Cortical and subcortical lesions impair skilled walking in the ladder rung walking test: a new task to evaluate fore- and hindlimb stepping, placing, and co-ordination

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Abstract

The ladder rung walking test is a new task to assess skilled walking and measure both forelimb and hindlimb placing, stepping, and inter-limb co-ordination. Rats spontaneously walk from a starting location to a goal along a horizontal ladder. The spacing between the rungs of the ladder is variable and can be changed to prevent the animal from learning either the absolute or relative location of the rungs. The testing procedure requires minimal training and allows detailed quantitative and qualitative analysis using video recording. The utility of the test is described with postoperative data obtained from animals with unilateral neocortical strokes produced by pial stripping over the motor cortex, neonatal and adult unilateral corticospinal tract lesions produced by tract section at the pyramids, and unilateral dopamine depletions produced by injection of 6-hydroxydopamine into the nigrostriatal bundle. In addition, a group of aged rats was examined. Deficits in limb placing, stepping and co-ordination displayed by the animals demonstrate that this test can discriminate between lesions of the motor system or age-associated impairments. The test is useful for assessing loss and recovery of function due to brain or spinal cord injury, the effectiveness of treatment therapies, as well as compensatory processes through which animals adapt to nervous system injury.

Introduction

Progress in the development of animal models for stroke, spinal cord injury, and other neurodegenerative disease requires tests that are sensitive enough to characterize distinct aspects of motor function. To enhance efficacy and resolution of testing, tests should permit qualitative and quantitative measures of motor function and be sensitive to changes in performance during recovery periods (Metz et al., 2000). Tests that have proved sensitive to motor system injury are tests of skilled limb use in reaching for food that have revealed impairments following motor cortex lesions (Castro, 1972, Merkler et al., 2001Whishaw et al., 1986, Whishaw, 2000), corticospinal tract injury (Whishaw et al., 1993, Whishaw et al., 1998, Thallmair et al., 1998, Z'Graggen et al., 1998), and basal ganglia degeneration (Whishaw et al., 1986, Whishaw et al., 1997a, Whishaw et al., 1997b, Miklyaeva et al., 1994, Metz et al., 2001). The advantage of skilled reaching tests is that the movements used in reaching have been well characterized and so descriptive analysis is able to distinguish details of recovery and chronic impairments, as well as details of compensatory changes (Whishaw et al., 1993, Whishaw et al., 1997a, Whishaw et al., 1997b, Whishaw, 2000).

In contrast to the long-term impairments produced in forelimb use in adult rats, motor system lesions result in only transient or very minor permanent deficits in hindlimb use (Stroemer et al., 1995, Kolb et al., 1997, Metz et al., 1998, Muir and Whishaw, 1999). Seemingly complete recovery of movement is observed when animals walk on a flat surface or traverse a narrow beam (Hernandez and Schallert, 1988, Kunkel-Bagden et al., 1992, Kunkel-Bagden et al., 1993, Soblosky et al., 1997, Soblosky et al., 2001, Z'Graggen et al., 1998). The impairments in skilled reaching versus walking may be related to differences in motor control of the limbs. For example, locomotion on a smooth horizontal surface may be achieved adequately by subcortical motor systems. Although locomotion on a narrow beam may appear more demanding in requiring forebrain motor circuits, the movements made while traversing a beam are difficult to analyze and so it is difficult to distinguish true recovery from compensatory changes. Nevertheless, studies on placing reactions in cats show that cortical and spinal lesions impair the ability to compensate for loss of voluntary control (Hiebert et al., 1994, Hiebert and Pearson, 1999).

The present study describes a new test that may be useful for assessing hindlimb and forelimb function. Animals are required to walk along a horizontal ladder on which the spacing of the rungs is variable and is periodically changed. Changes in the rung spacing prevent animals from learning the absolute and relative location of the rungs and minimize the ability of the animals to compensate for an impairment through learning. In addition, changing the spaces between the rungs allows the test to be used repeatedly. Thus, it is useful for assessing chronic deficits or long term treatments. Methods are described for both quantitative and qualitative description of both fore- and hindlimb performance. Co-ordination between forelimbs and hindlimbs can also be assessed, because a misstep or compensatory step by one limb can in principle result in a misstep by another limb. The utility of the test is demonstrated using animals with unilateral lesions of motor cortex, dopamine depletions of the nigrostriatal bundle, and infant and adult corticospinal tract (CST) lesions as well as aged rats. The results indicate that the skilled ladder rung walking test is a sensitive test for quantifying skilled locomotor movements.

Section snippets

Subjects

Seventy adult rats from either the Long Evans (n=55) or Wistar strain (n=15) (260–330 g) and of either sex were used. Five rats received motor cortex lesions, and five age-matched sham-lesion rats served as controls. Five rats received neonatal CST transection, and five control rats received neonatal CST sham lesion. Sixteen rats received CST lesions as adults and were matched by six sham control animals. Eight rats received a nigrostriatal bundle lesion as adults and five non-lesion rats

Histology

The lesion types used in this study were described in earlier studies. The unilateral motor cortex lesion included the rostral and caudal forelimb area and the hindlimb area, as shown previously by Whishaw (2000). The extent of neonatal unilateral CST lesions was comparable to that described by Z'Graggen et al. (2000). The extent of adult unilateral CST lesions was similar to the one described by Whishaw et al. (1993). The lesion extent after unilateral nigrostriatal 6-OHDA infusion was

Discussion

This study describes a new skilled walking test that is sensitive to placing impairments of fore- and hindlimbs produced by lesions to the motor system or by aging. The test requires that animals walk across rungs of a horizontal ladder. To challenge the animals, and to minimize compensatory learning, the spacing of the rungs can be varied. The results identified three kinds of chronic impairments in limb use after unilateral motor system lesion: (1) impairments in ipsilateral and contralateral

Conclusion and implications

The present results demonstrate that a wide variety of skilled fore- and hindlimb movements can be assessed using the ladder rung walking test. The animals’ task is relatively simple, as they spontaneously walk across the ladder to reach a refuge, and therefore no special training is required. In order to prevent the animals from learning the rung spacing pattern, spacing was variable and could be changed from trial to trial. To evaluate the test, we demonstrate that rats with a number of types

Acknowledgements

This research was supported by grants from the Medical Research Council, the Natural Sciences and Engineering Research Council of Canada, and the Canadian Stroke Network. G.M. was supported by the German National Science Foundation.

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