Biomedical subjects

G A Metz

Publications and source records attributed to G A Metz.

17 recordsLinked to original sources

PubMed2006

Enriched environment improves motor function in intact and unilateral dopamine-depleted rats.

Previous studies have suggested that experience and environmental conditions can affect the progression and severity of symptoms in Parkinson's disease. Furthermore, earlier reports have indicated that enriched environment promotes the survival of dopaminergic grafts in a rat model of Parkinson's disease. Here we investigated whether environmental enrichment affects normal motor function and the severity of dopamine depletion in a rat model of Parkinson's disease. Adult female Long-Evans rats were pre-trained and tested daily in a skilled reaching task. One group of rats was placed in an enriched environment while one group was housed under standard conditions. During this time period, reaching success of animals exposed to the enriched environment improved as compared with animals living in standard housing. The animals remained in the two housing conditions for six weeks prior to receiving unilateral infusion of the neurotoxin 6-hydroxydopamine into the nigrostriatal bundle. The daily behavioral testing continued up to four weeks after lesion. The observations showed that rats housed in an enriched environment significantly improved in reaching success during the first three weeks after lesion as compared with rats housed in the standard condition. Qualitative movement analysis, drug-induced rotation and histological findings indicate that compensatory processes in particular might have accounted for the behavioral improvements. These data are discussed in relation to possible mechanisms of experience-dependent modulation of the pathology of Parkinson's disease.

Animals↗

PubMed2004

Behavioral characterization in a comprehensive mouse test battery reveals motor and sensory impairments in growth-associated protein-43 null mutant mice.

The growth-associated protein (GAP)-43 is a major neuronal protein associated with axonal growth, neuronal plasticity and learning. The observation that only 5-10% of mice with a full GAP-43 gene deletion survive weaning suggests that basic neural functions are disturbed. Here we used a comprehensive test battery to characterise and quantify the motor and sensory function of surviving adult homozygous GAP-43 (-/-) mice as compared with GAP-43 (+/-) and wild-type animals. The test battery was comprised of motor, sensory, and reflex tests producing 25 measures of locomotion, as well as epicritic, auditory, olfactory and visual function. The analysis revealed significant impairments in muscle strength, limb coordination and balance in GAP-43 (-/-) mice. Furthermore, GAP-43 (-/-) animals were hyperactive and showed reduced anxiety as measured by open field and light dark tests. In sensory tests, GAP-43 (-/-) mice were tested for impaired tactile and labyrinthine function. Abnormal reflexes were found in the contact and vibrissa placing responses, and in the crossed extensor reflex. GAP-43 (+/-) animals showed only moderate abnormalities as compared with wild-type animals. We conclude that GAP-43 is necessary for the development and function of a variety of neuronal systems. The results also show that the comprehensive test battery used in the present study represents a sensitive approach to assess the functional integrity of ascending and descending pathways in genetically manipulated mice.

Analysis of Variance↗

PubMed2002

Drug-induced rotation intensity in unilateral dopamine-depleted rats is not correlated with end point or qualitative measures of forelimb or hindlimb motor performance.

The pharmacological induction of rotational (circling) behavior is widely used to assess the effects of lesions to the dopaminergic system and the success of treatment strategies in rat models of Parkinson's disease. While the number of rotations under apomorphine, L-DOPA and amphetamine is related to the extent of dopamine depletion after unilateral 6-hydroxydopamine lesion of the nigrostriatal dopamine system, the relationship of the intensity of rotational behavior to the degree of impairment in motor behavior is unclear. The present study examined this question by correlating rotational behavior and motor abilities in a rat analogue for Parkinson's disease produced by unilateral nigrostriatal bundle lesion with 6-hydroxydopamine. Ipsiversive and contraversive rotation was measured in the rats following systemic administration of low and high doses of apomorphine, the dopamine precursor L-DOPA, and amphetamine. The motor assessment included end point and qualitative measures of fore- and hindlimbs assessed in a skilled reaching task and a skilled ladder rung walking task. The intensity of drug-induced rotation did not correlate with the measures of motor performance. We conclude that independence of rotational behavior and motor performance argues that both the assessment of 6-hydroxydopamine behavioral deficits and potential treatments for the functional deficits require comprehensive assessment, including both measures of rotation and motor behavior.

Amphetamine↗

PubMed2001

Locomotor recovery in spinal cord-injured rats treated with an antibody neutralizing the myelin-associated neurite growth inhibitor Nogo-A.

The limited plastic and regenerative capabilities of axons in the adult mammalian CNS can be enhanced by the application of a monoclonal antibody (mAb), IN-1, raised against the myelin-associated neurite growth inhibitor Nogo-A. The aim of the present study was to investigate the effects of this treatment on the functional recovery of adult rats with a dorsal over-hemisection of the spinal cord. Directly after injury, half of the animals were implanted with mAb IN-1-secreting hybridoma cells, whereas the others received cells secreting a control antibody (anti-HRP). A broad spectrum of locomotor tests (open field locomotor) score, grid walk, misstep withdrawal response, narrow-beam crossing) was used to characterize locomotor recovery during the 5 weeks after the injury. In all behavioral tests, the recovery in the mAb IN-1-treated group was significantly augmented compared with the control antibody-treated rats. EMG recordings of flexor and extensor muscles during treadmill walking confirmed the improvement of the locomotor pattern in the mAb IN-1-treated rats; step-cycle duration, rhythmicity, and coupling of the hindlimbs were significantly improved. No differences between the two groups with regard to nociception were observed in the tail flick test 5 weeks after the operation. These results indicating improved functional recovery suggest that the increased plastic and regenerative capabilities of the CNS after Nogo-A neutralization result in a functionally meaningful rewiring of the motor systems.

Animals↗

PubMed2001

The pasta matrix reaching task: a simple test for measuring skilled reaching distance, direction, and dexterity in rats.

Skilled forelimb use has been used in many studies to examine motor system status, learning, and recovery from nervous system damage in rats. The dependent measures in many current skilled reaching models rely on endpoint measures, number of successful reaches, or qualitative measures, the movements used in performing a reach. The present study describes a new reaching task, which allows measurement of distance and direction of skilled forelimb movement while also permitting end point and qualitative measurements. Animals reached from a clear Plexiglas box through an aperture to retrieve pieces of straight, uncooked pasta from an array of 260 vertically oriented pieces of pasta arranged in rows distally and laterally away from the aperture (a matrix). By extending the range of a reach, more pasta is obtained. Limb movements, pieces of pasta removed, and the pattern of pasta removal are dependent measures. The usefulness of the test is demonstrated using control, dorsal column lesion, and unilateral dopamine depleted animals. The task uses a desired food, tests learning and skill, the range of limb movement, and the ability to reach for different distances and directions. The task can also be modified to investigate other features of limb use including skill adjustments, laterality, and force.

Adrenergic Agents↗

PubMed2001

Accelerated nervous system development contributes to behavioral efficiency in the laboratory mouse: a behavioral review and theoretical proposal.

The emergence of the laboratory mouse as a favored species for genetic research has posed a number of problems for scientists interested in the reflection of genetic influences in mouse behavior. It is commonly thought that rat behavior, which has been studied more extensively than mouse behavior, could be easily generalized to mice. In this article, a number of categories of behavior displayed by the mouse (motor, spatial, defensive, social) are reviewed and contrasted with the same categories of behavior displayed by the rat. The comparison suggests that mouse behavior is simpler and more dependent upon elementary actions than the behavior of the rat. We suggest that the behavioral simplification in the mouse adapts it for a different ecological niche than that occupied by the rat. We propose that this simplification may be mediated by accelerated brain maturation during development. We further propose that this developmental acceleration in the mouse renders it less dependent upon complex social behavior and plastic nervous system changes associated with learning than the rat. This difference poses problems for the development of relevant methods of behavioral analysis and interpretation. Since the mouse's biological adaptations will be reflected in laboratory behavior, suggestions are made for behavioral approaches to the study and interpretation of mouse behavior.

Animals↗

PubMed2001

The effects of acute and chronic stress on motor and sensory performance in male Lewis rats.

Any behavioral testing induces stress to some degree. A meaningful interpretation of behavioral results can be difficult if stress, caused by handling or the testing situation, modifies the experimental outcome. Especially for neurological animal models, it is important to know how stress affects motor and sensory performance. Therefore, we investigated the effects of varying degrees of stress on several motor and sensory tasks that are frequently used to assess functional recovery after lesion-induced impairments in adult rats. Acute, subchronic, and chronic stress impaired ladder walking and prolonged the duration of grasping a bar. Stress also altered walking patterns by increasing the base of support and foot rotation and reducing stride length. Furthermore, chronic stress induced hypersensitivity to painful stimuli, but did not significantly influence the latency to remove sticky papers from the hindpaws (sticky paper test). In the light--dark (L/D) test, stress reduced the latency to enter the dark compartment and enhanced the number of transitions supporting that cold swim stress modifies the animal's level of anxiety. These data point towards a critical influence of acute or chronic stress on motor control and sensory performance of rats, suggesting that stress might be a critical intervening variable of the outcome of behavioral tests.

Acute Disease↗

PubMed2001

Chronic levodopa therapy does not improve skilled reach accuracy or reach range on a pasta matrix reaching task in 6-OHDA dopamine-depleted (hemi-Parkinson analogue) rats.

L-dopa therapy reverses some but not all of the motor deficits in human Parkinson patients. Although a number rat analogues of human Parkinson's disease have been developed for evaluating the efficacy of drug therapies, it is not known whether L-dopa has a similar selective action on the motor symptoms in the rat models. To examine the effectiveness of L-dopa in reversing the motor deficits in rats, we administered 6-OHDA unilaterally to produce hemi-Parkinson rats, which were then trained to reach for food using either their impaired (contralateral to the lesion) limb or their good (ipsilateral to the lesion) limb. To assess the skill, accuracy and range of limb movement, rats reached for pasta from a horizontal array of 260 vertically orientated pieces of pasta. The number and location of pasta pieces taken from this matrix was calculated and the qualitative aspects of the reaching movements were rated. The quantitative data on pasta sticks retrieved indicated that forelimb extension and movement radius around the shoulder joint was reduced by 6-OHDA treatment and did not improve after chronic L-dopa treatment. The qualitative analysis showed that grasping patterns, paw movements and body movements impaired by the lesion were also not improved by L-dopa treatment. These findings are the first in the rat to suggest that whereas L-dopa has a general activating effect on the rat's whole-body movements, as displayed in contralateral rotation, its effectiveness does not extend to skilled forelimb movements. The results are discussed in relationship to the idea that the restoration of some skilled movements may require normal synaptic function.

Animals↗

PubMed2000

Skilled reaching an action pattern: stability in rat (Rattus norvegicus) grasping movements as a function of changing food pellet size.

Many animals in different mammalian orders display skilled forelimb use for prehension, but there has been little study of the rules underlying skilled forelimb use that may provide insight into its neural organization. Inflexibility of movement would imply an underlying fixed neural control characteristic of innate action pattern, whereas flexibility of movement would imply more plastic neural control. In the present study, rat reaching was examined by analyzing movements used to obtain nine different sized food pellets, weighing between 20 and 1000 mg. The prediction was that if the rats' reaching movements were flexible, then systematic modifications in reaching would occur as food pellet size changed; whereas if reaching was inflexible, disruptions should occur for extreme food pellet sizes. Reaching was filmed using normal (30 frames/s) and high-speed (60 frames/s) video-recording procedures. Behavior was scored in terms of successful reaches and, in addition, a new rating scale, derived from Eshkol-Wachman Movement Notation, was used to evaluate the qualitative aspects of movement. Reaching success was stable across smaller food pellet sizes but dropped sharply for larger food pellets sizes. Qualitative analysis of limb movements revealed that animals were unable to change their typical movement sequence to obtain the larger pellets. This result indicates that rat skilled reaching is relatively inflexible, supporting the position that it is produced by a complex, relatively fixed neural circuitry. This finding is discussed in relation to the evolution of skilled reaching, the modifications of skilled reaching that are observed after motor cortex and other nervous system injuries, and comparative differences in reaching in rats and primates.

Animals↗

PubMed2000

Efficient testing of motor function in spinal cord injured rats.

In experimental spinal cord injury studies, animal models are widely used to examine anatomical and functional changes after different treatments and lesion types. A variety of behavioral paradigms exists in the literature, but definitions and criteria for motor performance vary considerably. In this study, we examined the outcome and relation of tests such as the BBB open field locomotion score, footprint analysis, kinematic analysis, placing response, grid walk and narrow beam crossing following two different lesion types. The information obtained was used to design an efficient and reliable testing strategy, which includes a broad spectrum of parameters to enhance sensitivity. This approach should help to standardize modular testing procedures across different laboratories working on spinal cord injury.

Animals↗

PubMed2000

Compensatory sprouting and impulse rerouting after unilateral pyramidal tract lesion in neonatal rats.

After lesions of the developing mammalian CNS, structural plasticity and functional recovery are much more pronounced than in the mature CNS. We investigated the anatomical reorganization of the corticofugal projections rostral to a unilateral lesion of the corticospinal tract at the level of the medullary pyramid (pyramidotomy) and the contribution of this reorganization and other descending systems to functional recovery. Two-day-old (P2) and adult rats underwent a unilateral pyramidotomy. Three months later the corticofugal projections to the red nucleus and the pons were analyzed; a relatively large number of corticorubral and corticopontine fibers from the lesioned side had crossed the midline and established an additional contralateral innervation of the red nucleus and the pons. Such anatomical changes were not seen after adult lesions. Intracortical microstimulation of the primary motor cortex with EMG recordings of the elbow flexor muscles were used to investigate possible new functional connections from the motor cortex of the pyramidotomy side to the periphery. In rats lesioned as adults, stimulation of the motor cortex ipsilateral to the pyramidotomy never elicited EMG activity. In contrast, in P2 lesioned rats bilateral forelimb EMGs were found. EMG latencies were comparable for the ipsilateral and contralateral responses but were significantly longer than in unlesioned animals. Transient inactivation of both red nuclei with the GABA receptor agonist muscimol led to a complete loss of these bilateral movements. Movements and EMGs reappeared after wash-out of the drug. These results suggest an important role of the red nucleus in the reconnection of the cortex to the periphery after pyramidotomy.

Afferent Pathways↗

PubMed2000

Treadmill training in incomplete spinal cord injured rats.

Treadmill training has been shown to accelerate locomotor recovery and to improve weight bearing during treadmill walking in spinal cats. In human patients treadmill training is increasingly used in rehabilitation after incomplete spinal cord injury. In this study we examined training effects in spinal cord injured rats with an incomplete dorsal lesion. Recovery was examined with an open field locomotor score, kinematic analysis on the treadmill, and several functional tests (i.e. foot print evaluation, narrow beam crossing, grid walking, open field exploratory activity). During the course of 5 weeks after the injury, a substantial amount of recovery occurred in the treadmill trained as well as in the untrained rats. If compared to the control lesioned rats, which showed a high level of spontaneous hindlimb movements at 7-14 days post lesion, no additional beneficial effect of a 5-week daily treadmill training on the locomotor outcome could be detected in the trained group. The only change observed was a slightly larger exploratory activity of the trained rats. It is probable that the spared ventral and ventro-lateral fibers allowed spontaneous recovery and 'self-training' to occur to such an extend that systematic treadmill training did not provide additional improvement.

Animals↗

PubMed2000

Validation of the weight-drop contusion model in rats: a comparative study of human spinal cord injury.

Animal models are widely used for studying the pathophysiology as well as treatment strategies for injuries of the central nervous system. However, it is still unclear in how far the rat model of spinal cord injury (SCI) is valid for human SCI. Therefore, comparisons were made among functional, electrophysiological, and morphological outcome parameters following SCI in rats and humans. Contusion of the mid-thoracic spinal cord in 27 adult rats was induced by a weight-drop, leading to severe deficits in open field locomotion at a chronic stage. The data of 85 human patients with chronic SCI were collected and compared with the rat data. In electrophysiological recordings, prolonged latencies and reduced amplitudes in both motor evoked potentials (MEP) and somatosensory evoked potentials (SSEP) were closely correlated to the impairment of locomotor capacity of lower limbs in rats and humans. The morphological parameters assessed by high-resolution magnetic resonance imaging (MRI) in both species indicated that the lesion length and spinal cord atrophy were significantly related to the electrophysiological and functional outcome parameters. In rats, histological analysis was performed and showed, in addition to the MRI, a close relationship between spared white matter and locomotor capacity. Our results suggest an analogous relationship in rats and humans with respect to functional, electrophysiological, and morphological outcomes. Thus, the techniques for evaluating the extent and severity of SCI in humans and rats are of comparable value. This indicates that the rat can serve as an adequate animal model for research on functional and morphological changes after SCI and the effects of new treatment strategies.

Adolescent↗

PubMed1998

Functional recovery and enhanced corticofugal plasticity after unilateral pyramidal tract lesion and blockade of myelin-associated neurite growth inhibitors in adult rats.

After a lesion of the mature CNS, structural plasticity and functional recovery are very limited, in contrast to the developing CNS. The postnatal decrease in plasticity is correlated in time with the formation of myelin. To investigate the possible role of an important myelin-associated neurite growth inhibitor (NI-250; IN-1 antigen), one pyramidal tract of adult Lewis rats was lesioned (pyramidotomy), and the rats were treated with the antibody IN-1, a control antibody, or no antibody. Functional recovery was studied from postoperative day 14 until day 42 using a food pellet reaching task, rope climbing, and a grid walk paradigm. The corticofugal projections to the red nucleus and basilar pontine nuclei were analyzed after survival times of 2 and 16 weeks. Treatment with the monoclonal antibody IN-1 resulted in almost complete restoration of skilled forelimb use, whereas all the control groups showed severe and chronic impairments. This functional recovery was paralleled by sprouting of the corticorubral and the corticopontine fibers across the midline, thus establishing a bilateral, anatomically specific projection.

Animals↗

PubMed1998

Regeneration and sprouting of chronically injured corticospinal tract fibers in adult rats promoted by NT-3 and the mAb IN-1, which neutralizes myelin-associated neurite growth inhibitors.

Myelin-associated inhibitors of neurite growth play an important role in the regenerative failure after injury in the adult mammalian CNS. The application of the mAb IN-1, which efficiently neutralizes the NI-250/35 inhibitory proteins, alone or in combination with neurotrophin-3 (NT-3), has been shown to promote axonal regeneration when applied in acute injury models. To test whether IN-1 application can induce axonal growth also in a chronic injury model, we treated rats with IN-1 and NT-3 starting 2 or 8 weeks after injury. Rats underwent bilateral dorsal hemisection of the spinal cord at the age of 5-6 weeks. Regeneration of corticospinal (CST) fibers into the caudal spinal cord was observed in three of eight of those animals with a 2-week delay between lesion and treatment. CST fibers regenerated for 2-11.4 mm. In the control group sprouting occurred rostral to the lesion but no long-distance regeneration occurred. In animals where treatment started at 8 weeks after injury the longest fibers observed grew up to 2 mm into the caudal spinal cord. The results show that transected corticospinal axons retain the ability to regenerate at least for a few weeks after injury. Functional analysis of these animals showed a slight improvement of functional recovery.

Animals↗

PubMed1998

The effects of unilateral pyramidal tract section on hindlimb motor performance in the rat.

Most investigations on selective lesions of the pyramidal tract in rodents have focused on the functional impairment of the forelimbs. This study describes the effects of a unilateral transection of the pyramidal tract rostral to the decussation on hindlimb function. Using kinematic locomotion analysis, the narrow beam test, open field locomotion ranking, analysis of footprints and air righting, we found severe impairments including hypermetria, trunk instability, lateral shifts in weight support, toe dragging, and hindlimb exo-rotation. Most impairments recovered rapidly within the first week after operation. Slight hypermetria persisted after 4 weeks. The rather mild long term deficits after unilateral pyramidotomy may stress the need for extremely sensitive behavioural tasks to enable the detection. We conclude that the possibility to correlate regenerative changes following selective pyramidal tract lesions with hindlimb function is thus limited.

Animals↗

PubMed1998

Neurite growth inhibitors restrict plasticity and functional recovery following corticospinal tract lesions.

Anatomical plasticity and functional recovery after lesions of the rodent corticospinal tract (CST) decrease postnatally in parallel with myelin formation. Myelin-associated neurite growth inhibitory proteins prevent regenerative fiber growth, but whether they also prevent reactive sprouting of unlesioned fibers is less clear. Here we show that after unilateral CST lesion in the adult rat brainstem, both intact and lesioned tracts show topographically appropriate sprouting after treatment with a monoclonal antibody that neutralizes these inhibitory proteins. Antibody-treated animals showed full recovery in motor and sensory tests, whereas untreated lesioned rats exhibited persistent severe deficits. Neutralization of myelin-associated neurite growth inhibitors thus restores in adults the structural plasticity and functional recovery normally found only at perinatal ages.

Animals↗