Biomedical subjects

I Q Whishaw

Publications and source records attributed to I Q Whishaw.

At least 19 recordsLinked to original sources

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

Dead reckoning (path integration) requires the hippocampal formation: evidence from spontaneous exploration and spatial learning tasks in light (allothetic) and dark (idiothetic) tests.

Animals navigate using cues generated by their own movements (self-movement cues or idiothetic cues), as well as the cues they encounter in their environment (distal cues or allothetic cues). Animals use these cues to navigate in two different ways. When dead reckoning (deduced reckoning or path integration), they integrate self-movement cues over time to locate a present position or to return to a starting location. When piloting, they use allothetic cues as beacons, or they use the relational properties of allothetic cues to locate places in space. The neural structures involved in cue use and navigational strategies are still poorly understood, although considerable attention is directed toward the contributions of the hippocampal formation (hippocampus and associated pathways and structures, including the fimbria-fornix and the retrosplenial cortex). In the present study, using tests in allothetic and idiothetic paradigms, we present four lines of evidence to support the hypothesis that the hippocampal formation plays a central role in dead reckoning. (1) Control but not fimbria-fornix lesion rats can return to a novel refuge location in both light and dark (infrared) food carrying tasks. (2). Control but not fimbria-fornix lesion rats make periodic direct high velocity returns to a starting location in both light and dark exploratory tests. Control but not fimbria-fornix rats trained in the light to carry food from a fixed location to a refuge are able to maintain accurate outward and homebound trajectories when tested in the dark. (3). Control but not fimbria-fornix rats are able to correct an outward trajectory to a food source when the food source is moved when allothetic cues are present. These, tests of spontaneous exploration and foraging suggest a role for the hippocampal formation in dead reckoning.

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

Nicotine improvement of Morris water task performance after fimbria-fornix lesion is blocked by mecamylamine.

The focus of this study was to analyze the effects of nicotine on behavioural compensation after fimbria-fornix (FF) lesions in rats tested on the Morris water task (MWT). Nicotine (0.3 mg/kg) was injected subcutaneously for 11 consecutive days before, for 11 consecutive days after, or for 11 consecutive days before and after a FF lesion. Additionally, a lesion group was included that was given mecamylamine (1.0 mg/kg), a nicotine antagonist, 10 min before nicotine administration as well as mecamylamine-only, no treatment lesion, and sham groups. All drug administration ceased 24 h before three consecutive days of behavioural testing on the MWT. Results showed that the sham group and animals receiving both a pre- and post-lesion treatment of nicotine performed significantly better than all other groups, and the pre- and post-lesion nicotine group performed equivalent to sham controls on both acquisition and a probe trial. The compensatory effect of nicotine was blocked by mecamylamine. This study demonstrates that nicotine stimulates recovery from brain damage and the results are discussed in relation to neural mechanisms and potential applications.

Animals↗

PubMed2001

A grasp-related deficit in tactile discrimination following dorsal column lesion in the rat.

The dorsal columns of the spinal cord are a major source of haptic (sense of active touch) and proprioceptive input to the brainstem and sensory-motor cortex. Following injury in primates, there are impairments in two-point discrimination, direction of movement across the skin, and frequency of vibration, and qualitative control of the digits, but simple spatial discriminations recover. In the rat there are qualitative deficits in paw control in skilled reaching, but no sensory deficits have been reported. Because recent investigations of sensory control suggest that sensory functions may be related to specific actions, the present study investigated whether the dorsal columns contribute to hapsis during food grasping in the rat. Adult female Long-Evans rats were trained to reach with a single forepaw for a piece of uncooked pasta or for equivalent sized but tactually different nonfood items. One group was given lesions of the dorsal column ipsilateral to their preferred paw, while the second group served as a control. Postlesion, both groups were tested for skilled reaching success and force application as well as adhesive dot removal and forepaw placing. Performance levels on these tests were normal. Nevertheless, the rats with dorsal column lesions were unable to discriminate a food item from a tactually distinctive nonfood item as part of the reaching act, suggesting that the dorsal columns are important for on-line tactile discriminations, or "haptic actions," which contribute to the normal performance of grasping actions.

Animals↗

PubMed2001

Deficits in allothetic and idiothetic spatial behavior in rats with posterior cingulate cortex lesions.

The cingulate cortex plays a central role in bridging neocortical and limbic structures involved in allothetic navigation, a form of navigation requiring the use of external cues. Animals can also navigate using idiothetic cues, which are cues generated by self-movement, but there have been no definitive tests of whether cingulate cortex also plays a role in idiothetic navigation. Rats with anterior cingulate (medial frontal) and posterior cingulate cortex (retrosplenial) suction ablations were trained to search for large food pellets on an open table, and the accuracy with which they returned home with the food was measured. In the idiothetic task they searched for food from a novel starting location under infrared light, and with surface olfactory cues displaced. The rats also received two tests of allothetic navigation. They were tested on a matching-to-place task in which they foraged for food from a number of successively presented new locations under normal room light, and they were trained to locate a hidden platform in a swimming pool (Morris place task). The group with posterior cingulate cortex lesions was severely impaired on all of the navigation tasks whereas the group with anterior cingulate cortex lesions displayed no deficit on the idiothetic task and only moderate deficits on the other tasks. The results demonstrate a role for posterior cingulate region in idiothetic navigation.

Animals↗

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

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

Is there an optimal age for recovery from motor cortex lesions? I. Behavioral and anatomical sequelae of bilateral motor cortex lesions in rats on postnatal days 1, 10, and in adulthood.

Rats were given bilateral lesions of the motor cortex on the day of birth (P1), tenth day of life (P10), or in adulthood. They were trained on several motor tasks (skilled forelimb reaching, beam traversing, tongue extension), general motor activity, and a test of spatial learning (Morris water task). Although all lesion groups were impaired at skilled reaching, the P10 group was less impaired than either of the other two lesion groups. Furthermore, on the other motor tests the P10 group did not differ from controls whereas both P1 and adult groups were impaired. Only the P1 lesion group was impaired at the acquisition of the Morris water task. Anatomical analyses revealed that the P1 and P10 rats had smaller brains than the other two groups as well as having a generalized decrease in cortical thickness. Dendritic analysis of layer III pyramidal cells in the parietal cortex revealed a decrease in apical arbor in the lesion groups and an increase in the basilar arbor of the P1 and adult lesion animals. The P1 and adult operated groups showed an increase in spine density in the basilar dendrites of layer V pyramidal cells. Finally, analysis of the pattern of corticospinal projections revealed that the P1 animals had a markedly wider field of corticospinal projection neurons than any of the other groups. The widespread anatomical changes in all lesion groups versus the relatively better behavioral recovery after P10 lesions suggests that day 10 represents an optimal period for adapting to brain damage and subsequent brain reorganization.

Age Factors↗

PubMed2000

Immunosuppression prevents neuronal atrophy in lupus-prone mice: evidence for brain damage induced by autoimmune disease?

An early onset of systemic, lupus-like disease in MRL-lpr mice is accompanied by deterioration in their behavioral performance and atrophy of pyramidal neurons in the parietal cortex and the hippocampal CA1 area. Using the immunosuppressive drug cyclophosphamide (CY) to attenuate the disease, we have tested the hypothesis that the autoimmune/inflammatory process is responsible for changes in brain morphology. A modified Golgi impregnation method revealed that, in comparison to saline-treated controls, immunosuppressive treatment with CY (100 mg/kg/week i.p. over 8 weeks) increased dendritic branching and spine numerical density in the CA1 region of MRL-lpr mice and MRL +/+ mice, which develop less severe manifestations of the disease. More interestingly, CY selectively prevented the atrophy and aberrant morphology of pyramidal neurons in the parietal cortex of MRL-lpr mice. The neuropathological measures (in particular reduced dendritic spine density) significantly correlated with increased serum levels of antinuclear antibodies and splenomegaly. The present results support the hypothesis that chronic autoimmune disease induces functionally important changes in neuronal morphology, and provide an empirical basis for understanding the behavioral dysfunction in systemic lupus erythematosus and autoimmune phenomena reported in some forms of mental illness.

Animals↗

PubMed2000

Regulation of T cell activation, anxiety, and male aggression by RGS2.

Regulators of G protein signaling (RGS) proteins accelerate the GTPase activity of Galpha protein subunits in vitro, negatively regulating G protein-coupled receptor signaling. The physiological role of mammalian RGS proteins is largely unknown. The RGS family member rgs2 was cloned as an immediate early response gene up-regulated in T lymphocytes after activation. To investigate the role of RGS2 in vivo, we generated rgs2-deficient mice. We show that targeted mutation of rgs2 in mice leads to reduced T cell proliferation and IL-2 production, which translates in an impaired antiviral immunity in vivo. Interestingly, rgs2(-/-) mice also display increased anxiety responses and decreased male aggression in the absence of cognitive or motor deficits. RGS2 also controls synaptic development and basal electrical activity in hippocampal CA1 neurons. Thus, RGS2 plays an important role in T cell activation, synapse development in the hippocampus, and emotive behaviors.

Aggression↗

PubMed2000

Cervical motoneuron topography reflects the proximodistal organization of muscles and movements of the rat forelimb: a retrograde carbocyanine dye analysis.

Behavioral evidence reveals that the laboratory rat and other rodent species display skilled paw and digit use in handling food during eating and skilled limb use in reaching for food in formal laboratory skilled reaching tests that is comparable to that described in carnivores and primates. Because less is known about the central control of skilled movements in rodents than in carnivores or primates, the purpose of the current study was to examine the relation between the rat's spinal motoneurons and the individual forelimb muscles that they innervate. In two experiments, 14 forelimb muscles (in the shoulder and the upper and lower arm segments) were injected with carbocyanine dye tracers. The topography of spinal motoneurons was reconstructed by using fluorescence microscopy. Motor neurons were found to be organized in columns throughout the length of the cervical and upper thoracic area, with 1) extensor motoneurons located more laterally than flexor motoneurons, 2) rostral motoneurons innervating more proximal muscles than caudal motoneurons, and 3) more dorsally located motoneurons innervating more distal muscles. These results reveal that the topography of rodent cervical spinal cord motoneurons is very similar to that of carnivores and of primates, which also are characterized by well-developed, skilled movements. In addition, the proximal-distal organization of motoneuron columns parallels the proximal-to-distal pattern of forelimb movement used by the rat when reaching. The data from this study enable the development of predictions about the specific movements that would be compromised by experimental transections or other injuries at different levels of the spinal cord in rat models of spinal injury.

Animals↗

PubMed2000

Loss of the innate cortical engram for action patterns used in skilled reaching and the development of behavioral compensation following motor cortex lesions in the rat.

Damage to the motor cortex of the rat (Rattus norvegicus) impairs skilled movements used in reaching for food with the contralateral forepaw. Nevertheless, there is substantial recovery in success over a two-week postsurgical period. The profile of behavioral recovery is believed to reflect the eventual normalization of behavior, but this idea has not been explicitly examined. The present experiments examined postsurgical reaching success and reaching movements as a function of (1) lesion type, (2) lesion size, (3) lesion location, (4) depletion of forebrain noradrenaline, and (4) presurgical and postsurgical experience. The results show that at least two separate processes contribute to recovery in postsurgical performance. The early postsurgical period was characterized by extreme difficulties in making reaching movements. The experiments suggest that this initial impairment was due to the loss of the innate cortical engram that supports the action patterns used for skilled movements. Subsequent recovery in reaching success was not due to the reacquisition of normal movements, but was due rather to the use of compensatory movements. The results are discussed in relation to the idea that true recovery from motor cortex injury will require that damaged neurons and their connections be rescued or replaced.

Animals↗

PubMed2000

Similarities in the development of place and cue navigation by rats in a swimming pool.

The development of place and cue spatial navigation was evaluated in 18-, 19-, and 20-day-old males in the Morris water task (MWT). Past work has suggested that place and cue learning develop at different rates, suggesting that the two aspects of spatial navigation have different neural substrates. In the present study, a new training methodology was used in which animals received spaced training trials, drying and warming in between trials to maintain body temperature, and two probe trial-dependent measures to evaluate spatial memory performance. All ages of rats had lower latencies on the cue task than on the place task. Nevertheless, 18-day-old rats did not learn either task as measured by acquisition latencies and probe trial-dependent measures. The 19- and 20-day-old rats learned both the place and cue tasks as measured by acquisition latency and direct swims to the correct platform location on the probe trial, and both 19- and 20-day-old rats demonstrated a strong spatial bias to the former platform location on the place probe trial but not on the cue probe trial. The finding that developmental onset of place and cue spatial navigation is rapid and complete by day 19 is discussed in relation to contemporary theories of spatial navigation.

Aging↗

PubMed2000

On the origin of skilled forelimb movements.

Homologizing behaviour was once considered unreliable, but the application of modern comparative methods has been shown to provide strong evidence of behavioural homologies. Skilled forelimb movements were thought to originate in the primate lineage but in fact are common among tetrapod taxa and probably share a common origin in early tetrapods. Furthermore, skilled movements are likely to have been derived from, and elaborated through, food-handling behaviour. In addition, it is now thought that the role played by the lateral and medial descending pathways of the spinal cord in the execution of skilled forelimb movements could be synergistic, rather than the exclusive responsibility of an individual pathway.

Animals↗

PubMed2000

A cautionary note regarding drug and brain lesion studies that use swimming pool tasks: partial reinforcement impairs acquisition of place learning in a swimming pool but not on dry land.

Spatial tasks are used widely in neurobiological studies because it is thought that they provide an unbiased assessment of the integrity of neural structures that mediate spatial learning. For example, in the Morris swimming pool place task, animals are required to locate a hidden platform in a swimming pool in relation to environmental cues. Treatments that result in an animal's failure to find the platform are assumed to reflect defects in the function of neural systems involved in spatial learning. The present study demonstrates, however, that an animal's reinforcement history can contribute to its spatial performance. Animals were trained in the Morris place task with the platform present on 100, 75 or 50% of trials. Relative to the 100% group, the 75% group was impaired in place acquisition, and the 50% group failed to learn. Even placing the 50% group animals onto the platform at the completion of an unsuccessful trial failed to improve acquisition. Animals trained to search for food on an identical dry maze problem were not affected by similar reinforcement schedules. The present findings demonstrate that the Morris swimming pool place task does not provide an unbiased assessment of spatial learning: A treatment effect may be confounded with reinforcement history. The results are discussed in relation to widespread applications of the Morris place task to neurobiological problems.

Analysis of Variance↗

PubMed2000

The Dalila effect: C57BL6 mice barber whiskers by plucking.

Group-housed laboratory mice are frequently found with their whiskers and facial hair removed. It has been proposed that dominant mice are responsible for barbering the hair of the recipient (the Dalila effect), and early studies suggest that the hair is removed by nibbling. In the present study, pairs of C57BL6 mice, composed of a barber and recipient, were separated to allow hair to regrow. The animals were then placed together in an observation box and their social behavior was videorecorded. The videorecording was subjected to frame-by-frame analysis. Barbering was found to occur during acts of mutual grooming. During grooming, one member of a mouse pair removed the vibrissae of the conspecific and did so by grasping individual whiskers with the incisors and plucking them out. Although plucking appeared 'painful', recipients were passive in accepting barbering, and even pursued conspecifics for further grooming. Other measures indicated that barbers were heavier than recipients and brain weights were not different. Although cortical barrel fields appeared normal to cytochrome oxidization and zinc staining, Golgi analysis of layer three, barrel-field basilar dendrites indicated changes in cell morphology. The results are discussed in relation to the hypothesis that barbering is an expression of social dominance, the origins of the barbering behavior, and the consequences of barbering on brain function.

Animals↗