Recently, the biosafety and potential influences of nanoparticles on central nervous system have ... more Recently, the biosafety and potential influences of nanoparticles on central nervous system have received more attention. In the present study, we assessed the effect of aluminium oxide nanoparticles (Al 2 O 3 -NPs) on spatial cognition. Male Wistar rats were intravenously administered Al 2 O 3 -NP suspension (20 mg/kg body weight/day) for four consecutive days, after which they were assessed. The results indicated that Al 2 O 3 -NPs impaired spatial learning and memory ability. An increment in malondialdehyde levels with a concomitant decrease in superoxide dismutase activity confirmed the induction of oxidative stress in the hippocampus. Additionally, our findings showed that exposure to Al 2 O 3 -NPs resulted in decreased acetylcholinesterase activity in the hippocampus. Furthermore, Al 2 O 3 -NPs enhanced aluminium (Al) accumulation and disrupted mineral element homoeostasis in the hippocampus. However, they did not change the morphology of the hippocampus. Our results show a connection among oxidative stress, disruption of mineral element homoeostasis, and Al accumulation in the hippocampus, which leads to spatial memory deficit in rats treated with Al 2 O 3 -NPs.
Cancer and treatments may induce cognitive impairments in cancer patients, and the causal link be... more Cancer and treatments may induce cognitive impairments in cancer patients, and the causal link between chemotherapy and cognitive dysfunctions was recently validated in animal models. New cancer targeted therapies have become widely used, and their impact on brain functions and quality of life needs to be explored. We evaluated the impact of everolimus, an anticancer agent targeting the mTOR pathway, on cognitive functions, cerebral metabolism, and hippocampal cell proliferation/vascular density in mice. Adult mice received everolimus daily for 2 weeks, and behavioral tests were performed from 1 week after the last treatment. Everolimus-treated mice displayed a marked reduction in weight gain from the last day of the treatment period. Ex vivo analysis showed altered cytochrome oxidase activity in selective cerebral regions involved in energy balance, food intake, reward, learning and memory modulation, sleep/wake cycle regulation, and arousal. Like chemotherapy, everolimus did not alter emotional reactivity, learning and memory performances, but in contrast to chemotherapy, did not affect behavioral flexibility or reactivity to novelty. In vivo hippocampal neural cell proliferation and vascular density were also unchanged after everolimus treatments. In conclusion, two weeks daily everolimus treatment at the clinical dose did not evoke alteration of cognitive performances evaluated in hippocampal-and prefrontal cortex-dependent tasks that would persist at one to four weeks after the end of the treatment completion. However, acute everolimus treatment caused selective CO modifications without altering the mTOR effector P70S6 kinase in OPEN ACCESS cerebral regions involved in feeding behavior and/or the sleep/wake cycle, at least in part under control of the solitary nucleus and the parasubthalamic region of the hypothalamus. Thus, this area may represent a key target for everolimus-mediating peripheral modifications, which has been previously associated with symptoms such as weight loss and fatigue. Impact of Everolimus on Brain Function PLOS ONE |
In patients, cancer and treatments provoke cognitive impairments referred to “chemofog”. Here a v... more In patients, cancer and treatments provoke cognitive impairments referred to “chemofog”. Here a validated neurobehavioral animal model, the unique way to explore causal direct links between chemotherapy used in clinical practices and brain disorders, allowed investigation of the direct long-term impact of colo-rectal cancer chemotherapy on cognition and cerebral plasticity. Young and aged mice received three injections every 7 days during 2 weeks of 5-fluorouracil either alone (5-FU, 37.5 mg/kg) or in combination with oxaliplatin (3 mg/kg) or with glucose (5%). The long-term effects (from day 24 to day 60) of chemotherapy were tested on emotional reactivity, learning and memory, behavioral flexibility and hippocampal cell plasticity. 5-FU (in saline)-treated aged and also young mice exhibited specific altered cognitive flexibility and behavioral hyper-reactivity to novelty, whereas the combination 5-FU (in saline)/oxaliplatin (in glucose) did not provoke any cognitive dysfunction. We thus observed that glucose counteracted 5-FU-induced altered executive functions and hippocampal cell proliferation in vivo, and protected neural stem cells in vitro from toxicity of 5-FU or oxaliplatin. In conclusion, these data suggest that the lasting chemotherapy-induced selective impairment of executive functions, whatever the age, and associated with a reduced number of hippocampal proliferating cells, can be counteracted by co-administration with glucose.
Abstract The cerebellum is a structure of the central nervous
system involved in balance, motor c... more Abstract The cerebellum is a structure of the central nervous system involved in balance, motor coordination, and voluntary movements. The elementary circuit implicated in the control of locomotion involves Purkinje cells, which receive excitatory inputs from parallel and climbing fibers, and are regulated by cerebellar interneurons. In mice as in human, the cerebellar cortex completes its development mainly after birth with the migration, differentiation, and synaptogenesis of granule cells. These cellular events are under the control of numerous extracellular matrix molecules including pleiotrophin (PTN). This cytokine has been shown to regulate the morphogenesis of Purkinje cells ex vivo and in vivo via its receptor PTPζ. Since Purkinje cells are the unique output of the cerebellar cortex, we explored the consequences of their PTN-induced atrophy on the function of the cerebellar neuronal circuit in mice. Behavioral experiments revealed that, despite a normal overall development, PTN-treated mice present a delay in the maturation of their flexion reflex. Moreover, patch clamp recording of Purkinje cells revealed a significant
Lurcher mutant mice (+/Lc) exhibit a massive loss of neurons in the cerebellar cortex and the inf... more Lurcher mutant mice (+/Lc) exhibit a massive loss of neurons in the cerebellar cortex and the inferior olivary nucleus, while deep cerebellar nuclei are essentially intact. To discriminate the relative participation of the cerebellar cortex and deep structures in learning and memory, 3 to 6-month-old +/Lc mice were subjected to a spatial learning task derived from the Morris water escape. They were able to learn to escape as well as their strain-matched controls (+/+). Seven days later, their scores showed that they had memorized the spatial environment but not as accurately as +/+ mice. Cerebellectomy before training did not significantly alter the escape learning capabilities of either group, whereas cerebellectomy performed after learning completely abolished retention in +/+, as well as in +/Lc, mice. These results suggest that the cerebellum, although not necessary for learning a spatial task, plays a crucial role in its retention, and that the storing structure of spatial information differs in +/+ and +/Lc mice.
Administration of harmaline to the rat, which activates synchronously and rhythmically the olivar... more Administration of harmaline to the rat, which activates synchronously and rhythmically the olivary neurons and the olivocerebellar pathway, elicits visuo-motor, spatial learning and spatial memory deficiencies which are dose-dependent. Since activation and lesion of the olivocerebellar pathway have similar effects, it is concluded that normal functioning of this pathway is required for spatial learning achievement. q
Heterozygous cerebellar mutant (Rora ' /Rora sg ) mice and control (Rora ' /Rora ' ) mice of the ... more Heterozygous cerebellar mutant (Rora ' /Rora sg ) mice and control (Rora ' /Rora ' ) mice of the same C57Bl6/J strain, 3 Á/24 months old, were subjected to motor training on a rotorod for 10 days. Falling latency and percentage of time spent walking were measured. A good correlation was found between falling latency and walking time: the mice which maintained equilibrium for a long time were those which were walking, and the mice which fell early were those which were gripping suggesting that walking is obviously the most adapted strategy to keep balance on the rotorod. In Rora ' /Rora ' mice, scores before training were altered very precociously (from 6 months of age). Moreover, scores of Rora ' /Rora sg mice were lower than those of Rora ' /Rora ' mice from the age of 3 months, while neuronal number in the cerebellar cortex of these mutants was quite normal and similar to that of Rora ' / Rora ' mice. This suggests that the motor skill disability would be due to fine structural and/or biochemical changes preceding neuronal death. Such subtle changes would begin several months earlier in Rora ' /Rora sg than in Rora ' /Rora ' mice. Training on the rotorod resulted in increased scores in both genotypes at all ages. Motor learning abilities were therefore preserved in animals with a moderate neuronal loss in the cerebellum. It may be that motor learning is partly compensated by the striatum, which is known to play a major role in learning of motor skills. #
The present study evaluated the effects of the principal active component of marijuana (delta 9 T... more The present study evaluated the effects of the principal active component of marijuana (delta 9 THC) on motor abilities and motor learning in mice with cerebellar dysfunction. For this purpose, spontaneous locomotor activity, equilibrium abilities, muscular tone, motor coordination and motor learning were investigated in Lurcher mutant and non-mutant B6/CBA mice 20 min after i.p. administration of 4 or 8 mg kg −1 of delta 9 tetra hydro cannabinol (delta 9 THC). The performances were compared to those obtained by Lurcher and non-mutant mice injected with vehicle (Tween 80).
Background: Interstitial flow in and around tumour tissue not only has particular importance in d... more Background: Interstitial flow in and around tumour tissue not only has particular importance in delivering anticancer agents to tumour tissue, but also affects the microenvironment to modulate tumour cell growth and metastasis. We investigated the roles of flow-induced shear stress in modulating radiosensitivity in two colon cancer cell lines and the underlying mechanisms. Materials and Methods: T84 and SW480 colon cancer cells were trypsinized and seeded onto glass slides (75×38 mm) pre-coated with fibronectin (10 mg/ml). A parallel-plate flow chamber system was used to impose fluid shear stress. Irradiation was delivered using 160kV RS 2000 X-ray irradiator (Rad Source Technologies, Inc.). Cell proliferation, apoptosis and colony assay were measured after various combinations between shear stress and radiation. Cell cycle analysis and immunoblots of integrin b1/FAK/Akt signal molecules were evaluated. The combination effect of shear stress was reversed by neutralizing integrin b1 or using FAK overexpressed cell lines. Results: In both cell lines, incubation under shear stress (12 dynes/cm 2 ) for 24 hours enhanced radiation induced cytotoxicity. Protein expression of integrin b1 was moderately while FAK was significantly suppressed. FAK down-regulation was mainly due to ubiquitin-dependent proteasomal pathway but not transcriptional suppression. The amount of ILK, GSK3b was not affected. Using FAK overexpressed cell lines, we demonstrated that shear stress enhanced colon cancer cell radiosensitivity by regulating FAK expression. On the other hand, incubation under shear stress for 3 hours did not revealed radiosensitizing effect in both cell lines. Using integrin b1 neutralizing antibody, we suppressed FAK/Akt activation by 3-hr shear stress and enhanced radiation related cytotoxicity in both colon cancer cell lines. Conclusions: Shear stress of 24 hours provides radio-sensitization to colon cancer cell through proteosomal degradation of FAK via integrin b1. Our findings provide insights into the mechanism by which shear stress modulates colon cancer cell cytotoxicity in response to radiation. The results impact rationale combination between radiation and strategy in modulating tumour interstitial fluid pressure.
AbstractÐMotor learning abilities on the rotorod and motor skills (muscular strength, motor coord... more AbstractÐMotor learning abilities on the rotorod and motor skills (muscular strength, motor coordination, static and dynamic equilibrium) were investigated in three-, nine-, 15-and 21-month-old Lurcher and control mice. Animals were subjected to motor training on the rotorod before being subjected to motor skills tests. The results showed that control mice exhibited decrease of muscular strength and speci®c equilibrium impairments in static conditions with age, but were still able to learn the motor task on the rotorod even in old age. These results suggest that, in control mice, ef®ciency of the reactive mechanisms, which are sustained by the lower transcerebellar loop (cerebello-rubro-olivo-cerebellar loop), decreased with age, while the ef®ciency of the proactive adjustments, which are sustained by the upper transcerebellar loop (cerebello-thalamo-cortico-ponto-cerebellar loop), did not. In spite of their motor de®cits, Lurcher mutants were able to learn the motor task at three months, but exhibited severe motor learning de®cits as soon as nine months. Such a de®cit seems to be associated with dynamic equilibrium impairments, which also appeared at nine months in these mutants. By two months of age, degeneration of the cerebellar cortex and the olivocerebellar pathway in Lurcher mice has disrupted both lower and upper transcerebellar loops. Disruption of the lower loop could well explain precocious static equilibrium de®cits. However, in spite of disruption of the upper loop, motor learning and dynamic equilibrium were preserved in young mutant mice, suggesting that either deep cerebellar nuclei and/or other motor structures involved in proactive mechanisms needed to maintain dynamic equilibrium and to learn motor tasks, such as the striatopallidal system, are suf®cient. The fact that, in Lurcher mutant mice, motor learning decreased by the age of nine months suggests that the above-mentioned structures are less ef®cient, likely due to degeneration resulting from precocious and focused neurodegeneration of the cerebellar cortex.
Heterozygous cerebellar mutant (Rora ' /Rora sg ) mice and control (Rora ' /Rora ' ) mice of the ... more Heterozygous cerebellar mutant (Rora ' /Rora sg ) mice and control (Rora ' /Rora ' ) mice of the same C57Bl6/J strain, 3 Á/24 months old, were subjected to motor training on a rotorod for 10 days. Falling latency and percentage of time spent walking were measured. A good correlation was found between falling latency and walking time: the mice which maintained equilibrium for a long time were those which were walking, and the mice which fell early were those which were gripping suggesting that walking is obviously the most adapted strategy to keep balance on the rotorod. In Rora ' /Rora ' mice, scores before training were altered very precociously (from 6 months of age). Moreover, scores of Rora ' /Rora sg mice were lower than those of Rora ' /Rora ' mice from the age of 3 months, while neuronal number in the cerebellar cortex of these mutants was quite normal and similar to that of Rora ' / Rora ' mice. This suggests that the motor skill disability would be due to fine structural and/or biochemical changes preceding neuronal death. Such subtle changes would begin several months earlier in Rora ' /Rora sg than in Rora ' /Rora ' mice. Training on the rotorod resulted in increased scores in both genotypes at all ages. Motor learning abilities were therefore preserved in animals with a moderate neuronal loss in the cerebellum. It may be that motor learning is partly compensated by the striatum, which is known to play a major role in learning of motor skills. #
Harmaline (HA) is a beta-carboline commonly known to provoke motor alterations through activation... more Harmaline (HA) is a beta-carboline commonly known to provoke motor alterations through activation of cells in the inferior olive. In addition, this pharmacological agent also induces cognitive disturbances such as motor and spatial learning impairments. In order to complete and extend these data, we examined the effects of this drug on state anxiety in mice, employing elevated plus maze test. We report here that lower doses of harmaline (5-10 mg/kg) have anxiogenic since higher doses (20 mg/kg) have anxiolytic-like properties. Overall pattern of our behavioral results provides evidence that harmaline also acts on emotional reactivity in mice by influencing their decision making when placed in an anxiogenic situation.
It is now well accepted that besides its roles in motor control, the cerebellum is involved in no... more It is now well accepted that besides its roles in motor control, the cerebellum is involved in non-motor functions with emotional aspects. Consistent with this view, several studies highlighted that the cerebellar Lurcher mutant mice (+/Lc), with motor impairments, also exhibited altered emotional reactivity, previously interpreted in term of behavioural disinhibition. In this study, we investigated the effects of a classical anxiolytic on such disinhibition. For that, behaviours of +/Lc and control (+/+) mice injected with NaCl or chlordiazepoxide (CDP 5 and 7.5 mg/kg) were evaluated in the elevated plus-maze test. The motor impact of the drug (7.5 mg/kg only) was also evaluated in the hole-board and unstable platform tests. Our results showed that, compared to the +/+ mice, CDP injection greatly influenced the anxious-related behaviours in the +/Lc mice by reducing their preference to the open areas in the elevated plus-maze test. Furthermore, we found that injection of CDP at the dose of 7.5 mg/kg aggravated motor coordination deficit, altered motor learning capabilities in the mutants and provoked equilibrium disturbances in the non-mutant mice in the unstable platform test. These results indicated that CDP was able to reduce behavioural disinhibition in the cerebellar +/Lc mice and were discussed in term of implication of the cerebellar connections into CDP-sensitive neural circuitries involved in both emotional and motor processes.
Le travail entrepris a permis de préciser le rôle joué par le cortex cérébelleux dans les comport... more Le travail entrepris a permis de préciser le rôle joué par le cortex cérébelleux dans les comportements moteurs et non moteurs, chez la souris, et de mettre en évidence que la dégénérescence précoce de cette structure a des conséquences à moyen et à long terme sur le comportement des ...
Beyond their motor impairments, the cerebellar Lurcher mutant mice show an alteration of the anxi... more Beyond their motor impairments, the cerebellar Lurcher mutant mice show an alteration of the anxietyrelated behaviors we called "behavioral disinhibition". This is characterized by a low avoidance towards the open arms of the elevated plus-maze device paradoxically combined with a dramatic blood corticosterone level rise induced by the exposure to the experimental conditions. The present study was aimed at determining if the disinhibition of the mutants could be caused by their stress-induced high corticosterone rate. For this purpose, we compared the behaviors of Lurcher and control mice in the elevated plus-maze test after injection of either 2-methyl-1.2-di-3-pyridil-1-propanone (metyrapone; 75 mg/kg), a corticosterone synthesis inhibitor, or vehicle alone (Tween 80, 5%). Our results showed that metyrapone, although efficiently reducing their blood corticosterone rate, provoked only modest modifications of the anxietyrelated behaviors in mice of both genotypes. As a result, the behavioral distance between the Lurcher and control mice slightly decreased, without being totally abolished. Thus, it seems that the behavioral disinhibition of the mutants is caused only in part by their stress-provoked high corticosterone level. As a complementary hypothesis, we propose that the behavioral disturbances observed in the Lurcher mice also might arise from dysfunctions of the neural pathways connecting the cerebellum with some limbic structures known to be highly involved in the regulation of emotions.
Recently, the biosafety and potential influences of nanoparticles on central nervous system have ... more Recently, the biosafety and potential influences of nanoparticles on central nervous system have received more attention. In the present study, we assessed the effect of aluminium oxide nanoparticles (Al 2 O 3 -NPs) on spatial cognition. Male Wistar rats were intravenously administered Al 2 O 3 -NP suspension (20 mg/kg body weight/day) for four consecutive days, after which they were assessed. The results indicated that Al 2 O 3 -NPs impaired spatial learning and memory ability. An increment in malondialdehyde levels with a concomitant decrease in superoxide dismutase activity confirmed the induction of oxidative stress in the hippocampus. Additionally, our findings showed that exposure to Al 2 O 3 -NPs resulted in decreased acetylcholinesterase activity in the hippocampus. Furthermore, Al 2 O 3 -NPs enhanced aluminium (Al) accumulation and disrupted mineral element homoeostasis in the hippocampus. However, they did not change the morphology of the hippocampus. Our results show a connection among oxidative stress, disruption of mineral element homoeostasis, and Al accumulation in the hippocampus, which leads to spatial memory deficit in rats treated with Al 2 O 3 -NPs.
Cancer and treatments may induce cognitive impairments in cancer patients, and the causal link be... more Cancer and treatments may induce cognitive impairments in cancer patients, and the causal link between chemotherapy and cognitive dysfunctions was recently validated in animal models. New cancer targeted therapies have become widely used, and their impact on brain functions and quality of life needs to be explored. We evaluated the impact of everolimus, an anticancer agent targeting the mTOR pathway, on cognitive functions, cerebral metabolism, and hippocampal cell proliferation/vascular density in mice. Adult mice received everolimus daily for 2 weeks, and behavioral tests were performed from 1 week after the last treatment. Everolimus-treated mice displayed a marked reduction in weight gain from the last day of the treatment period. Ex vivo analysis showed altered cytochrome oxidase activity in selective cerebral regions involved in energy balance, food intake, reward, learning and memory modulation, sleep/wake cycle regulation, and arousal. Like chemotherapy, everolimus did not alter emotional reactivity, learning and memory performances, but in contrast to chemotherapy, did not affect behavioral flexibility or reactivity to novelty. In vivo hippocampal neural cell proliferation and vascular density were also unchanged after everolimus treatments. In conclusion, two weeks daily everolimus treatment at the clinical dose did not evoke alteration of cognitive performances evaluated in hippocampal-and prefrontal cortex-dependent tasks that would persist at one to four weeks after the end of the treatment completion. However, acute everolimus treatment caused selective CO modifications without altering the mTOR effector P70S6 kinase in OPEN ACCESS cerebral regions involved in feeding behavior and/or the sleep/wake cycle, at least in part under control of the solitary nucleus and the parasubthalamic region of the hypothalamus. Thus, this area may represent a key target for everolimus-mediating peripheral modifications, which has been previously associated with symptoms such as weight loss and fatigue. Impact of Everolimus on Brain Function PLOS ONE |
In patients, cancer and treatments provoke cognitive impairments referred to “chemofog”. Here a v... more In patients, cancer and treatments provoke cognitive impairments referred to “chemofog”. Here a validated neurobehavioral animal model, the unique way to explore causal direct links between chemotherapy used in clinical practices and brain disorders, allowed investigation of the direct long-term impact of colo-rectal cancer chemotherapy on cognition and cerebral plasticity. Young and aged mice received three injections every 7 days during 2 weeks of 5-fluorouracil either alone (5-FU, 37.5 mg/kg) or in combination with oxaliplatin (3 mg/kg) or with glucose (5%). The long-term effects (from day 24 to day 60) of chemotherapy were tested on emotional reactivity, learning and memory, behavioral flexibility and hippocampal cell plasticity. 5-FU (in saline)-treated aged and also young mice exhibited specific altered cognitive flexibility and behavioral hyper-reactivity to novelty, whereas the combination 5-FU (in saline)/oxaliplatin (in glucose) did not provoke any cognitive dysfunction. We thus observed that glucose counteracted 5-FU-induced altered executive functions and hippocampal cell proliferation in vivo, and protected neural stem cells in vitro from toxicity of 5-FU or oxaliplatin. In conclusion, these data suggest that the lasting chemotherapy-induced selective impairment of executive functions, whatever the age, and associated with a reduced number of hippocampal proliferating cells, can be counteracted by co-administration with glucose.
Abstract The cerebellum is a structure of the central nervous
system involved in balance, motor c... more Abstract The cerebellum is a structure of the central nervous system involved in balance, motor coordination, and voluntary movements. The elementary circuit implicated in the control of locomotion involves Purkinje cells, which receive excitatory inputs from parallel and climbing fibers, and are regulated by cerebellar interneurons. In mice as in human, the cerebellar cortex completes its development mainly after birth with the migration, differentiation, and synaptogenesis of granule cells. These cellular events are under the control of numerous extracellular matrix molecules including pleiotrophin (PTN). This cytokine has been shown to regulate the morphogenesis of Purkinje cells ex vivo and in vivo via its receptor PTPζ. Since Purkinje cells are the unique output of the cerebellar cortex, we explored the consequences of their PTN-induced atrophy on the function of the cerebellar neuronal circuit in mice. Behavioral experiments revealed that, despite a normal overall development, PTN-treated mice present a delay in the maturation of their flexion reflex. Moreover, patch clamp recording of Purkinje cells revealed a significant
Lurcher mutant mice (+/Lc) exhibit a massive loss of neurons in the cerebellar cortex and the inf... more Lurcher mutant mice (+/Lc) exhibit a massive loss of neurons in the cerebellar cortex and the inferior olivary nucleus, while deep cerebellar nuclei are essentially intact. To discriminate the relative participation of the cerebellar cortex and deep structures in learning and memory, 3 to 6-month-old +/Lc mice were subjected to a spatial learning task derived from the Morris water escape. They were able to learn to escape as well as their strain-matched controls (+/+). Seven days later, their scores showed that they had memorized the spatial environment but not as accurately as +/+ mice. Cerebellectomy before training did not significantly alter the escape learning capabilities of either group, whereas cerebellectomy performed after learning completely abolished retention in +/+, as well as in +/Lc, mice. These results suggest that the cerebellum, although not necessary for learning a spatial task, plays a crucial role in its retention, and that the storing structure of spatial information differs in +/+ and +/Lc mice.
Administration of harmaline to the rat, which activates synchronously and rhythmically the olivar... more Administration of harmaline to the rat, which activates synchronously and rhythmically the olivary neurons and the olivocerebellar pathway, elicits visuo-motor, spatial learning and spatial memory deficiencies which are dose-dependent. Since activation and lesion of the olivocerebellar pathway have similar effects, it is concluded that normal functioning of this pathway is required for spatial learning achievement. q
Heterozygous cerebellar mutant (Rora ' /Rora sg ) mice and control (Rora ' /Rora ' ) mice of the ... more Heterozygous cerebellar mutant (Rora ' /Rora sg ) mice and control (Rora ' /Rora ' ) mice of the same C57Bl6/J strain, 3 Á/24 months old, were subjected to motor training on a rotorod for 10 days. Falling latency and percentage of time spent walking were measured. A good correlation was found between falling latency and walking time: the mice which maintained equilibrium for a long time were those which were walking, and the mice which fell early were those which were gripping suggesting that walking is obviously the most adapted strategy to keep balance on the rotorod. In Rora ' /Rora ' mice, scores before training were altered very precociously (from 6 months of age). Moreover, scores of Rora ' /Rora sg mice were lower than those of Rora ' /Rora ' mice from the age of 3 months, while neuronal number in the cerebellar cortex of these mutants was quite normal and similar to that of Rora ' / Rora ' mice. This suggests that the motor skill disability would be due to fine structural and/or biochemical changes preceding neuronal death. Such subtle changes would begin several months earlier in Rora ' /Rora sg than in Rora ' /Rora ' mice. Training on the rotorod resulted in increased scores in both genotypes at all ages. Motor learning abilities were therefore preserved in animals with a moderate neuronal loss in the cerebellum. It may be that motor learning is partly compensated by the striatum, which is known to play a major role in learning of motor skills. #
The present study evaluated the effects of the principal active component of marijuana (delta 9 T... more The present study evaluated the effects of the principal active component of marijuana (delta 9 THC) on motor abilities and motor learning in mice with cerebellar dysfunction. For this purpose, spontaneous locomotor activity, equilibrium abilities, muscular tone, motor coordination and motor learning were investigated in Lurcher mutant and non-mutant B6/CBA mice 20 min after i.p. administration of 4 or 8 mg kg −1 of delta 9 tetra hydro cannabinol (delta 9 THC). The performances were compared to those obtained by Lurcher and non-mutant mice injected with vehicle (Tween 80).
Background: Interstitial flow in and around tumour tissue not only has particular importance in d... more Background: Interstitial flow in and around tumour tissue not only has particular importance in delivering anticancer agents to tumour tissue, but also affects the microenvironment to modulate tumour cell growth and metastasis. We investigated the roles of flow-induced shear stress in modulating radiosensitivity in two colon cancer cell lines and the underlying mechanisms. Materials and Methods: T84 and SW480 colon cancer cells were trypsinized and seeded onto glass slides (75×38 mm) pre-coated with fibronectin (10 mg/ml). A parallel-plate flow chamber system was used to impose fluid shear stress. Irradiation was delivered using 160kV RS 2000 X-ray irradiator (Rad Source Technologies, Inc.). Cell proliferation, apoptosis and colony assay were measured after various combinations between shear stress and radiation. Cell cycle analysis and immunoblots of integrin b1/FAK/Akt signal molecules were evaluated. The combination effect of shear stress was reversed by neutralizing integrin b1 or using FAK overexpressed cell lines. Results: In both cell lines, incubation under shear stress (12 dynes/cm 2 ) for 24 hours enhanced radiation induced cytotoxicity. Protein expression of integrin b1 was moderately while FAK was significantly suppressed. FAK down-regulation was mainly due to ubiquitin-dependent proteasomal pathway but not transcriptional suppression. The amount of ILK, GSK3b was not affected. Using FAK overexpressed cell lines, we demonstrated that shear stress enhanced colon cancer cell radiosensitivity by regulating FAK expression. On the other hand, incubation under shear stress for 3 hours did not revealed radiosensitizing effect in both cell lines. Using integrin b1 neutralizing antibody, we suppressed FAK/Akt activation by 3-hr shear stress and enhanced radiation related cytotoxicity in both colon cancer cell lines. Conclusions: Shear stress of 24 hours provides radio-sensitization to colon cancer cell through proteosomal degradation of FAK via integrin b1. Our findings provide insights into the mechanism by which shear stress modulates colon cancer cell cytotoxicity in response to radiation. The results impact rationale combination between radiation and strategy in modulating tumour interstitial fluid pressure.
AbstractÐMotor learning abilities on the rotorod and motor skills (muscular strength, motor coord... more AbstractÐMotor learning abilities on the rotorod and motor skills (muscular strength, motor coordination, static and dynamic equilibrium) were investigated in three-, nine-, 15-and 21-month-old Lurcher and control mice. Animals were subjected to motor training on the rotorod before being subjected to motor skills tests. The results showed that control mice exhibited decrease of muscular strength and speci®c equilibrium impairments in static conditions with age, but were still able to learn the motor task on the rotorod even in old age. These results suggest that, in control mice, ef®ciency of the reactive mechanisms, which are sustained by the lower transcerebellar loop (cerebello-rubro-olivo-cerebellar loop), decreased with age, while the ef®ciency of the proactive adjustments, which are sustained by the upper transcerebellar loop (cerebello-thalamo-cortico-ponto-cerebellar loop), did not. In spite of their motor de®cits, Lurcher mutants were able to learn the motor task at three months, but exhibited severe motor learning de®cits as soon as nine months. Such a de®cit seems to be associated with dynamic equilibrium impairments, which also appeared at nine months in these mutants. By two months of age, degeneration of the cerebellar cortex and the olivocerebellar pathway in Lurcher mice has disrupted both lower and upper transcerebellar loops. Disruption of the lower loop could well explain precocious static equilibrium de®cits. However, in spite of disruption of the upper loop, motor learning and dynamic equilibrium were preserved in young mutant mice, suggesting that either deep cerebellar nuclei and/or other motor structures involved in proactive mechanisms needed to maintain dynamic equilibrium and to learn motor tasks, such as the striatopallidal system, are suf®cient. The fact that, in Lurcher mutant mice, motor learning decreased by the age of nine months suggests that the above-mentioned structures are less ef®cient, likely due to degeneration resulting from precocious and focused neurodegeneration of the cerebellar cortex.
Heterozygous cerebellar mutant (Rora ' /Rora sg ) mice and control (Rora ' /Rora ' ) mice of the ... more Heterozygous cerebellar mutant (Rora ' /Rora sg ) mice and control (Rora ' /Rora ' ) mice of the same C57Bl6/J strain, 3 Á/24 months old, were subjected to motor training on a rotorod for 10 days. Falling latency and percentage of time spent walking were measured. A good correlation was found between falling latency and walking time: the mice which maintained equilibrium for a long time were those which were walking, and the mice which fell early were those which were gripping suggesting that walking is obviously the most adapted strategy to keep balance on the rotorod. In Rora ' /Rora ' mice, scores before training were altered very precociously (from 6 months of age). Moreover, scores of Rora ' /Rora sg mice were lower than those of Rora ' /Rora ' mice from the age of 3 months, while neuronal number in the cerebellar cortex of these mutants was quite normal and similar to that of Rora ' / Rora ' mice. This suggests that the motor skill disability would be due to fine structural and/or biochemical changes preceding neuronal death. Such subtle changes would begin several months earlier in Rora ' /Rora sg than in Rora ' /Rora ' mice. Training on the rotorod resulted in increased scores in both genotypes at all ages. Motor learning abilities were therefore preserved in animals with a moderate neuronal loss in the cerebellum. It may be that motor learning is partly compensated by the striatum, which is known to play a major role in learning of motor skills. #
Harmaline (HA) is a beta-carboline commonly known to provoke motor alterations through activation... more Harmaline (HA) is a beta-carboline commonly known to provoke motor alterations through activation of cells in the inferior olive. In addition, this pharmacological agent also induces cognitive disturbances such as motor and spatial learning impairments. In order to complete and extend these data, we examined the effects of this drug on state anxiety in mice, employing elevated plus maze test. We report here that lower doses of harmaline (5-10 mg/kg) have anxiogenic since higher doses (20 mg/kg) have anxiolytic-like properties. Overall pattern of our behavioral results provides evidence that harmaline also acts on emotional reactivity in mice by influencing their decision making when placed in an anxiogenic situation.
It is now well accepted that besides its roles in motor control, the cerebellum is involved in no... more It is now well accepted that besides its roles in motor control, the cerebellum is involved in non-motor functions with emotional aspects. Consistent with this view, several studies highlighted that the cerebellar Lurcher mutant mice (+/Lc), with motor impairments, also exhibited altered emotional reactivity, previously interpreted in term of behavioural disinhibition. In this study, we investigated the effects of a classical anxiolytic on such disinhibition. For that, behaviours of +/Lc and control (+/+) mice injected with NaCl or chlordiazepoxide (CDP 5 and 7.5 mg/kg) were evaluated in the elevated plus-maze test. The motor impact of the drug (7.5 mg/kg only) was also evaluated in the hole-board and unstable platform tests. Our results showed that, compared to the +/+ mice, CDP injection greatly influenced the anxious-related behaviours in the +/Lc mice by reducing their preference to the open areas in the elevated plus-maze test. Furthermore, we found that injection of CDP at the dose of 7.5 mg/kg aggravated motor coordination deficit, altered motor learning capabilities in the mutants and provoked equilibrium disturbances in the non-mutant mice in the unstable platform test. These results indicated that CDP was able to reduce behavioural disinhibition in the cerebellar +/Lc mice and were discussed in term of implication of the cerebellar connections into CDP-sensitive neural circuitries involved in both emotional and motor processes.
Le travail entrepris a permis de préciser le rôle joué par le cortex cérébelleux dans les comport... more Le travail entrepris a permis de préciser le rôle joué par le cortex cérébelleux dans les comportements moteurs et non moteurs, chez la souris, et de mettre en évidence que la dégénérescence précoce de cette structure a des conséquences à moyen et à long terme sur le comportement des ...
Beyond their motor impairments, the cerebellar Lurcher mutant mice show an alteration of the anxi... more Beyond their motor impairments, the cerebellar Lurcher mutant mice show an alteration of the anxietyrelated behaviors we called "behavioral disinhibition". This is characterized by a low avoidance towards the open arms of the elevated plus-maze device paradoxically combined with a dramatic blood corticosterone level rise induced by the exposure to the experimental conditions. The present study was aimed at determining if the disinhibition of the mutants could be caused by their stress-induced high corticosterone rate. For this purpose, we compared the behaviors of Lurcher and control mice in the elevated plus-maze test after injection of either 2-methyl-1.2-di-3-pyridil-1-propanone (metyrapone; 75 mg/kg), a corticosterone synthesis inhibitor, or vehicle alone (Tween 80, 5%). Our results showed that metyrapone, although efficiently reducing their blood corticosterone rate, provoked only modest modifications of the anxietyrelated behaviors in mice of both genotypes. As a result, the behavioral distance between the Lurcher and control mice slightly decreased, without being totally abolished. Thus, it seems that the behavioral disinhibition of the mutants is caused only in part by their stress-provoked high corticosterone level. As a complementary hypothesis, we propose that the behavioral disturbances observed in the Lurcher mice also might arise from dysfunctions of the neural pathways connecting the cerebellum with some limbic structures known to be highly involved in the regulation of emotions.
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Papers by Pascal Hilber
neurobehavioral animal model, the unique way to explore causal direct links between chemotherapy
used in clinical practices and brain disorders, allowed investigation of the direct long-term
impact of colo-rectal cancer chemotherapy on cognition and cerebral plasticity. Young and aged mice
received three injections every 7 days during 2 weeks of 5-fluorouracil either alone (5-FU, 37.5 mg/kg) or
in combination with oxaliplatin (3 mg/kg) or with glucose (5%). The long-term effects (from day 24 to day
60) of chemotherapy were tested on emotional reactivity, learning and memory, behavioral flexibility
and hippocampal cell plasticity.
5-FU (in saline)-treated aged and also young mice exhibited specific altered cognitive flexibility and
behavioral hyper-reactivity to novelty, whereas the combination 5-FU (in saline)/oxaliplatin (in glucose)
did not provoke any cognitive dysfunction. We thus observed that glucose counteracted 5-FU-induced
altered executive functions and hippocampal cell proliferation in vivo, and protected neural stem cells
in vitro from toxicity of 5-FU or oxaliplatin. In conclusion, these data suggest that the lasting
chemotherapy-induced selective impairment of executive functions, whatever the age, and associated
with a reduced number of hippocampal proliferating cells, can be counteracted by co-administration
with glucose.
system involved in balance, motor coordination, and voluntary
movements. The elementary circuit implicated in the control
of locomotion involves Purkinje cells, which receive excitatory
inputs from parallel and climbing fibers, and are regulated
by cerebellar interneurons. In mice as in human, the
cerebellar cortex completes its development mainly after birth
with the migration, differentiation, and synaptogenesis of
granule cells. These cellular events are under the control of
numerous extracellular matrix molecules including
pleiotrophin (PTN). This cytokine has been shown to regulate
the morphogenesis of Purkinje cells ex vivo and in vivo via its
receptor PTPζ. Since Purkinje cells are the unique output of
the cerebellar cortex, we explored the consequences of their
PTN-induced atrophy on the function of the cerebellar neuronal
circuit in mice. Behavioral experiments revealed that, despite
a normal overall development, PTN-treated mice present
a delay in the maturation of their flexion reflex. Moreover,
patch clamp recording of Purkinje cells revealed a significant
neurobehavioral animal model, the unique way to explore causal direct links between chemotherapy
used in clinical practices and brain disorders, allowed investigation of the direct long-term
impact of colo-rectal cancer chemotherapy on cognition and cerebral plasticity. Young and aged mice
received three injections every 7 days during 2 weeks of 5-fluorouracil either alone (5-FU, 37.5 mg/kg) or
in combination with oxaliplatin (3 mg/kg) or with glucose (5%). The long-term effects (from day 24 to day
60) of chemotherapy were tested on emotional reactivity, learning and memory, behavioral flexibility
and hippocampal cell plasticity.
5-FU (in saline)-treated aged and also young mice exhibited specific altered cognitive flexibility and
behavioral hyper-reactivity to novelty, whereas the combination 5-FU (in saline)/oxaliplatin (in glucose)
did not provoke any cognitive dysfunction. We thus observed that glucose counteracted 5-FU-induced
altered executive functions and hippocampal cell proliferation in vivo, and protected neural stem cells
in vitro from toxicity of 5-FU or oxaliplatin. In conclusion, these data suggest that the lasting
chemotherapy-induced selective impairment of executive functions, whatever the age, and associated
with a reduced number of hippocampal proliferating cells, can be counteracted by co-administration
with glucose.
system involved in balance, motor coordination, and voluntary
movements. The elementary circuit implicated in the control
of locomotion involves Purkinje cells, which receive excitatory
inputs from parallel and climbing fibers, and are regulated
by cerebellar interneurons. In mice as in human, the
cerebellar cortex completes its development mainly after birth
with the migration, differentiation, and synaptogenesis of
granule cells. These cellular events are under the control of
numerous extracellular matrix molecules including
pleiotrophin (PTN). This cytokine has been shown to regulate
the morphogenesis of Purkinje cells ex vivo and in vivo via its
receptor PTPζ. Since Purkinje cells are the unique output of
the cerebellar cortex, we explored the consequences of their
PTN-induced atrophy on the function of the cerebellar neuronal
circuit in mice. Behavioral experiments revealed that, despite
a normal overall development, PTN-treated mice present
a delay in the maturation of their flexion reflex. Moreover,
patch clamp recording of Purkinje cells revealed a significant