Claudia L. R. Gonzalez

A comparison of different models of stroke on behaviour and brain morphology

We compared the effects of three models of permanent ischemia, as well as cortical aspiration, on behaviour and brain morphology. Rats received a stroke either by devascularization or by two different procedures of medial cerebral artery occlusion (MCAO; small vs. large). Animals were trained in a reaching task, forepaw asymmetry, forepaw inhibition, sunflower seed task and tongue extension. Behaviour was assessed 1 week after the lesion and at 2‐week intervals for a total of 9 weeks. One week after the surgery all animals were severely impaired on all tasks and although they improved over time they only reached preoperative base lines on tongue extension. Animals with small MCAOs performed better in reaching and sunflower tasks; no other behavioural differences were detected among the groups. Pyramidal cells in forelimb and cingulate areas as well as spiny neurons of the striatum were examined for dendritic branching and spine density using a Golgi–Cox procedure. Each lesion type had a different impact on cell morphology. Overall, different changes (atrophy or hypertrophy) were observed with each kind of lesion and these changes were specific for the region (forelimb, cingulate, striatum) and the condition (intact vs. damaged hemisphere). These results suggest that: (i) different lesions to the motor cortex produce subtle differences in behaviour, and (ii) the method used to induce the lesion produces striking differences in cortical and subcortical plasticity.

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.

Evidence for bilateral control of skilled movements: ipsilateral skilled forelimb reaching deficits and functional recovery in rats follow motor cortex and lateral frontal cortex lesions.

Unilateral damage to cortical areas in the frontal cortex produces sensorimotor deficits on the side contralateral to the lesion. Although there are anecdotal reports of bilateral deficits after stroke in humans and in experimental animals, little is known of the effects of unilateral lesions on the same side of the body. The objective of the present study was to make a systematic examination of the motor skills of the ipsilateral forelimb after frontal cortex lesions to either the motor cortex by devascularization of the surface blood vessels (pial stroke), or to the lateral cortex by electrocoagulation of the distal branches of the middle cerebral artery (MCA stroke). Plastic processes in the intact hemisphere were documented using Golgi–Cox dendritic analysis and by intracortical microstimulation analysis. Although tests of reflexive responses in forelimb placing identified a contralateral motor impairment following both cortical lesions, quantitative and qualitative measures of skilled reaching identified a severe ipsilateral impairment from which recovery was substantial but incomplete. Golgi‐impregnated pyramidal cells in the forelimb area showed an increase in dendritic length and branching. Electrophysiological mapping showed normal size forelimb representations in the lesioned rats relative to control animals. The finding of an enduring ipsilateral impairment in skilled movement is consistent with a large but more anecdotal literature in rats, nonhuman primates and humans, and suggests that plastic changes in the intact hemisphere are related to that hemispheres contribution to skilled movement.

Skilled reaching impairments from the lateral frontal cortex component of middle cerebral artery stroke: a qualitative and quantitative comparison to focal motor cortex lesions in rats

The classical approach to investigating brain contributions to behavior has been to localize function to a region. In clinical investigations, however, injury is frequently multifocal, raising the question of how individual brain regions contribute to a resulting behavioral syndrome. For example, middle cerebral artery (MCA) ischemia in humans can concurrently damage a number of cortical and subcortical areas and the same areas are damaged in rat models of MCA stroke. In the rat, MCA occlusion produces severe motor deficits, but the cortical area of damage is the lateral neocortex, sparing motor cortex. This anatomical finding raises the question of whether the rat lateral neocortex contributes to MCA-related motor impairments, a question that was investigated in the present study. Rats received unilateral neocortical lesions via electrocoagulation of the MCA and were compared to rats with standard motor cortex lesions produced by devascaulrization of the overlaying blood vessels. The MCA group was as impaired as the motor cortex group in skilled reaching movements as assessed by quantitative measures of the contralateral-to-lesion forelimb in a single pellet task and in a tray-reaching task. Although there was improvement in success scores over a 2-week period in both groups, the groups were characterized by distinctive and enduring qualitative impairments. The motor cortex deficit was exemplified by use of trunk musculature and head movements to assist the reaching limb while the MCA impairment included sensory abnormalities. The results are discussed in relation to the contribution of lateral frontal cortex injury to MCA stroke sensorimotor syndromes.

Middle cerebral artery (MCA) stroke produces dysfunction in adjacent motor cortex as detected by intracortical microstimulation in rats.

Middle cerebral artery (MCA) stroke in the rat produces impairments in skilled movements. The lesion damages lateral neocortex but spares primary motor cortex (M1), raising the question of the origin of skilled movement deficits. Here, the behavioral deficits of MCA stroke were identified and then M1 was examined neurophysiologically and neuroanatomically. Rats were trained on a food skilled reaching task then the lateral frontal cortex was damaged by unilateral MCA electrocoagulation contralateral to the reaching forelimb. Reach testing and training on two tasks was conducted over 30 post-surgical days. Later, M1 and the corticospinal tract were investigated using intracortical microstimulation (ICMS), anterograde and retrograde axon tracing. A skilled reaching impairment was observed post-surgery, which partly recovered with time and training. ICMS revealed a diminished forelimb movement representation in MCA rats, but a face representation comparable in size to sham rats. Anterograde and retrograde tract tracing suggest that M1 efferents were intact. Although M1 appears to be in the main anatomically spared after MCA stroke its function as assessed electrophysiologically and behaviorally is disrupted.

Chronic low-dose administration of nicotine facilitates recovery and synaptic change after focal ischemia in rats

The current study examines the effects of chronic administration of nicotine on motor behavior after focal stroke in rats. Animals were trained in a tray-reaching task for 2weeks and then they were divided into: (1) control+saline (2) control+nicotine (3) stroke+saline, and (4) stroke+nicotine groups. Lesions were produced by devascularization of the surface blood vessels of the sensorimotor cortex contralateral to the forepaw used for reaching. Forty-eight hours after the lesions, and for a total of 12days, animals received two daily injections of either nicotine (0.3mg/kg) or saline (0.9%). Animals were tested in a motor battery 1week after the lesions and every other week for a total of 7weeks. Pyramidal cells in forelimb and cingulate areas were then examined for dendritic length and branching using a Golgi-Cox procedure. Behavioral results demonstrated that by the end of the testing stroke+nicotine animals showed significant behavioral improvement relative to stroke+saline animals. Stroke+nicotine animals showed an increase in dendritic length and branching in pyramidal cells of the forelimb and cingulate areas. The results suggest that the behavioral enhancement in the stroke+nicotine group might be attributable to the enhanced dendritic growth in residual cortical motor regions.

Nicotine improves Morris water task performance in rats given medial frontal cortex lesions

The object of this study was to investigate whether nicotine would improve cognitive impairments produced by medial frontal cortex lesions in rats behaviorally tested on the Morris water task (MWT). Rats were assigned to either a lesion or sham group. In the lesion group, animals were given vehicle (peanut oil) treatment or treatment with nicotine for 11 consecutive days before, after, or before and after a medial frontal cortex lesion. Additionally, a sham group was included that was given vehicle both before and after the lesion. Results showed that lesioned rats receiving pre- or post-operative nicotine treatment demonstrated improved Morris task acquisition performance relative to the lesioned group given the vehicle, although a deficit was shown relative to shams. On the probe trial, rats that received a pre- and post-treatment of nicotine demonstrated performance equivalent to shams and had significantly better performance than rats that received nicotine treatment before the lesion and lesioned animals treated with the vehicle. These results demonstrate that nicotine has therapeutic effects in rats that have received cortical injury.

Hand use for grasping in a bimanual task: evidence for different roles?

It has been proposed that the two hands play different roles during bimanual object interaction. The right hand takes on an explorative, highly precise, manipulative role while the left hand supports and stabilizes the object. Does this division of labour influence hand use during visually guided grasping? Three experiments were designed to address this question: right-handed individuals put together 3D models using big or small building blocks scattered across a tabletop. Participants were free to build the models; however, it felt comfortable (Experiment 1) or they were required to build on a large (Experiment 2) or small (Experiment 3) base plate. In Experiment 1, the right hand was preferred for grasping while the left hand stabilized the building model. When participants used the large base plate (Experiment 2), right hand use for grasping decreased and left hand use increased. The plate provided freedom to the left hand from having to stabilize the building model, but it also interfered with right/left hand movements directed towards the opposite side of the grasping hand (contralateral movements). To investigate which of these two factors would explain the change in hand use for grasping, a very small base plate was used in the last experiment. Results showed similar right hand use values to those seen in the first experiment (without the use of a plate), even though the left hand was ‘released from its stabilizing duties.’ The results predict a left-hemisphere right hand advantage in the control of grasping.

Tactile stimulation promotes motor recovery following cortical injury in adult rats.

Tactile stimulation has been reported to be effective as a treatment for inducing growth in premature human babies and infant rats and for improving functional recovery after brain injury in infant rats. We wondered if the behavioral impairments following injury in adulthood would show similar improvements with tactile stimulation. To test this hypothesis, rats were given either bilateral medial frontal cortex aspiration lesions or a unilateral focal stroke produced in the sensorimotor cortex using the pial stripping technique. In both conditions, rats that were designated to the tactile stimulation treatment group received the stimulation for one week before the surgery to accustom them to the stimulation procedure and then two weeks postoperatively. After a three-week recovery period, the animals with frontal damage were tested in a tray-reaching task. Animals with sensorimotor cortex damage were tested in a single pellet reaching task. Following behavioral testing brains were processed for Golgi-Cox analyses. Marked improvement was found in motor performance in the lesion-tactile stimulation animals regardless of the nature of the cortical injury. The observed behavioral recovery was associated with an increase in dendritic length in pyramidal cells adjacent cortex in the frontal operates and in the intact sensorimotor cortex in the stroke animals. Taken together, these data show tactile stimulation can improve motor performance in adult animals and the improvement is correlated with dendritic sprouting. This finding could have implications for therapy in humans following stroke.

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.