Biomedical subjects

C Strazielle

Publications and source records attributed to C Strazielle.

At least 19 recordsLinked to original sources

PubMed2007

Brain regions and genes affecting postural control.

Postural control is integrated in all facets of motor commands. The role of cortico-subcortical pathways underlying postural control, including cerebellum and its afferents (climbing, mossy, and noradrenergic fibers), basal ganglia, motor thalamus, and parieto-frontal neocortex has been identified in animal models, notably through the brain lesion technique in rats and in mice with spontaneous and induced mutations. These studies are complemented by analyses of the factors underlying postural deficiencies in patients with cerebellar atrophy. With the gene deletion technique in mice, specific genes expressed in cerebellum encoding glutamate receptors (Grid2 and Grm1) and other molecules (Prkcc, Cntn6, Klf9, Syt4, and En2) have also been shown to affect postural control. In addition, transgenic mouse models of the synucleinopathies and of Huntington's disease cause deficiencies of motor coordination resembling those of patients with basal ganglia damage.

Afferent Pathways↗

PubMed2006

Regional brain variations of cytochrome oxidase activity and motor coordination in Girk2(Wv) (Weaver) mutant mice.

The Girk2(Wv) (weaver) phenotype, caused by a mutated inward rectifying potassium channel, is characterized by degeneration of cerebellar granule cell population as well as midbrain dopamine-containing cells of the nigrostriatal pathway. To investigate the regional brain metabolic consequences of this combined pathology, cytochrome oxidase (CO) activity was measured by histochemistry from brain regions of wild-type and homozygous Girk2(Wv) mutant mice and correlated with motor performances. CO activity of Girk2(Wv) mutants was abnormal in cerebellar cortex, dentate nucleus, and brainstem regions (medial and lateral vestibular nuclei, prepositus, superior colliculus, lateral cuneiform nucleus, and reticular nuclei) implicated in the gaze system. CO activity increased in midbrain dopaminergic regions after correcting for tissue density, regions with severe depletion of tyrosine hydroxylase activity. Forebrain regions were relatively spared in term of CO activity, except for subthalamic nucleus, lateral geniculate nucleus, and cortical eye field. Similarly to the Rora(sg) cerebellar mutant, metabolic alterations in cerebellar and vestibular regions were linearly correlated with poor motor coordination, underlining the sensitivity of these tests to cerebellar dysfunction.

Analysis of Variance↗

PubMed2006

Spontaneous and induced mouse mutations with cerebellar dysfunctions: behavior and neurochemistry.

Grid2(Lc) (Lurcher), Grid2(ho) (hot-foot), Rora(sg) (staggerer), nr (nervous), Agtpbp1(pcd) (Purkinje cell degeneration), Reln(rl) (reeler), and Girk2(Wv) (Weaver) are spontaneous mutations with cerebellar atrophy, ataxia, and deficits in motor coordination tasks requiring balance and equilibrium. In addition to these signs, the Dst(dt) (dystonia musculorum) spinocerebellar mutant displays dystonic postures and crawling. More recently, transgenic models with human spinocerebellar ataxia mutations and alterations in calcium homeostasis have been shown to exhibit cerebellar anomalies and motor coordination deficits. We describe neurochemical characteristics of these mutants with respect to regional brain metabolism as well as amino acid and biogenic amine concentrations, uptake sites, and receptors.

Animals↗

PubMed2006

Regional brain variations of cytochrome oxidase activity in Relnrl-orl mutant mice.

Cell malpositioning has been described in laminated structures of the spontaneous mutation, reeler, including the cerebellum, the hippocampus, and the neocortex. Despite the ectopic positions of different neuronal populations, the specificity of synaptic connections is maintained. The metabolic consequences of this form of neuropathology were examined in Reln(rl) mutant mice by quantitative measures of cytochrome oxidase (CO) activity, a mitochondrial enzyme essential for oxidative metabolism in neurons. Despite severe tissue disorganization but in line with the intact synaptic organization, the reeler mutation did not affect global metabolic activity of the laminated structures of the brain. CO activity, however, was altered in specific subregions of the cerebellum, hippocampus, and neocortex, as well as in septum and various brainstem (medial pontine, paramedial reticular, paragigantocellular reticular) regions anatomically related to these structures, attesting to large functional alterations in Reln(rl-orl) brain. Metabolic activity variations were also detected in the ventral tegmental area and ventral neostriatum of the mesolimbic dopaminergic pathway. The results are discussed and compared to the regional CO variations found in other ataxic mice, in regard to the structural defects, the integrity of the connections, and the mutation-specific effects.

Animals↗

PubMed2005

Regional acetylcholinesterase activity and its correlation with behavioral performances in 15-month old transgenic mice expressing the human C99 fragment of APP.

In addition to Abeta plaques and neurofibrillary tangles, Alzheimer's disease (AD) is characterized by increased brain levels of APP C-terminal fragments. In the present investigation, the cholinergic innervation in forebrain regions of transgenic mice (Tg13592) expressing the human betaAPP C99 fragment was compared to that of non-transgenic controls by measuring the activity of the non-specific catabolic enzyme, acetylcholinesterase (AChE). The AchE activity of Tg13592 mice was altered in several regions implicated in the functional loop of regulation between septum and hippocampus, vulnerable in Alzheimer pathology and critically involved in cognitive functions. In particular, AChE activity was upregulated in three basal forebrain regions containing cholinergic cell bodies, prelimbic cortex, anterior subiculum, and paraventricular thalamus, but downregulated in lateral septum and reticular thalamus. The increased activity in medial septum and anterior subiculum was linearly correlated with poor performances in a spatial learning task, possibly due to cell stress mechanisms. Because of some similarities in terms of neurochemistry and behavior, this mouse model may be of use for studying prodromal AD.

Acetylcholinesterase↗

PubMed2005

Primary neurologic screening and motor coordination of Dstdt-J mutant mice (dystonia musculorum) with spinocerebellar atrophy.

The autosomal recessive dystonia musculorum (Dst(dt-J)) mutation causes degenerative lesions of peripheral and central sensory pathways. A test battery of motor, sensory, postural, and autonomic functions was used to compare young control and homozygous Dst(dt-J) mice. The Dst(dt-J) mutants were severely impaired for muscle strength, limb coordination, and postural reflexes. As a result of a loss in motor control, the mutants were hypoactive in the open-field and fell quickly from the stationary beam. In sensory tests, the acoustic startle response was impaired, but not tactile reflexes and contact righting, attesting to preserved labyrinthine function and non-lemniscal pathways. Dst(dt-J) mutants were also distinguishable from controls on the basis of tremor, a paler skin, piloerection, and half-open eyes, as well as low body weight and fecal boli. Grooming episodes were less frequent in the mutants but without any reduction in grooming time. The neurologic screening battery delineated the functional integrity of some sensorimotor pathways in a spinocerebellar mutant whose severe phenotype prevents a more elaborate evaluation.

Analysis of Variance↗

PubMed2005

PS1 knockin mice with the Japanese I213T mutation: effects on exploratory activity, motor coordination, and spatial learning.

Knockin (KI) mice with a PS1/I213T mutation were compared to wild-type controls on the SHIRPA primary screening battery and for exploratory activity, motor coordination, and spatial learning. By comparison to non-transgenic controls, PS1/I213T KI mice had retarded acquisition of place learning in the Morris water maze without being impaired in the probe trial and in the visible platform subtest. PS1/I213T KI mice were more likely to display whole-body startle to an auditory stimulus and a tighter grip on a horizontal grid. PS1/I213T KI mice also had fewer enclosed arm entries in the elevated plus-maze, but did not differ from controls in open-field, photocell actimeter, and T-maze spontaneous alternation tests. No intergroup difference was seen in three motor coordination tests. The dissociation between hidden and visible platform versions in the water maze is consistent with the hypothesis that elevated Abeta42 concentrations cause cognitive disturbances.

Acoustic Stimulation↗

PubMed2005

Exploratory activity and motor coordination in wild-type SOD1/SOD1 transgenic mice.

SOD1 is one of several overexpressed genes in trisomy 21. In order to dissect possible genetic causes of the syndrome, wild-type SOD1/SOD1 transgenic mice were compared to FVB/N non-transgenic controls at 5 months of age in tests of exploratory activity and motor coordination. Wild-type SOD1/SOD1 transgenic mice had fewer stereotyped movements in an open-field and fell sooner from a rotorod than controls. In contrast, wild-type SOD1/SOD1 transgenic mice had fewer falls on a wire suspension test. There was no intergroup difference for ambulatory movements in the open-field, exploration of the elevated plus-maze, emergence from a small compartment, and motor coordination on a stationary beam. These results indicate that homozygous mice expressing human SOD1 are impaired in their ability to adjust their posture in response to a moving surface and make fewer small-amplitude movements without any change in general exploratory activity.

Analysis of Variance↗

PubMed2005

Mice with the deleted neurofilament of low-molecular-weight (Nefl) gene: 1. Effects on regional brain metabolism.

Neuronal intermediate filaments consist of the NFL subunit linked with NFM and NFH, and their alterations have been proposed as a pathogenesic cause in motor neuron diseases. Depletion of the Nefl gene in mice mimicks the reduced NFL mRNA levels seen in amyotrophic lateral sclerosis and causes perikaryal accumulation of neurofilament proteins and axonal hypotrophy in motoneurons. NFL -/- mice were evaluated for regional brain metabolism by means of quantitative histochemical estimation of cytochrome oxidase (COx) activity. The NFL null mice displayed enzymatic activity alterations in numerous hindbrain regions, mainly the cerebellum, connected regions of the brainstem (red nucleus, vestibular nuclei, and reticular formation), and cranial nerve nuclei. All of the affected regions presented elevated COx activity, except for the Purkinje cells of the cerebellum and the magnocellular red nucleus, where enzymatic activity was lower. NFL-disrupted mice displayed functional alterations in brainstem sensorimotor regions affected in amyotrophic lateral sclerosis.

Amyotrophic Lateral Sclerosis↗

PubMed2005

Mice with the deleted neurofilament of low molecular weight (Nefl) gene: 2. Effects on motor functions and spatial orientation.

Mice with a null mutation of the Nefl gene were compared with normal controls in tests of motor activity, equilibrium, and spatial orientation. Despite a normal capacity to ambulate, NFL -/- mice had fewer rears in an open field, crossed fewer segments on stationary beams, and fell more frequently when suspended on a horizontal bar. In addition, the distance swum before reaching the escape platform was greater in NFL -/- mice than in controls during acquisition of place learning in the Morris water maze at the start of training. The motor impairments were linearly correlated with increased cytochrome oxidase activity seen in cerebellum and brainstem. These results indicate that, as early as 6 months, depletion of the NFL protein is sufficient to cause mild sensorimotor dysfunctions and spatial deficits, but without overt signs of paresis.

Amyotrophic Lateral Sclerosis↗

PubMed2005

Neurobehavioral characterization of APP23 transgenic mice with the SHIRPA primary screen.

The SHIRPA primary screen comprises 40 measures covering various reflexes and basic sensorimotor functions. This multi-test battery was used to compare non-transgenic controls with APP23 transgenic mice, expressing the 751 isoform of human beta-amyloid precursor protein and characterized by amyloid deposits in parenchyma and vessel walls. The APP23 mice were distinguishable from controls by pathological limb reflexes, myoclonic jumping, seizure activity, and tail malformation. In addition, this mouse model of Alzheimer's disease was also marked by a crooked swimming trajectory. APP23 mice were also of lighter weight and were less inclined to stay immobile during a transfer arousal test. Despite the neurologic signs, APP23 transgenic mice were not deficient in stationary beam, coat-hanger, and rotorod tests, indicating intact motor coordination abilities.

Alzheimer Disease↗

PubMed2004

Spatial learning and exploration of environmental stimuli in 24-month-old female APP23 transgenic mice with the Swedish mutation.

Transgenic mice overexpressing the betaAPP gene with the Swedish mutation under the control of the murine thy1 promoter show Alzheimer-like characteristics such as Abeta plaques in cerebral cortex and vessel walls. By comparison to age-matched non-transgenic controls, 2-year-old female APP23 transgenic mice crossed more segments in the open-field and had a higher number of fast ambulatory and stereotyped movements in a photocell activity chamber. In addition, APP23 mice entered more often and spent more time in the open arms of the elevated plus-maze. The acquisition of place learning in the Morris water maze was impaired in APP23 transgenic mice, but not in probe and visible platform subtasks. These results indicate that hyperactivity and impaired learning abilities characterize this mouse model of Alzheimer's disease and cerebral angiopathy.

Age Factors↗

PubMed2004

Characterization of hemizygous SOD1/wild-type transgenic mice with the SHIRPA primary screen and tests of sensorimotor function and anxiety.

SOD1 is one of several overexpressed genes in Down's syndrome. In order to dissect genetic causes of the syndrome, hemizygous human wild-type SOD1 transgenic mice were compared to FVB/N non-transgenic controls at 3 months of age in the SHIRPA primary screen of neurologic function as well as in tests of motor activity and coordination. The responsiveness of SOD1/wt transgenic mice to visual and somatosensory stimuli was reduced in placing, pinna, corneal, and toe-pinch tests. In addition, SOD1/wt transgenic mice crossed fewer segments on a stationary beam. On the contrary, there was no intergroup difference for motor activity and anxiety in open-field and emergence tests and for latencies before falling on the stationary beam, coat-hanger, and rotorod. These results indicate mild deficits in sensorimotor responsiveness in a mouse model expressing human SOD1 and that the overexpressed gene may be responsible for some Down symptoms.

Animals↗

PubMed2004

Regional brain variations of cytochrome oxidase activity in spontaneously hypertensive mice.

To explore the central disturbances resulting from blood pressure changes, spontaneously hypertensive mice (SHM) were compared to normotensive controls for cytochrome oxidase (CO) activity, an index of oxidative capacity in the central nervous system and a marker of long-term regional brain metabolism and neuronal activity. In all brain areas presenting significant enzymatic variations, only increases in CO activity were found in SHM, particularly the central autonomic network. However, only specific regions were affected, namely the insular cortex and the hypothalamic nuclei principally involved in high-order autonomic control. Altered limbic structures included the lateral septum, various hippocampal subregions, as well as prelimbic cortex. CO activity was also elevated in several forebrain regions, including those directly connected to the limbic system, such as the nucleus accumbens, the claustrum, and dorsomedial and reticular thalamic nuclei, as well as subthalamic and ventrolateral thalamic nuclei. In the brainstem, the only regions affected were the locus coeruleus, site of noradrenergic cell bodies, the trigeminal system, and four interconnected regions: the inferior colliculus, the paramedial reticular formation, the medial vestibular, and the cerebellar fastigial nuclei. These data show that specific regions modulating sympathetic nerve discharge are activated in young adult SHM, possibly due to mitochondrial dysfunction and excitotoxicity.

Animals↗

PubMed2004

Transgenic mice expressing the human C99 terminal fragment of betaAPP: effects on cytochrome oxidase activity in skeletal muscle and brain.

In order to furnish a combined model of relevance to human inclusion-body myopathy and Alzheimer's disease, transgenic mice expressing human betaAPP-C99 in skeletal muscle and brain under the control of the cytomegalovirus/beta-actin promoter were produced (Tg13592). These transgenic mice develop Abeta deposits in muscles but not in brain. Cell metabolic activity was analyzed in brain regions and muscle by cytochrome oxidase (CO) histochemistry, the terminal enzyme of the electron transport chain. By comparison to age-matched controls of the C57BL/6 strain, CO activity was selectively increased in dark skeletal muscle fibers of Tg13592 mice. In addition, only increases in CO activity were obtained in those brain regions where a significant difference appeared. The CO activity of Tg13592 mice was elevated in several thalamic nuclei, including laterodorsal, ventromedial, and midline as well as submedial, intralaminar, and reticular. In contrast, the groups did not differ in most cortical regions, except for prefrontal, secondary motor, and auditory cortices, and in most brainstem regions, except for cerebellar (fastigial and interpositus) nuclei and related areas (red and lateral vestibular nuclei). No variation in cell density and surface area appeared in conjunction with these enzymatic alterations. The overproduction of betaAPP-C99 fragments in brain without (amyloidosis did not appear to affect the metabolic activity of structures particularly vulnerable in Alzheimer's disease.

Alzheimer Disease↗

PubMed2004

Neurobehavioral evaluation of Reln-rl-orl mutant mice and correlations with cytochrome oxidase activity.

The Reln-rl-orl mutation is characterized by a marked deficit in cerebellar granule cell and Purkinje cell number as well as ectopias in cerebellum, hippocampus, and neocortex. By comparison to Balb/c controls, Reln-rl-orl mutants did not alternate spontaneously in a T-maze and were deficient for visuomotor guidance in a water maze. Despite cerebellar ataxia and motor coordination impairments on stationary beam, coat-hanger, and rotorod tests, the horizontal motor activity of Reln-rl-orl mutants was not reduced in an open-field. The elevated cytochrome oxidase (CO) activity in Purkinje cells and the reduced CO activity in the roof nuclei (interpositus and dentate) of the mutants were associated with poor performance on the small stationary beam. In addition, deficient CO activity of the granular layer of the motor cortex was associated with shorter latencies before falling from the larger stationary beam and a lower number of rears in the open-field. Conversely, elevated CO activity in the polymorphic layer of primary somatosensory cortex was congruent with higher latencies before falling from the same apparatus, indicating functional compensation.

Animals↗

PubMed2003

Transgenic mice expressing the betaAPP695SWE mutation: effects on exploratory activity, anxiety, and motor coordination.

The functional consequences of the betaAPP transgene with the Swedish mutation in mice were assessed in tests of exploratory activity and motor coordination. The betaAPP(695)SWE (Tg2576) transgenic mice are characterized by Abeta plaque formation in the neocortex and hippocampus. By comparison to non-transgenic mice controlled for age and gender, 17-month-old betaAPP(695)SWE transgenic mice displayed impaired spontaneous alternation, increased activity levels in the peripheral part of the open-field, and reduced anxiety in the elevated plus-maze. These results are similar to the loss of inhibitory control observed in some patients with Alzheimer's disease. These measures may be added to cognitive dysfunctions as testing ground for Abeta vaccination and other attempts at experimental therapies.

Alzheimer Disease↗

PubMed2003

Characterization of NFH-LacZ transgenic mice with the SHIRPA primary screening battery and tests of motor coordination, exploratory activity, and spatial learning.

NFH-LacZ transgenic mice express a fusion protein between a truncated form of the endogenous neurofilament of heavy molecular weight and the complete E. coli beta-galactosidase. NFH-LacZ transgenic mice could be distinguished from controls in the SHIRPA neurological battery by the appearance of action tremor and hindlimb clasping and a lower body weight. Despite normal exploratory activity and spatial learning, NFH-LacZ transgenic mice were deficient in stationary beam, coat-hanger, and rotorod tests of motor coordination. These results are concordant with neuropathological findings in spinal motoneurons and the cerebellum and indicate that despite the absence of paralysis, these transgenic mice may serve as an experimental model of the early stage of amyotrophic lateral sclerosis.

Journal Article↗