Biomedical subjects

R Lalonde

Publications and source records attributed to R Lalonde.

At least 55 records · Page 3Linked to original sources

PubMed2002

Biochemical and autoradiographic studies of the central noradrenergic system in dystonia musculorum mutant mice.

The autosomal recessive mutation dystonia musculorum (dt(J)/dt(J)) causes degenerative alterations of peripheral and central sensory pathways leading to ataxia. To determine the consequences of this pathology on the central noradrenergic (NA) system, NA contents were measured by high-performance liquid chromatography (HPLC) in 22 brain regions and spinal cord, while NA transporters, or uptake sites, were evaluated by quantitative ligand binding autoradiography, using [3H]nisoxetine, in wild-type and dt(J)/dt(J) mutant mice. The only significant differences in NA contents between the two genotypes were increased levels in hypothalamus and mesencephalic dopaminergic regions A9/A10 of dt(J)/dt(J) mutants. The dt(J)/dt(J) spinal cord showed a similar result, but its NA content remained unchanged when taking into account its reduced volume. Binding to NA transporters revealed increased densities in sensory nuclei of cranial nerves, granular layer of the cerebellar cortex, as well as in cerebellar-related and basal ganglia structures, such as the lateral cuneate nucleus, pontine nuclei, substantia nigra, pontine reticular formation, median raphe nucleus and superior colliculus. Forebrain regions were relatively unaffected in the dt(J)/dt(J) mutants, although NA transporter densities were higher in piriform cortex, hippocampal subdivisions and ventro-anterior thalamic nucleus. In contrast, densities of NA transporters were decreased in hypothalamic subregions and in two ventrobasal thalamic nuclei. The results are discussed in relation to expression of the dystonin gene in normal brain, cellular defects resulting from the loss of gene transcription in the dt(J)/dt(J) mutation, functional circuits of the central nervous system and some of the phenotypical characteristics of dystonia musculorum mutants.

Animals↗

PubMed2001

Motor performance and regional brain metabolism of spontaneous murine mutations with cerebellar atrophy.

Three spontaneous mutations with cerebellar atrophy were evaluated for motor coordination and regional brain metabolism, as assessed by cytochrome oxidase (CO) activity. Despite similar neuropathological characteristics, the behavioral phenotype of Lurcher is less severe than that of staggerer, possibly caused by the slower onset of their neuronal degeneration. Although fewer cerebellar cells degenerate in hot-foot than in Lurcher, their motor deficits are more severe, indicating the presence of dysfunctional cells. CO activity in the deep cerebellar nuclei was increased in Lurcher and staggerer but unchanged in hot-foot, probably due to the severe loss of GABAergic input from Purkinje cells in the first two mutants but not the third. Altered CO activity in cerebellar-related pathways was linearly correlated with motor performance, indicating that the activity of this enzyme is associated not only with neuronal activity but also with motor performance.

Animals↗

PubMed2001

Longitudinal analysis of motor activity and coordination, anxiety, and spatial learning in mice with altered blood pressure.

Mice with either high or low blood pressure (BP) were compared to normotensive controls at 2 and 12 months of age for motor activity, equilibrium, anxiety, and spatial learning. Irrespective of age, high BP mice were more active in an open field than normotensive controls, whereas low BP mice were hypoactive at 2 months of age. High BP mice had a higher number of entries and a longer duration of visits in the open arms, a higher open arm/total arm ratio, a longer duration for the first visit into an open arm, and lower latencies before entering the first open arm than controls in the elevated +-maze, indicative of reduced anxiety. Reduced levels of anxiety were also displayed by low BP mice for the duration of the first open arm visit (both age groups) and for the time spent in the open arms (older group). In the motor coordination test (coat-hanger), high BP mice had higher two-paw movement time and reached the top of the apparatus on fewer occasions than controls. Both groups with abnormal BP values were deficient during visuomotor guidance in the water maze. These results indicate strain-, age-, and test-specific abnormalities in mice with uncontrolled hypertension or hypotension.

Aging↗

PubMed2001

Cytochrome oxidase activity in the olfactory system of staggerer mutant mice.

The staggerer mutation is characterized by the disruption of a single recessive gene encoding for the nuclear hormone receptor RORalpha. In addition to the well-studied gene expression in the cerebellum causing massive primary Purkinje cell loss, the RORalpha gene is also expressed in the thalamus and the olfactory bulb. A quantitative histochemical study of cytochrome oxidase activity was performed in staggerer mutants and their respective controls in order to determine whether olfactory bulb neuropathology leads to neuronal metabolic alterations in olfactory and related limbic regions. In the staggerer olfactory bulb, the core and the shell of the glomeruli had lower levels of cytochrome activity, whereas higher levels were found in the external plexiform and granular layers. Other olfactory and limbic regions were unchanged, except for a higher level in the accessory olfactory bulb and a lower level in the most ventral part of the medial orbital cortex. These results are discussed with regard to the olfactory deficits and changes in social interactions previously observed in this mutant.

Animals↗

PubMed2001

Effects of dentate nucleus lesions on spatial and postural sensorimotor learning in rats.

The role of the dentate nucleus on spatial orientation, assessed by the Morris water maze test, and on postural sensorimotor performance, assessed by vertical grid, suspended wire, and rotorod tests, was investigated. Bilateral electrolytic lesions of the dentate nucleus slowed down the acquisition of the hidden platform task of the Morris water maze, without affecting long-term retention, the probe trial, and the visuomotor guidance necessary for swimming toward a visible goal. In addition, reversal learning was impaired in the submerged platform condition. The lesions did not affect any of the motor performance scores. The selective impairment seen during acquisition of the hidden platform task is similar to that previously reported in rats with combined lesions of the cerebellar hemispheres and dentate, indicating a specific role for this region in spatial orientation.

Animals↗

PubMed2001

The effects of a mild stressor on spontaneous alternation in mice.

Adult mice of the C57BL/6J strain were subjected to an acute mild stress at different periods before the choice trial of a spontaneous alternation test. The stressful event was either inescapable (forced exploration in a brightly lit open field) or escapable (temporary entries into an adjacent dark chamber). While unstressed control mice alternated above chance in each condition, mice subjected to inescapable stress did not alternate when forced exposure to the open field occurred during the entire retention interval. The same effect was seen when forced exposure to the open field occurred after a post-forced trial delay period. However, no change in the alternation rate was observed when the inescapable stress occurred before the forced trial, or if the delay intervened between the stressful event and the choice trial. The escapable stressful event had no effect on spontaneous alternation. These results indicate the role of cognitive mediation in the behavioral effects of inescapable stress, causing either a retrieval deficit or neophobia.

Analysis of Variance↗

PubMed2001

The effects of the lurcher mutation on object localization, T-maze discrimination, and radial arm maze tasks.

The Lurcher mutation is characterized by degeneration of the cerebellar cortex and cerebellar ataxia. The mutants were compared to littermate controls of the same background strain in three spatial tasks: 1) left-right discrimination in a water-filled T-maze, a reference memory task requiring a win-stay strategy; 2) the radial arm maze, a working memory task requiring a win-shift strategy; 3) object localization, a reference memory task requiring the use of cognitive mapping. Lurcher mutants were impaired in the object localization and radial arm maze tasks but not in the left-right discrimination task. These results indicate that trial-independent tasks and reference memory tasks using cognitive mapping may be particularly vulnerable to cerebellar degeneration.

Animals↗

PubMed2001

Population pharmacokinetics of clinafloxacin in healthy volunteers and patients with infections: experience with heterogeneous pharmacokinetic data.

OBJECTIVE: Clinafloxacin is a new fluoroquinolone antibacterial with inhibitory activity against aerobic, anaerobic and atypical bacterial pathogens. The objectives of this study are to evaluate the pharmacokinetics of clinafloxacin in healthy volunteers and patients with infections and to describe our experience with mixed-effects modelling using heterogeneous pharmacokinetic data. DESIGN AND SETTING: Retrospective analysis of data from phase I to III trials. PATIENTS AND PARTICIPANTS: 204 healthy volunteers and 221 patients with infections. METHODS: Nonlinear mixed-effects modelling (MEM) was used to evaluate 3437 clinafloxacin plasma concentrations collected in 15 phase I to III trials. Models were developed separately for the healthy volunteers and patients, and then for the combined study population. RESULTS: The phase I data were best described with a 2-compartment linear model with first-order absorption. The absorption lag-time and absorption rate constant were 0.24h and 1.17h(-1), respectively. The volumes of distribution were found to be nonlinear functions of body surface area. Estimated creatinine clearance was the most important covariate for systemic clearance (CL). Interoccasion variability (IOV) in CL was observed in the patients in the phase II trial. In the combined study population, the variability in CL was best described by a model including IOV and distinct variabilities for healthy volunteers and patients. CONCLUSION: MEM was useful for evaluating data collected during different phases of drug development for this new fluoroquinolone agent.

Administration, Oral↗

PubMed2001

Event-related potentials for category-specific information during passive viewing of faces and objects.

Normal subjects passively viewed an upright or inverted face or objects during recording of event-related potentials. Face inversion augmented N170 amplitude and latency in the temporal region, but only the latency in the parietal region. The same manipulation slowed down the onset of the P220 and caused disappearance of the N300, whereas none of these effects was seen after object inversion. Item-specific processing of objects was observed, namely disappearance of the N190 and the appearance of a P170 wave in the left posterior hemisphere to one object but not the other. These results are concordant with the hypothesis of category-specific processing during the recognition of faces and objects.

Adult↗

PubMed2001

Electrophysiological correlates of the visual after effect by means of visual evoked potentials.

An attempt was made to determine whether changes of electrical activity could be seen in the posterior cortex during an after image of high frequency luminance gratings. Steady state visual evoked potentials were recorded (midoccipital, right and left temporo-occipital sites) immediately after a period of visual adaptation (15 min) to the stimulus, while the subjects experienced the after image. During this illusion, frequencies of the fast Fourier transform spectra linked to the stimulation differed from the noise and were larger at temporo-occipital sites than at the midoccipital one. In view of these results, the hypothesis that the after effect represents a short term storage of the temporal characteristics of the stimulus is evoked.

Adaptation, Physiological↗

PubMed2001

Associations between a cerebellar motor dysfunction scale and movement initiation and completion in olivopontocerebellar atrophy.

Correlations were drawn between subscores of a cerebellar motor dysfunction (CMD) scale and simple reaction time (RT) and movement time (MT) in patients diagnosed with olivopontocerebellar atrophy (OPCA). Poor performance on CMD subscores was correlated with long disease duration and lengthening of visual and auditory RT and MT, with the motor speed subscore showing the highest correlations. OPCA patients with severe cerebellar HMPAO uptake deficiency on single photon emission computed tomography scans had poorer performances on three of the four subscores (static equilibrium, dynamic equilibrium and nystagmus, and motor speed) than patients with mild deficiency. These results are discussed in terms of the role of cerebellar afferent/efferent pathways on different types of motor dysfunction in patients with cerebellar atrophy.

Adult↗

PubMed2000

Effects of buspirone on brain indoleamines and catecholamines in wild-type mice and Lurcher mutants.

The effects of a chronic serotoninergic stimulation on brain monoamine levels and metabolism were studied in wild-type (+/+) mice and Lurcher (Lc/+) mutants. Endogenous serotonin, dopamine, noradrenaline and some of their major metabolites were measured in the frontal cortex, neostriatum, thalamus, brainstem, cerebellum and spinal cord. In +/+ mice, buspirone (1 mg/kg; i.p.) treatment during 40 days increased indoleamines, albeit with moderate changes in the ratios between tissue serotonin metabolites and endogenous serotonin, augmented noradrenaline contents in the spinal cord, and caused elevations of dopamine metabolites in most regions. In Lc/+ mutants, the effects of buspirone were attenuated, but higher L-tryptophan and indoleamine levels, suggest a storage of serotonin in a non-releasable compartment. In the hypoplastic Lc/+ cerebellum, indoleamine content was accrued, but with a decreased [serotonin metabolites]/[serotonin] ratio, indicating that the reorganized nerve terminals in Lc/+ mutants although they can synthesize and accumulate serotonin, may not utilize it efficiently in synaptic transmission.

Animals↗

PubMed2000

Differential effects of L-trytophan and buspirone on biogenic amine contents and metabolism in Lurcher mice cerebellum.

The effects of serotoninergic stimulation on monoamines were studied in the heterozygous Lurcher (Lc/+) mutant mouse, a model of human cerebellar ataxia. Wild type (+/+) and Lc/+ mice were treated for 40 days with L-tryptophan or buspirone, and serotonin (5-HT), dopamine (DA), noradrenaline (NA) and their main metabolites were measured in the cerebellum. In +/+ mice, only buspirone increased concentrations of 5-HT metabolites. In the hypoplastic Lc/+ cerebellum, indoleamines were higher, and increased further after both treatments. The 5-HT turnover index was increased in +/+ mice by buspirone, while in Lc/+ mutants it increased after L-tryptophan but was decreased by buspirone, indicating that in the mutants nerve terminals synthesize and accumulate 5-HT, but may not utilize it efficiently. Catecholamine contents remained unchanged in +/+ mice, but in Lc/+ mutants with higher endogenous NA, L-tryptophan further increased NA and 3,4-dihydroxy-phenylacetic acid (DOPAC), and buspirone augmented NA, DA and DOPAC levels.

3,4-Dihydroxyphenylacetic Acid↗

PubMed2000

Treadmill performance of mice with cerebellar lesions: 2. Lurcher mutant mice.

The sensorimotor skills of a spontaneous mouse mutant with cerebellar cortical atrophy, Lurcher, were examined on either a fast or a slow treadmill inclined at one of three slopes, requiring forward movements in order to avoid footshocks. During the early part of acquisition, Lurcher mutants had lower latencies before falling on either treadmill than normal mice, but not during a retention test. For both Lurcher mutants and controls, the amount of time spent walking as a function of time spent on the belt increased with an increase in belt speed. Lurcher mutants had higher walking time/total time ratios on the slow but not on the fast treadmill. It is concluded that cerebellar cortical degeneration impaired the time course of acquisition but not long-term retention of the treadmill task.

Animals↗

PubMed2000

Effects of centrolateral or medial thalamic lesions on motor coordination and spatial orientation in rats.

The effects of central lateral (CL) or medial thalamic lesions were evaluated on tests requiring balance and equilibrium (rotorod, stationary beam, and hole-board), and spatial orientation (Morris water maze). Lesions of the medial nuclei impaired rotorod and spatial orientation, while CL lesions impaired only rotorod performance. Neither lesion affected stationary beam and hole-board tests or visuomotor guidance while swimming toward a visible platform. These spatial and sensorimotor deficits cannot be explained by reduced cerebral activation, but instead are attributable to specific projections from the anterior intralaminar nuclei to the basal ganglia and neocortex.

Animals↗

PubMed2000

Regional brain variations of cytochrome oxidase activity and motor co-ordination in staggerer mutant mice.

A mutant mouse with cerebellar cortical atrophy, staggerer, was examined in tests of motor activity and co-ordination as well as in regional brain metabolism as assessed by cytochrome oxidase activity. Compared with non-ataxic controls, staggerer mutants had inferior performances in the open field, the wooden beam, the wooden edge, and the rotorod tests. An increase in cytochrome oxidase activity in the deep cerebellar nuclei and in some cerebellar efferent regions, such as the lateral vestibular nucleus, the parvicellular red nucleus, and the ventral tegmental area, was found in staggerer mutant mice. Abnormally high cytochrome oxidase activity in the interpositus and the dentate nuclei was linearly correlated with poor performance on the wooden beam and on the rotorod. High cytochrome oxidase activity in the lateral vestibular nucleus was also associated with poor performance on the wooden beam. Moreover, high cytochrome oxidase activity in the fastigial nucleus was associated with poor performance on the wooden beam but with high motor activity in the open field. These results indicate that a lack of innervation of Purkinje cells to the deep cerebellar nuclei is in part the cause of motor co-ordination deficits in staggerer mutant mice.

Animals↗

PubMed2000

Neuropsychologic and neuropsychiatric characteristics of patients with Friedreich's ataxia.

UNLABELLED: OBJECTIVES AND MATERIALS AND METHODS: Due to recent evidence of frontal-lobe related dysfunctions in patients with cerebellar atrophy, patients with Friedreich's ataxia were compared to normal subjects controlled for age, gender, and educational level on tests measuring information processing speed, visuospatial organization, selective attention, executive functions, and mood. RESULTS: Patients with Friedreich's ataxia had slowed information speed, as indicated by lengthened simple visual reaction time and increased color-word interference in the Stroop task. However, the patient group was not impaired in several tests sensitive to neocortical and particularly prefrontal cortex lesions, including an untimed version of block design, verbal fluency, Wisconsin card sorting, Tower of Hanoi, and picture arrangement. Despite serious sensorimotor dysfunctions, the patient group did not differ from controls in terms of mood, as evaluated by the Symptoms Checklist (SCL-90) and the Hamilton depression scale. CONCLUSION: These results indicate that the slowed information processing speed of patients with Friedreich's ataxia is not accompanied by major prefrontal cortex and mood disorders.

Adolescent↗

PubMed2000

Longitudinal age-related changes in motor activities and spatial orientation in CD-1 mice.

Female CD-1 mice were evaluated on three occasions over a nineteen month span in tests of exploration, motor coordination, and spatial orientation in a water maze. Aging decreased motor activity and exploration of specific environmental stimuli found in a hole-board and in a T-maze. Age-related deficits were also found in three motor coordination tasks (inclined grid, coat-hanger, and round bridge) and during retention but not acquisition of the hidden platform version of the water maze task. Performance on some motor coordination tests was linearly correlated with either motor activity or exploration, implying the existence of similar neurobiological pathways responsible for these age-related changes.

Aging↗