Respiratory function following bilateral mid-cervical contusion injury in the adult rat

Abstract

The consequences of spinal cord injury (SCI) are often viewed as the result of white matter damage. However, injuries occurring at any spinal level, especially in cervical and lumbar enlargement regions, also entail segmental neuronal loss. Yet, the contributions of gray matter injury and plasticity to functional outcomes are poorly understood. The present study addressed this issue by investigating changes in respiratory function following bilateral C3/C4 contusion injuries at the level of the phoenix motoneuron (PhMN) pool which in the adult rat extends from C3–C5/6 and provides innervation to the diaphragm. Despite extensive white and gray matter pathology associated with two magnitudes of injury severity, ventilation was relatively unaffected during both quiet breathing and respiratory challenge (hypercapnia). On the other hand, bilateral diaphragm EMG recordings revealed that the ability to increase diaphragm activity during respiratory challenge was substantially, and chronically, impaired. This deficit has not been seen following predominantly white matter lesions at higher cervical levels. Thus, the impact of gray matter damage relative to PhMNs and/or interneurons becomes evident during conditions associated with increased respiratory drive. Unaltered ventilatory behavior, despite significant deficits in diaphragm function, suggests compensatory neuroplasticity involving recruitment of other spinal respiratory networks which may entail remodeling of connections. Transynaptic tracing, using pseudorabies virus (PRV), revealed changes in PhMN-related interneuronal labeling rostral to the site of injury, thus offering insight into the potential anatomical reorganization and spinal plasticity following cervical contusion.

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

“…Previously developed contusion injuries at mid-cervical levels in rodents have also been associated with respiratory complications. 6,23 Interestingly, the C5 impact was almost never associated with mortality in the present study, suggesting a greater susceptibility of overall ventilation to contusion injury at the C4 region. Preliminary data from our laboratory showed that generation of a single impact at the C4 level only was sufficient to obtain long-lasting deficits in ipsilateral hemi-diaphragm function (not shown); however, the double C4 + C5 injury paradigm resulted in significantly greater functional compromise.…”

“…Several contusion models at mid-cervical levels (C3, C4, C5) that show chronic abnormalities in respiratory parameters have been developed in the rat. [22][23][24][25] The extension of a contusion injury model to the mouse provides opportunities for manipulating genes of interest and for evaluating their role in relevant outcome measures affected by cervical spinal contusion such as forelimb motor function, respiratory function, and neuropathic pain.…”

“…In addition, this model allows for the use of genetically modified animals for exploring the function of specific genes in the pathophysiology of respiratory motor neuron degeneration and functional respiratory compromise following cervical SCI. [19][20][21][22][23] Methods…”

A Murine Model of Cervical Spinal Cord Injury to Study Post-lesional Respiratory Neuroplasticity

“…A more clinically relevant animal model is a contusive injury at the cervical level [26][27][28] . However, the reproducibility of the injury is inconsistent, mainly due to the location of the descending respiratory pathways and the impossibility to do an extensive contusion (which will drastically reduce the survival rate of the animals).…”

Human iPS cell-derived astrocyte transplants preserve respiratory function after spinal cord injury

“…The majority of these injuries affect mid-cervical levels (Shanmuganathan et al, 2008) (the location of the PhMN pool), and respiratory function following mid-cervical SCI is significantly determined by PhMN loss/sparing (Strakowski et al, 2007). Although use of thoracic models has predominated, cervical SCI animal models have recently been developed (Aguilar and Steward, 2010; Awad et al, 2013; Gensel et al, 2006; Lane et al, 2012; Lee et al, 2010; Sandrow-Feinberg et al, 2009; Sandrow-Feinberg et al, 2010; Sandrow et al, 2008; Stamegna et al, 2011), including our own (Nicaise et al, 2012). Because of the relevance of astrocyte and GLT1 dysfunction to PhMN loss/injury following cervical trauma, we targeted transplantation in the present study to cervical spinal cord ventral horn in a cervical contusion SCI model.…”