Degenerative effects of nerve tissues are often accompanied by changes in vascularization. In this regard, knowledge about hereditary cerebellar degeneration is limited. In this study, we compared the vascularity of the individual cerebellar components of 3-month-old wild-type mice (n = 8) and Purkinje cell degeneration (pcd) mutant mice, which represent a model of hereditary cerebellar degeneration (n = 8). Systematic random samples of tissue sections were processed, and laminin was immunostained to visualize microvessels. A computer-assisted stereology system was used to quantify microvessel parameters including total number, total length, and associated densities in cerebellar layers. Our results in pcd mice revealed a 45% (p < 0.01) reduction in the total volume of the cerebellum, a 28% (p < 0.05) reduction in the total number of vessels and a lower total length, approaching 50% (p < 0.001), compared to the control mice. In pcd mutants, cerebellar degeneration is accompanied by significant reduction in the microvascular network that is proportional to the cerebellar volume reduction therefore does not change density of in the cerebellar gray matter of pcd mice.
- MeSH
- mikrocévy MeSH
- mozeček * MeSH
- myši - mutanty neurologické MeSH
- myši inbrední C57BL MeSH
- myši MeSH
- Purkyňovy buňky * fyziologie MeSH
- zvířata MeSH
- Check Tag
- myši MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- MeSH
- Alzheimerova nemoc genetika patofyziologie MeSH
- Huntingtonova nemoc patofyziologie MeSH
- modely nemocí na zvířatech * MeSH
- myši - mutanty neurologické MeSH
- neurodegenerativní nemoci * genetika klasifikace patologie MeSH
- Parkinsonova nemoc genetika patofyziologie MeSH
- Publikační typ
- přehledy MeSH
Exercise therapy represents an important tool for the treatment of many neurological diseases, including cerebellar degenerations. In mouse models, exercise may decelerate the progression of gradual cerebellar degeneration via potent activation of neuroprotective pathways. However, whether exercise could also improve the condition in mice with already heavily damaged cerebella remains an open question. Here we aimed to explore this possibility, employing a mouse model with dramatic early-onset cerebellar degeneration, the Lurcher mice. The potential of forced physical activity and environmental enrichment (with the possibility of voluntary running) for improvement of behaviour and neuroplasticity was evaluated by a series of behavioural tests, measuring BDNF levels and using stereological histology techniques. Using advanced statistical analysis, we showed that while forced physical activity improved motor learning by ∼26 % in Lurcher mice and boosted BDNF levels in the diseased cerebellum by 57 %, an enriched environment partially alleviated some behavioural deficits related to behavioural disinhibition. Specifically, Lurcher mice exposed to the enriched environment evinced reduced open arm exploration in elevated plus maze test by 18 % and increased immobility almost 9-fold in the forced swim test. However, we must conclude that the overall beneficial effects were very mild and much less clear, compared to previously demonstrated effects in slowly-progressing cerebellar degenerations.
- MeSH
- bydlení zvířat * MeSH
- chování zvířat fyziologie MeSH
- hra a hračky MeSH
- kondiční příprava zvířat fyziologie MeSH
- modely nemocí na zvířatech MeSH
- mozeček * metabolismus patologie MeSH
- mozkový neurotrofický faktor metabolismus MeSH
- myši - mutanty neurologické MeSH
- myši MeSH
- neurodegenerativní nemoci * metabolismus patologie rehabilitace MeSH
- terapie cvičením MeSH
- zvířata MeSH
- Check Tag
- myši MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
Anxiety-related behaviors in mice are often assessed over short periods starting immediately after introducing the animals in a dedicated apparatus. In these usual conditions (5-10 min periods), the cerebellar Lurcher mutants showed disinhibited behaviors characterized by abnormally high exploration of the aversive areas in the elevated plus-maze test. We nevertheless observed that this disinhibition sharply weakened after 10 min. We therefore decided to further investigate the influence of the disinhibition on the intrinsic and anxiety-related exploratory behaviors in Lurcher mice, with a special focus on familiarization effects. To this end, we used an innovative apparatus, the Dual Maze, permitting to tune the familiarization level of animals to the experimental context before they are faced with more (open configuration of the device) or less (closed configuration of the device) aversive areas. Chlordiazepoxide administration in BALB/c mice in a preliminary experiment confirmed both the face and the predictive validity of our device as anxiety test and its ability to measure exploratory motivation. The results obtained with the Lurcher mice in the open configuration revealed that 20 min of familiarization to the experimental context abolished the behavioral abnormalities they exhibited when not familiarized with it. In addition, their exploratory motivation, as measured in the closed configuration, was comparable to that of their non-mutant littermates, whatever the level of familiarization applied. Exemplifying the interest of this innovative device, the results we obtained in the Lurcher mutants permitted to differentiate between the roles played by the cerebellum in exploratory motivation and stress-related behaviors.
- MeSH
- bludiště - učení fyziologie MeSH
- chování zvířat fyziologie MeSH
- inhibice (psychologie) * MeSH
- motivace fyziologie MeSH
- mozeček MeSH
- myši - mutanty neurologické MeSH
- myši inbrední BALB C MeSH
- myši MeSH
- neuropsychologické testy * MeSH
- pátrací chování fyziologie MeSH
- rozpoznávání (psychologie) fyziologie MeSH
- úzkost patofyziologie MeSH
- zvířata MeSH
- Check Tag
- mužské pohlaví MeSH
- myši MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
Hereditary cerebellar degenerations are severe and complex diseases for which there is currently no effective causal treatment. A hopeful method could be the support of plasticity or neurotransplantation. However, there are still many unknown aspects which could influence the outcome of treatment. As neurotrophic factors are essential in neuroplasticity and neuronal integration, potential abnormalities in their levels could be involved in the pathogenesis of the disease and would possibly explain the unsuitability of diseased cerebellum for the graft integration. The aim of this study was to identify and compare basal levels of trophic factors BDNF and GDNF in the cerebellum in two mouse models of cerebellar degeneration - Lurcher and pcd. Basal levels of BDNF in the cerebellum have been shown to be lower in both mutant models than in healthy controls. However, the GDNF levels were surprisingly increased in the cerebella of Lurcher mutant mice compared to both wild type and pcd mice. In addition, a different distribution of GFAP-positive cells in the cerebellum was revealed in Lurcher mice. These differences suggest that the niche of the Lurcher mutant cerebellum is changed. The question, however, remains how these changes are related to the neurodegenerative process and how they could influence potential compensatory mechanisms, plasticity and response to therapeutic interventions.
- MeSH
- biologické markery metabolismus MeSH
- mozeček chemie metabolismus MeSH
- mozkový neurotrofický faktor genetika metabolismus MeSH
- mutace fyziologie MeSH
- myši - mutanty neurologické MeSH
- myši inbrední CBA MeSH
- myši transgenní MeSH
- myši MeSH
- neurodegenerativní nemoci genetika metabolismus MeSH
- růstový faktor GDNF genetika metabolismus MeSH
- zvířata MeSH
- Check Tag
- myši MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
Lurcher mutant mice of the C3H strain provide a model of both cerebellar and retinal degeneration. Therefore, they enable the study of the behavior of cerebellar mutants under disabled visual orientation conditions. We aimed to examine cerebellar Lurcher mutants and wild type mice with intact cerebella with and without retinal degeneration employing the rotarod and Morris water maze tests. The positions of the hidden platform and the starting point in the water maze test were stable so as to enable the use of both idiothetic navigation and visual inputs. The Lurcher mice evinced approximately 90 % shorter fall latencies on the rotarod than did the wild type mice. Retinal degeneration exerted no impact on motor performance. Only the wild type mice with normal retina were able to find the water maze platform efficiently. The wild type mice with retinal degeneration developed immobility (almost 25 % of the time) as a sign of behavioral despair. The Lurchers maintained high swimming activity as a potential manifestation of stress-induced behavioral disinhibition and their spatial performance was related to motor skills and swim speed. We demonstrated that both motor deficit and pathological behavior have the potential to contribute to abnormal performance in spatial tasks. Thus, spatial disability in cerebellar mutants is most likely a complex consequence of multiple disturbances related to cerebellar dysfunction.
- MeSH
- bludiště - učení fyziologie MeSH
- degenerace retiny genetika patologie MeSH
- motorické dovednosti fyziologie MeSH
- mozeček patologie MeSH
- myši - mutanty neurologické MeSH
- myši inbrední C3H MeSH
- myši MeSH
- neurodegenerativní nemoci genetika patologie MeSH
- slepota genetika patologie MeSH
- vnímání prostoru fyziologie MeSH
- zvířata MeSH
- Check Tag
- mužské pohlaví MeSH
- myši MeSH
- ženské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
Cerebellar diseases causing substantial cell loss often lead to severe functional deficits and restoration of cerebellar function is difficult. Neurotransplantation therapy could become a hopeful method, but there are still many limitations and unknown aspects. Studies in a variety of cerebellar mutant mice reflecting heterogeneity of human cerebellar degenerations show promising results as well as new problems and questions to be answered. The aim of this work was to compare the development of embryonic cerebellar grafts in adult B6CBA Lurcher and B6.BR pcd mutant mice and strain-matched healthy wild type mice. Performance in the rotarod test, graft survival, structure, and volume was examined 2 months after the transplantation or sham-operation. The grafts survived in most of the mice of all types. In both B6CBA and B6.BR wild type mice and in pcd mice, colonization of the host's cerebellum was a common finding, while in Lurcher mice, the grafts showed a low tendency to infiltrate the host's cerebellar tissue. There were no significant differences in graft volume between mutant and wild type mice. Nevertheless, B6CBA mice had smaller grafts than their B6.BR counterparts. The transplantation did not improve the performance in the rotarod test. The study showed marked differences in graft integration into the host's cerebellum in two types of cerebellar mutants, suggesting disease-specific factors influencing graft fate.
- MeSH
- modely nemocí na zvířatech * MeSH
- mozeček fyziologie transplantace MeSH
- myši - mutanty neurologické MeSH
- myši inbrední C57BL MeSH
- myši inbrední CBA MeSH
- myši MeSH
- nemoci mozečku patologie terapie MeSH
- neurodegenerativní nemoci patologie terapie MeSH
- přežívání štěpu fyziologie MeSH
- transplantace fetální tkáně metody MeSH
- transplantace mozkové tkáně metody MeSH
- zvířata MeSH
- Check Tag
- mužské pohlaví MeSH
- myši MeSH
- ženské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
For many degenerative cerebellar diseases, currently, no effective treatment that would substantially restore cerebellar functions is available. Neurotransplantation could be a promising therapy for such cases. Nevertheless, there are still severe limitations for routine clinical use. The aim of the work was to assess volume and morphology and functional impact on motor skills of an embryonic cerebellar graft injected in the form of cell suspension in Lurcher mutant and wild-type mice of the B6CBA and C3H strains after a 6-month survival period. The grafts survived in the majority of the mice. In both B6CBA and C3H Lurcher mice, most of the grafts were strictly delimited with no tendency to invade the host cerebellum, while in wild-type mice, graft-derived Purkinje cells colonized the host's cerebellum. In C3H Lurcher mice, but not in B6CBA Lurchers, the grafts had smaller volume than in their wild-type counterparts. C3H wild-type mice had significantly larger grafts than B6CBA wild-type mice. No positive effect of the transplantation on performance in the rotarod test was observed. The findings suggest that the niche of the Lurcher mutant cerebellum has a negative impact on integration of grafted cells. This factor seems to be limiting for specific functional effects of the transplantation therapy in this mouse model of cerebellar degeneration.
- MeSH
- druhová specificita MeSH
- longitudinální studie MeSH
- metoda rotující tyčky MeSH
- modely nemocí na zvířatech MeSH
- motorické dovednosti MeSH
- mozeček embryologie patologie transplantace MeSH
- myši - mutanty neurologické MeSH
- myši inbrední C3H MeSH
- myši inbrední CBA MeSH
- myši transgenní MeSH
- nemoci mozečku patologie patofyziologie terapie MeSH
- neurodegenerativní nemoci patologie patofyziologie terapie MeSH
- přežívání štěpu * fyziologie MeSH
- transplantace mozkové tkáně * MeSH
- zelené fluorescenční proteiny genetika metabolismus MeSH
- zvířata MeSH
- Check Tag
- mužské pohlaví MeSH
- ženské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
