Localization of the corticospinal tract within the porcine spinal cord: Implications for experimental modeling of traumatic spinal cord injury

Abstract

Spinal cord injury (SCI) researchers have predominately utilized rodents for SCI modeling and experimentation. Unfortunately, a large number of novel therapies developed in rodent models have failed to demonstrate efficacy in human clinical trials which suggests that improved animal models are an important translational tool. Recently, porcine models of SCI have been identified as a valuable intermediary model for preclinical evaluation of promising therapies to aid clinical translation. However, the localization of the major spinal tracts in pigs has not yet been described. Given that significant differences exist in the location of the corticospinal tract (CST) between rodents and humans, determining its location in pigs will provide important information related to the translational potential of the porcine pre-clinical model of SCI. Thus, the goal of this study is to investigate the localization of the CST within the porcine spinal cord. Mature female domestic pigs (n=4, 60kg) received microinjections of fluorescent dextran tracers (Alexa Fluor, 10,000MW) into the primary motor cortex, using image-guided navigation (StealthStation), to label the CST. At 5 weeks post-tracer injection animals were euthanized, the entire neuroaxis harvested and processed for histological examination. Serial sections of the brain and spinal cord were prepared and imaged using confocal microscopy to observe the location of the CST in pigs. Results demonstrate that the CST of pigs is located in the lateral white matter, signifying greater similarity to human anatomical structure compared to that of rodents. We conclude that the corticospinal tract in pigs demonstrates anatomical similarity to human, suggesting that the porcine model has importance as a translational intermediary pre-clinical model.

The Cortical Motor System in the Domestic Pig: Origin and Termination of the Corticospinal Tract and Cortico-Brainstem Projections

“…Although the tracer injections likely labeled a limited number of cortical neurons, thousands of CST axons were present at C2 and traveled down to the thoracic spinal cord indistinctly of their cortical origin. These results confirm that pigs have a complete pyramidal system with cortico-bulbar and corticospinal components, in agreement with recent studies in swine that found CST axons descending along the complete cervical spinal cord after injection of anterograde tracers in M1 (Leonard et al, 2017). Our results likewise confirm and extend the suggestion that PM contributes corticospinal axons (Bech et al, 2018).…”

“…Studies on axonal Wallerian degeneration ensuing M1 lesion in domestic pigs led to the conclusion that the porcine CST was essentially inexistent, the pyramidal tract consisting only of cortico-bulbar axons that innervated cranial motoneurons and ended at the pyramidal decussation ( Palmieri et al, 1987 ). This notion prevailed for two decades until it was re-addressed by injecting anterograde neural tracers in M1 ( Leonard et al, 2017 ), showing that porcine CST axons travel along the complete cervical spinal cord. Also using anterograde tracers, Bech et al (2018) found that about 86% of the porcine CST fibers crossed in the pyramidal decussation and descended by the contralateral dorsolateral fasciculus of the upper cervical spinal cord, and suggested that the premotor cortex may contribute CST axons.…”

Hypothermia in the course of acute traumatic spinal cord injury

“…This is in contrast to rodents, where the rubrospinal tract is predominantly involved. These anatomical and functional similarities to humans provide support for pigs as a reliable animal model for preclinical research into traumatic SCI (Leonard et al, 2017). In general, it should be noted that both small and large animal models of SCI have limitations in their ability to predict outcomes in human SCI (Rosenzweig and McDonald, 2004;Bassols et al, 2014).…”

“…They share similar anatomical and physiological characteristics with humans, particularly the cardiovascular, urinary, reproductive and digestive systems (Bassols et al, 2014). In the pig spinal cord, the localization of the corticospinal tract (CST) inside the lateral columns of the white matter is more similar to humans than to rodents (Leonard et al, 2017). In terms of anatomical function, the CST plays a key role in locomotion of the pigs' hindlimbs.…”

A new technique for minimal invasive complete spinal cord injury in minipigs

“…Even though huge progress has been made in the preclinical field in the understanding of the tSCI pathophysiology, in the identification of therapeutically relevant targets, and in the development of molecular, cellular, and technology-supported therapies, none of these approaches has reached approval as a standard therapy [ 8 ]. Among many reasons for this are (i) general low translational value of rodent models, (ii) different neuroanatomical features of rodent and human spinal cord such as different locations of the corticospinal tracts, (iii) the usage of SCI lesion models with little relevance for human SCI, for example, the wire knife transection model [ 6 , 8 , 9 ].…”