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 SCIDxRag2-Gamma(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.

Modeling chronic cervical spinal cord injury in aged rats for cell therapy studies

“…Recently, Nishi et al [28] published a similar approach to ours in terms of modeling cervical unilateral SCI in young and aged mice, using two different mouse strains to characterize this type of injury. To our knowledge, however, ours is the first study on cell therapy-based treatment of severe, early chronic SCI in a population of aged rats.…”

“…While the majority of pre-clinical studies on SCI have used animal models with thoracic lesions, some studies have focused on cervical SCI [25][26][27][28]. These studies are remarkable given that cervical lesions are more frequent than thoracic ones and the symptoms are much more severe.…”

Pluripotent Stem Cells for Spinal Cord Injury Repair

“…In the last few decades, SCI in the elderly population has increased substantially due to life expectancy [ 1 , 67 ]. In this regard, some studies have arisen to model the condition [ 68 ]. Our own laboratory has recently published a study that models chronic cervical SCI in aged rats that were further treated with iPSC–NSC.…”

Gait Analysis Using Animal Models of Peripheral Nerve and Spinal Cord Injuries

“…An SCI is an incapacitating condition causing weakened motor function or even full paralysis, and there are more than 2.5 million people worldwide currently living with an SCI [24]. In the following period, after the initial mechanical injury to the spinal cord, there are clear processes in which inflammation and apoptosis induce additional injuries to the initially harmed tissues [25].…”

“…Moreover, when investigating young (e.g., 3-4 months old) and aging (e.g., 16-17 months old) Rag2gamma(c)−/− mice, age-related pre-injury differences in strength and rearing were found. When testing therapeutic SCI approaches, the experimental design and analysis has to take into account all these differences [24].…”