, preventing loss of innervation by PhMNs and/or inducing plasticity in spared PhMN axons at the diaphragm NMJ are relevant long-term targets.

Project description:Fine motor skills are thought to rely on the integrity of ascending sensory pathways in the spinal dorsal column as well as descending motor pathways that have a neocortical origin. However, the neurophysiological processes underlying communication between the somatosensory and motor pathways that regulate fine motor skills during spontaneous recovery after spinal cord contusion injury remain unclear. Here, we established a rat model of cervical hemicontusive injury using C5 laminectomy followed by contusional displacement of 1.2 mm (mild injury) or 2.0 mm (severe injury) to the C5 spinal cord. Electrophysiological recordings were performed on the brachial muscles up to 12 weeks after injury to investigate the mechanisms by which spinal cord pathways participate in motor function. After spinal cord contusion injury, the amplitudes of somatosensory and motor-evoked potentials were reduced, and the latencies were increased. The forelimb open field locomotion test, grooming test, rearing test and Montoya staircase test revealed improvement in functions. With increasing time after injury, the amplitudes of somatosensory and motor-evoked potentials in rats with mild spinal cord injury increased gradually, and the latencies gradually shortened. In comparison, the recovery times of somatosensory and motor-evoked potential amplitudes and latencies were longer, and the recovery of motor function was delayed in rats with severe spinal cord injury. Correlation analysis revealed that somatosensory-evoked potential and motor-evoked potential parameters were correlated with gross and fine motor function in rats with mild spinal cord contusion injury. In contrast, only somatosensory-evoked potential amplitude was correlated with fine motor skills in rats with severe spinal cord injury. Our results show that changes in both somatosensory and motor-evoked potentials can reflect the changes in gross and fine motor functions after mild spinal cord contusion injury, and that the change in somatosensory-evoked potential amplitude can also reflect the change in fine motor function after severe spinal cord contusion injury. This study was approved by the Animal Ethics Committee of Nanfang Hospital, Southern Medical University, China (approval No. NFYY-2017-67) on June 11, 2017.

Dataset Information

The effects of mouse strain and age on a model of unilateral cervical contusion spinal cord injury.

Publications

The effects of mouse strain and age on a model of unilateral cervical contusion spinal cord injury.

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