Biomedical subjects

C Strazielle

Publications and source records attributed to C Strazielle.

At least 37 records · Page 2Linked to original sources

PubMed2003

Transgenic mice expressing the PS1-A246E mutation: effects on spatial learning, exploration, anxiety, and motor coordination.

The functional consequence of the PS1-A246E mutation was assessed in transgenic mice on a background lacking the endogenous PS1 gene. These mice have elevated concentrations of A-beta protein (Abeta(42)) in the absence of plaque formation. By comparison to a mixed background strain (50% B6, 25% SJl, 25% 129Sv) controlled for age and gender, PS1-A246E transgenic mice displayed disinhibitory tendencies, as indicated by increased entries and duration in the open arms of the elevated plus-maze. Despite normal spontaneous alternation rates in a T-maze, latencies before responding were higher in PS1-A246E transgenic mice than controls. Moreover, the PS1-A246E transgenic mice fell more often from two stationary beams, but not from the coat-hanger and the rotorod. By contrast, ambulation in an automated photocell chamber and in an open-field was not affected. Nor was acquisition of place learning in the Morris water maze task. These results indicate that elevated Abeta(42) levels were insufficient for causing spatial defects but caused disinhibition, psychomotor slowing, and loss of motor skills in this model of familial Alzheimer's disease.

Alzheimer Disease↗

PubMed2003

Motor coordination in mice with hotfoot, Lurcher, and double mutations of the Grid2 gene encoding the delta-2 excitatory amino acid receptor.

Grid2(ho/ho) is a loss of function gene mutation resulting in abnormal dendritic arborizations of Purkinje cells. These mutants were compared in a series of motor coordination tests requiring balance and equilibrium to nonataxic controls (Grid2(ho/+)) and to a double mutant (Grid2(ho/Lc)) with an inserted Lc mutation. The performance of Grid2(ho/ho) mutant mice was poorer than that of controls on stationary beam, coat hanger, unsteady platform, and rotorod tests. Grid2(ho/Lc) did not differ from Grid2(Lc/+) mice. However, the insertion of the Lc mutation in Grid2(ho/Lc) potentiated the deficits found in Grid2(ho/ho) in stationary beam, unsteady platform, and rotorod tests. These results indicate a deleterious effect of the Lc mutation on Grid2-deficient mice.

Alleles↗

PubMed2003

Effects of ventrolateral-ventromedial thalamic lesions on motor coordination and spatial orientation in rats.

The ventrolateral-ventromedial (VL-VM) nuclei are classified as a motor area of the thalamus on the basis of predominant input from the cerebellum and the basal ganglia and output to the motor cortex. The sensitivity to electrolytic lesions of the VL-VM thalamic nuclei in rats was evaluated for tests requiring balance and equilibrium. VL-VM lesions impaired acquisition of the rotorod test but had no effect on stationary beam and hole-board tests. A selective impairment was also observed in the Morris water maze, as VL-VM thalamic lesions slowed down acquisition of the hidden platform but not the visible platform condition. These results support the hypothesis that thalamic motor nuclei participate in the acquisition of sensorimotor and spatial learning.

Animals↗

PubMed2003

Regional brain cytochrome oxidase activity in beta-amyloid precursor protein transgenic mice with the Swedish mutation.

Cytochrome oxidase activity was examined in a transgenic mouse model of Alzheimer's disease with overexpression of the 751 amino acid isoform of beta-amyloid precursor protein with the Swedish mutation under control of the murine thy-1 promoter. The neuritic plaques, abundantly localized in the hippocampus and anterior neocortical areas, showed a core devoid of enzymatic activity surrounded by higher cytochrome oxidase activity at the sites of the dystrophic neurites and activated glial cells. Quantitative measures, taken only in the healthy-appearing regional areas without neuritic plaques, were higher in numerous limbic and non-limbic regions of transgenic mice in comparison with controls. Enzymatic activity was higher in the dentate gyrus and CA2-CA3 region of the hippocampus, the anterior cingulate and primary visual cortex, two olfactory structures, the ventral part of the neostriatum, the parafascicularis nucleus of the thalamus, and the subthalamic nucleus. Brainstem regions anatomically related with altered forebrain regions were more heavily labeled as well, including the substantia nigra, the periaqueductal gray, the superior colliculus, the medial raphe, the locus coeruleus and the adjacent parabrachial nucleus, as well as the pontine nuclei, red nucleus, and trigeminal motor nucleus. Functional brain organization is discussed in the context of Alzheimer's disease. Although hypometabolism is generally observed in this pathology, the increased cytochrome oxidase activity obtained in these transgenic mice can be the result of a functional compensation on the surviving neurons, or of an early mitochondrial alteration related to increased oxidative damage.

Alzheimer Disease↗

PubMed2003

Motor coordination, exploration, and spatial learning in a natural mouse mutation (nervous) with Purkinje cell degeneration.

The nervous mouse mutation causes a relatively selective degeneration of Purkinje cells in the cerebellar cortex. The mutants were compared to age-matched controls of the same background strain in tests of motor activity and coordination, spontaneous alternation, and spatial learning in the Morris water maze. As expected from their ataxia, the nervous mutants were impaired in stationary beam, coat-hanger, and rotorod tests of motor coordination. The nervous mutants were also impaired in the submerged but not in the visible platform condition of the Morris water maze, attributable to a spatial deficit, and displayed a higher level of motor activity in an automated chamber. The deficit in spontaneous alternation rates seen in nervous mutants is accountable by reduced motivation, disinhibition, or spatial disorientation.

Analysis of Variance↗

PubMed2003

The effects of cerebellar damage on maze learning in animals.

The role of the cerebellum in spatial learning has recently been investigated in genetically and non-genetically lesioned animal models, particularly in water mazes, in view of the minimal impact such lesions exert on swimming movements. A dissociation between place and cued learning in the Morris water maze has been observed in several models, including cerebellar mutant mice (Rora(sg), Nna1(pcd-1J), nervous), rats with lesions of either the lateral cerebellar cortex or the dentate nucleus, and rats with selective Purkinje cell loss caused by intracerebroventricular injections of OX-7-saporin, confirming the hypothesis that cerebellar damage may cause a cognitive deficit independently of fine motor control. In addition, the results of hemicerebellectomized rats indicate the probable involvement of the cerebellum in working memory and the procedural aspect of maze learning. The findings of impaired maze learning in cerebellar-lesioned mice and rats are concordant with those of deficient visuospatial functions in patients with cerebellar atrophy. The spatial deficits may be ascribed to altered metabolic activity in cerebellar-related pathways.

Animals↗

PubMed2003

Neurobehavioral characteristics of mice with modified intermediate filament genes.

Intermediate proteins comprise cytoskeletal elements that preserve the shape and structure of neurons. These proteins have been proposed to be involved in the onset and progression of amyotrophic lateral sclerosis (ALS), mainly characterized by motoneuron atrophy and paresis. In support of this hypothesis are the findings that genetically modified mice for intermediate filaments successfully mimic certain neuropathological aspects of ALS, such as reduced axonal caliber and retarded conduction speed in peripheral nerves, although often without leading to paresis. Nevertheless, even in those models with no overt phenotype, the involvement of intermediate proteins in motor function is underlined by the deficits in tests of balance and equilibrium revealed in mice containing transgenes for neurofilament of heavy molecular weight (NFH), alpha-internexin, peripherin, and vimentin. In addition, spatial learning was impaired in transgenic mice expressing transgenes for NFH and NFM, similar to the memory deficits reported in patients with ALS.

Amyotrophic Lateral Sclerosis↗

PubMed2002

Spatial learning, exploration, anxiety, and motor coordination in female APP23 transgenic mice with the Swedish mutation.

Transgenic mice overexpressing the betaAPP gene with the Swedish mutation under the control of the murine thy-1 promoter show Alzheimer-like characteristics including the accumulation of Abeta protein in the cerebral cortex. Female 16-month-old APP23 transgenic mice were compared to age-matched non-transgenic mice in behavioral tests measuring spatial learning, exploration of environmental stimuli, anxiety, and motor coordination. APP23 transgenic mice had fewer fast ambulatory movements, either fast or slow stereotypy movements, and slow rears in a photocell activity chamber. The acquisition of spatial learning in the Morris water maze was impaired in APP23 transgenic mice, but not during the probe test or while swimming towards a visible platform. Neither were there intergroup differences in tests of anxiety or motor coordination. These results indicate that a learning deficit and hypoactivity, concordant with the early stages of Alzheimer's disease, characterize this mouse model with Abeta accumulation.

Alzheimer Disease↗

PubMed2002

NFH-LacZ transgenic mice: regional brain activity of cytochrome oxidase.

Expression of the NFH-LacZ fusion protein in transgenic mice causes an early accumulation of neurofilament proteins in the cell bodies of neurons, as well as a reduction of motor neuron axonal caliber and Purkinje cell number in the cerebellum. Young (3 month old) and older (12-20 months) NFH-LacZ transgenic mice were compared to normal controls for regional brain metabolism, as assessed by cytochrome oxidase (CO) activity. Irrespective of age, CO activity was reduced in three cerebellar-related regions of NFH-LacZ transgenic mice: (1) the lateral reticular nucleus, (2) the parvicellular red nucleus, and (3) the superior colliculus, possibly as a secondary consequence of cerebellar Purkinje cell histopathology. Aged NFH-LacZ mice had lower CO activity relative to either age-matched controls or young transgenic mice in the following regions: the motor nucleus of the vagus nerve, the trapezoid nucleus, the subiculum, the motor cortex, the superior olive, and the lateral dorsal thalamus. These results indicate regional and age-selective deficits of brain metabolism in a transgenic model with neurofilament maldistribution.

Age Factors↗

PubMed2002

Sensorimotor functions in transgenic mice expressing the neurofilament/heavy-LacZ fusion protein on two genetic backgrounds.

NFH-LacZ transgenic mice are characterized by expression of a non-endogenous fusion protein between a truncated form of mouse NFH (neurofilament of heavy molecular weight) and the complete Escherichia coli beta-galactosidase protein. These transgenic mice were compared to their respective controls on two background strains (C3H and FVB) in several sensorimotor tests. NFH-LacZ mice were deficient in tests requiring balance and equilibrium in a manner generally independent of genetic background. In particular, NFH-LacZ mice fell more quickly than controls from two stationary beams and had fewer rears in an open-field. The transgenic mice were also impaired during the initial trials of sensorimotor learning on the rotorod. We conclude that despite the absence of overt signs of sensorimotor weakness in their home cage, the disruption of the NFH gene, causing neurofilament accumulations in the cell body and diminished axonal calibers of motoneurons, is sufficient to cause motor deficits that resemble the early stages of amyotrophic lateral sclerosis.

Animals↗

PubMed2002

Transgenic mice expressing the human C99 terminal fragment of betaAPP: effects on spatial learning, exploration, anxiety, and motor coordination.

The functional consequence of beta-amyloid precursor protein (betaAPP) manipulation on behavior was assessed in Tg13592 mice, characterized by transgene expression of the 99 amino acid C-terminal sequence of human betaAPP in brain and skeletal muscle but with plaque formation only in muscle. By comparison to the C57BL/6 background strain controlled for age and gender, Tg13592 transgenic mice had fewer movements in an automated chamber and fewer enclosed arm entries in the elevated plus-maze. This hypoactivity was probably due to a loss in the motivation to explore novel environmental stimuli rather than motor weakness or anxiety. In addition, the acquisition of place learning in the Morris water maze task was impaired in Tg13592 mice. The transgenic mice were not impaired in a probe trial or while swimming toward a visible platform. These results are concordant with the hypothesis that transgene expression of the C-terminal sequence of human betaAPP in brain is sufficient for causing behavioral abnormalities. The hypoactivity and the spatial learning deficit were associated with higher cytochrome oxidase activity seen in thalamic nuclei, indicating that altered regional brain metabolism caused by betaAPP transgene expression may be responsible for the behavioral changes.

Amyloid beta-Protein Precursor↗

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

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↗

PubMed2000

Central serotonin system in Dystonia musculorum mutant mice: biochemical, autoradiographic and immunocytochemical data.

The autosomal recessive mutation dystonia musculorum (dt(J)/dt(J)) causes degenerative alterations of peripheral and central sensory pathways that lead to ataxia. To investigate possible changes in the central serotonin system of these mice, HPLC measurements of 5-hydroxytryptophan, 5-hydroxy-tryptamine (serotonin; 5-HT), and 5-HT metabolites were obtained from 22 brain regions and the spinal cord of wild type and dt(J)/dt(J) mutant mice. Also, 5-HT transporters were quantified by [(3)H]citalopram autoradiography in 72 brain regions, subregions, and nuclei, and the 5-HT innervation visualized by immunocytochemistry throughout the brain and spinal cord. In all brain regions measured for indoleamine content, there were no significant differences between the two genotypes. In the spinal cord, an increased tissue concentration of 5-HT (+34%), 5-hydroxyindole-3-acetic acid (+33%), 5-hydroxytryptophol (+21%), and 5-hydroxytryptophan (+45%) in dt(J)/dt(J) actually corresponded to the same total amount of each of these indoleamines in the entire spinal cord, when taking into account its reduced size in the mutants. Quantification of the binding to 5-HT transporters showed increases in the medial geniculate nucleus (+14%), medial (+24%) and lateral (+18%) hypothalamus, interpeduncular (+13%), vestibular (+22%), and deep cerebellar nuclei (+37%) of dt(J)/dt mice, and decreases in the ventral tegmental area (-13%), median and linear raphe nuclei (-20%), as well as in the solitary complex (-35%). There were no apparent differences in the distribution of 5-HT-immunostained fibers in these and other regions of brain and in the spinal cord of dt(J)/dt(J) compared to wild type mice. The bulk of these results indicates a relative sparing of the central 5-HT system in the dt(J)/dt(J) mice, even though alterations in 5-HT transporters could justify attempts at improving the sensorimotor dysfunction by administration of serotoninergic agents in these mice.

5-Hydroxytryptophan↗

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↗