Elsevier

Experimental Neurology

Volume 206, Issue 2, August 2007, Pages 318-331
Experimental Neurology

Spinal pathways involved in the control of forelimb motor function in rats

https://doi.org/10.1016/j.expneurol.2007.05.024Get rights and content

Abstract

There is increasing interest in developing rodent models for cervical spinal cord injury (SCI) and techniques to assess forelimb motor function. Previously, we demonstrated that in rats, complete unilateral hemisection at cervical level five (C5) permanently eliminated the ability to grip and caused severe impairments in food retrieval by the forepaw ipsilateral to the lesion [Anderson, K.D., Gunawan, A., Steward, O., 2005. Quantitative behavioral analysis of forepaw function after cervical spinal cord injury in rats: Relationship to the corticospinal tract. Exp. Neurol. 194, 161–174]. Here, we analyzed the functional consequences of partial lesions that damaged tracts/cells located in the medial vs. lateral portion of the spinal cord. Female Sprague–Dawley rats were trained on the Grip Strength Meter (GSM) and the food pellet reaching task. Rats then received either a “medial lesion” that destroyed an approximately 0.5 mm wide zone from the midline laterally (which included the dorsal column) or “lateral lesion” that destroyed the lateral column at C5 and were tested for 8 weeks. Rats with histologically-verified medial lesions exhibited a complete loss of gripping ability for 7 weeks post-injury; only 1 of 4 animals exhibited any recovery of grip strength, and this occurred at 54 days. In contrast, rats with lateral lesions exhibited deficits, but the majority (7/10) recovered the ability to grip by 43 days post-injury. Interestingly, when tested on the food retrieval task, rats with medial lesions exhibited deficits that recovered; rats with lateral lesions exhibited more permanent deficits. These results suggest that different spinal circuits are involved in recovery of grip strength vs. recovery of skilled reaching.

Introduction

Recently, there has been a surge in the development and characterization of rodent cervical spinal cord injury (SCI) paradigms (Schrimsher and Reier, 1992, Schrimsher and Reier, 1993, Soblosky et al., 2001, Anderson et al., 2004, Anderson et al., 2005, Collazos-Castro et al., 2005, Pearse et al., 2005, Gensel et al., 2006). The importance of expanding cervical SCI research is reinforced by the fact that more than half of human SCIs occur in the cervical region (Jackson et al., 2004) and regaining arm and hand function is the highest priority for people living with quadriplegia (Anderson, 2004). Additionally, from a practical standpoint, return of segmental function is easier to detect and analyze in cervical injury models in comparison to lesions at mid-thoracic levels. A necessary feature of cervical injury models is that they must be partial to preserve a sufficient degree of function to allow survival of the experimental animals. Accordingly, it is important to assess the relationship between damaging or sparing of particular pathways and the resulting deficits and recovery of forelimb function.

One important behavioral function is that of the digital flexors and extensors in the forepaw, which are necessary for grasping, manipulating, and releasing objects. This type of function requires fine, skilled movement of the fingers and the behavior is quite similar between rodents and humans (Whishaw et al., 1992). The underlying anatomical tracts mediating this behavior, however, may not be evolutionarily conserved between species. In humans, fine motor control of the fingers appears to be mediated by the corticospinal tract (CST; Kuypers, 1981, Lemon, 1993, Lemon et al., 1995). In rodents, the degree to which particular aspects of motor control of the forelimb and digits are mediated by the CST vs. other tracts is not known. Other pathways that may participate include the rubrospinal and reticulospinal tracts, propriospinal relays, and possibly other brainstem pathways that mediate reflex grasping behavior that have not been fully worked out. In particular, it is not known how damage to different parts of the spinal cord in which these tracts travel affects forelimb motor function.

We have previously shown that measurements of grip strength with a Grip Strength Meter (GSM) provide sensitive, quantitative, and reproducible assessments of deficits and recovery of forepaw motor function after cervical SCI (Anderson et al., 2004, Anderson et al., 2005). Unilateral transections (lateral hemisections) at different cervical levels cause a loss of gripping ability in the ipsilateral forepaw in mice and rats. In young mice, there is significant recovery of gripping ability, whereas recovery is less in older mice (manuscript in preparation). In young adult rats, the impairment in gripping ability following complete lateral hemisections is permanent (or at least does not recover up to 56 days post-injury). The mechanism underlying the spontaneous recovery (or lack of recovery) of grip strength is not known, although studies in mice reveal that normal gripping ability is dependent upon the contralateral motor cortex suggesting involvement of the CST (Blanco et al., 2007).

A unilateral hemisection destroys a number of important descending motor pathways, including the main corticospinal tract in the dorsal column, the dorsolateral corticospinal tract (dlCST) in the lateral column, the rubrospinal, reticulospinal, and vestibulospinal tracts in the lateral and ventral columns, and the ventral corticospinal tract in the ventral column. The lesion also damages the gray matter and propriospinal circuitry at the level of the transection and ascending sensory tracts. It is not known how the striking deficits in gripping ability that are seen relate to damage to different tracts. The goal of the present study was to begin to define the role of particular tracts in forelimb motor control by assessing two aspects of forelimb motor function after two types of selective, unilateral, lesions at C5. The first lesion (termed a medial lesion) damaged the main CST in the dorsal column (dCST), ascending sensory tracts in the dorsal column, the medial gray matter at C5, contralateral spinothalamic tracts crossing the midline at C5, and the medial part of the ventral funiculus, but spared the dorsal and ventral horns as well as the dorsolateral, lateral, and ventrolateral funiculi. The second lesion (termed a lateral lesion) destroyed portions of the dorsal and ventral horns as well as the dorsolateral, lateral, and ventrolateral funiculi, but spared the dCST, the medial gray matter, and the ventral funiculus. Forelimb function was assessed using the GSM and using a more complex assessment of arm and hand integration involving a food pellet reaching task.

Section snippets

SCI surgery

Experimental animals were female Sprague–Dawley rats (from Harlan, Inc., San Diego, CA) that were 200–230 g at the beginning of each experiment and between 3 and 4 months of age. In two separate experiments, a total of 24 rats received a partial lesion surgery and 8 received sham surgery (n = 32). All lesions were assessed via histology.

For surgery, rats were anesthetized with an intraperitoneal injection of Ketamine and Xylazine (100 mg/kg and 10 mg/kg, respectively; Western Medical Supply,

Two types of partial lesions of the cervical spinal cord: medial and lateral

In rats, a full, unilateral hemisection at cervical level five (C5) results in a complete loss of gripping function in the ipsilateral forepaw (Anderson et al., 2005). Here, we analyzed the pathways involved in gripping function by assessing the functional consequences of partial, unilateral lesions at C5. The goal was to compare the consequences of two types of lesions: 1) a medial lesion that destroyed the dorsal column on one side and extended through the medial gray matter to the ventral

Discussion

Our goal in the present study was to begin to define how partial lesions of different parts of the spinal cord affect forelimb motor function. The original rationale was based on our desire to compare the effects of two types of selective, unilateral, C5 lesions in rats that target different descending motor pathways: 1) a medial lesion that destroyed the main component of CST axons in the dorsal column; and 2) a lateral lesion that destroyed the dorsolateral CST and rubrospinal tract.

Acknowledgments

Thanks to Karla Baños, Kelli Sharp, and Kelly Yee for technical assistance. This work was supported by the NIH-NO1-NS-3-2354.

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