Anatomical correlates of recovery in single pellet reaching in spinal cord injured rats
Introduction
Modeling spinal cord injury (SCI) in animals to test potential treatments is challenging, partly due to the variables involved, including different lesion levels, severities and causes of injury (e.g., contusion, compression, section). A number of combinations of these variables have been applied, driven by different treatment questions ranging from neuroprotection to axonal regeneration. Much of the early research in the field of SCI focused on lesions at the thoracic level using locomotor recovery as functional readout (Barbeau and Rossignol, 1987, Behrmann et al., 1992, Little et al., 1988). Because of its clinical relevance and convenient neuroanatomical access (relatively easy to trace and examine because it descends in the dorsal funiculus), the corticospinal tract (CST) was the preferred descending system involved in many of these studies (Eidelberg and Yu, 1981, Liebscher et al., 2005, Metz et al., 1998, Muir and Whishaw, 1999). However, it became clear that (at least in rodents) it is not lesions to the CST, but to the reticulospinal tract, projecting in the ventrolateral funiculus, that determine the degree of locomotor deficits (Loy et al., 2002, Schucht et al., 2002, Steeves and Jordan, 1980). Another challenge in the interpretation of locomotor recovery is that locomotion is orchestrated by so called spinal central pattern generating networks. Thus, locomotor patterns can be initiated without direct descending input (Barbeau and Rossignol, 1987, Lovely et al., 1986), making the interpretation of treatment effects even more difficult.
A shift in the field of SCI research towards cervical lesions occurred as a result of a number of factors. These factors included a strong base of knowledge that hand/paw function involves CST function (Lawrence and Kuypers, 1968, Schwartzman, 1978), an increase in the frequency of incomplete, cervical SCIs in humans (National Spinal Cord Injury Statistical Centre, 2012), and the assumption that reaching movements are volitional, and directly orchestrated by the brain and not only by spinal networks. The majority of these studies involved rats, which can be trained to grasp for food pellets in tests such as a single pellet skilled reaching task (Whishaw and Pellis, 1990, Whishaw et al., 1993), tray reaching (Whishaw et al., 1986) or the Montoya staircase test (Montoya et al., 1991). Studies using these reaching tests showed that damage to both the lateral and dorsal funiculus, housing the rubrospinal tract (RST) and CST respectively, results in permanent functional deficits in reaching recovery (Anderson et al., 2007, Morris et al., 2011, Whishaw et al., 1998). Although spinal tracts involved in the control of reaching have been identified, an ideal combination of efficient functional readout and lesion type is still lacking. The current study attempts to address this issue by evaluating the reaching recovery of rats with various lesion severities to highlight the ideal lesion to be used to test plasticity-promoting treatments with single pellet skilled reaching.
To be useful for demonstrating the benefits of regeneration and/or plasticity-promoting treatments, an animal model of SCI must fulfill various requirements. First, considering the currently limited treatment options for SCI and the fact that effective treatments will likely consist of combinatory approaches, moderate treatment effects should be detectable. By assessing the effects of rehabilitative training we utilize one of the currently most effective treatments for promoting recovery following SCI, thereby providing a good estimation of how sensitive a current testing approach needs to be. Second, the injury has to induce significant functional deficits, but should not be so severe that a floor effect is observed. A floor effect describes the effect when data cannot be recorded lower than a designated value (e.g., success of 0% in the single pellet test). This can result in an accumulation of animals with success rates of 0 although they still might vary in their reaching abilities. It also has to be kept in mind that plasticity-inducing treatments require a certain amount of tissue sparing. Lastly, the variability in spontaneous functional recovery should be small because the margin between spontaneous recovery, treatment effects and pre-lesion motor function are often very small.
To define an optimal cervical lesion model for testing effects of regeneration and/or plasticity-promoting treatments (including training), we investigated functional deficits caused by unilateral lesions, ranging from a minimal dorsolateral lesion to a complete lateral hemisection. To also investigate the effect of lesion location (with respect to projection of descending tracts) we distributed the lesions into categories and studied spontaneous recovery as well as the effect of reaching training (as a potent plasticity-promoting treatment) to identify the most appropriate lesion type to use when testing treatments following cervical SCI.
Section snippets
Animals and experimental groups
All experimental procedures were approved by the University of Alberta Animal Care and Use Committee and complied with the guidelines of the Canadian Council for Animal Care. The rats in this study were derived from control groups in earlier studies from our laboratory. A total of 139 female Lewis rats (Charles River Laboratories, Canada) weighing 180 g–200 g were included in this study. Rats were group housed on a 12 h:12 h light/dark cycle and received a cervical (C4) lesion with the intention to
Correlating lesion size with reaching success
The severity of a SCI is frequently described in two ways, either as the percentage of lesioned tissue or as spared white matter in a spinal cross section. In contrast to thoracic injuries, both gray and white matter damage at cervical levels greatly influence functional recovery so we measured the total area of lesioned tissue in this study. The results ranged from 6% to 50% of the total spinal cross section in trained animals and 8% to 52% in untrained animals. There was no statistical
The “optimal” lesion model
Although SCI research has substantially increased our basic understanding of the processes limiting the self-repair of the injured CNS, effective treatments to promote repair are still missing. This could be due in part to limitations in animal models, where functional recovery is a key outcome measure. Devising functional tests and scores according to lesion location and severity is important to ensure that the potential to observe meaningful treatment effects is maximized. It is possible that
Conclusion
To test functional recovery using the single pellet reaching task in spinal cord injured rats, a lesion like the DLQ lesion should be used. This will maximize the limited potential to observe spontaneous and treatment-promoted reaching recovery. However, following the analysis of the relation between recovery and lesion size of 145 rats, we have come to the conclusion that due to high variability, the large number of “non performers”, a very small range of lesion size that allows detection of
Acknowledgments
This study is based on various projects supported by the Canadian Institute for Health Research (CIHR), the International Spinal Research Trust (ISRT) and Wings for Life. KF is supported by Alberta Innovates Health Solutions. Special thanks to Susan Armijo-Olivo for statistical assistance.
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