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Gavigan, Thomas. "VOLUMETRIC GROWTH MODEL OF HUMAN MEDULLOBLASTOMA IN THE NUDE MOUSE CEREBELLUM." VCU Scholars Compass, 2010. http://scholarscompass.vcu.edu/etd/133.
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Medulloblastoma is the most common brain tumor in children, accounting for 10-20% of primary central nervous system (CNS) neoplasms and approximately 40% of all posterior fossa tumors. It is a highly invasive embryonal neuroepithelial tumor that typically arises in the cerebellar vermis and has a tendency to disseminate throughout the CNS early in its course. The molecular mechanisms of the disease largely remain uncharacterized, as the clinical treatment is still associated with mortality and severe side effects. The development of a clinically relevant in vivo model is important not only to further understand the disease but also to provide a method with which to test novel therapeutics. This study quantified the volumetric growth of a human medulloblastoma (VC312) in the athymic nude mouse cerebellum using Gd- enhanced T1-weighed MRI scans. Additionally, a medulloblastoma flank tumor model was used to explore the in vivo effect of the oral anti-cancer agent that inhibits Akt activation in the phosphoinositide 3-kinase (PI3K) pathway. In the orthotopic intracerebellar tumor model, perifosine significantly increased the survival of treated mice while qualitatively reducing leptomeningeal dissemination. In the flank model, perifosine effectively suppressed the volumetric growth, decreased activation of the AKT pathway and reduced cellular proliferation in treated mice.
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Senatore, Rosa. "The role of basal ganglia and cerebellum in motor learning. A computational model." Doctoral thesis, Universita degli studi di Salerno, 2012. http://hdl.handle.net/10556/373.
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2010 - 2011Our research activity investigates the computational processes underlying the execution of complex sequences of movements and aims at understanding how different levels of the nervous system interact and contribute to the gradual improvement of motor performance during learning. Many research areas, from neuroscience to engineering, investigate, from different perspectives and for diverse purposes, the processes that allow humans to efficiently perform skilled movements. From a biological point of view, the execution of voluntary movements requires the interaction between nervous and musculoskeletal systems, involving several areas, from the higher cortical centers to motor circuits in the spinal cord. Understanding these interactions could provide important insights for many research fields, from machine learning to medicine, from the design of robotic limbs to the development of new treatments for movement disorders, such as Parkinson’s disease. This goal could be achieved by finding an answer to the following questions: · How does the central nervous system control and coordinate natural voluntary movements? · Which brain areas are involved in learning a new motor skill? What are the changes that happen in these neural structures? What are the aspects of the movement memorized? · Which is the process that allows people to perform a skilled task, such as playing an instrument, being apparently unaware of the movements they are performing? · What happen when a neurodegenerative disease affects the brain areas involved in executing movements? These questions have been addressed from different perspectives and levels of analysis, from the exploration of the anatomical structure of the neural systems thought to be involved in motor learning (such as the basal ganglia, cerebellum and hippocampus) to the investigation of their neural interaction; from the analysis of the activation of these systems in executing a motor task to the specific activation of a single or a small group of neurons within them. In seeking to understand all the breadth and facets of motor learning, many researchers have used different approaches and methods, such as genetic analysis, neuroimaging techniques (such as fMRI, PET and EEG), animal models and clinical treatments (e.g. drugs administration and brain stimulation). These studies have provided a large body of knowledge that has led to several theories related to the role of the central nervous system in controlling and learning simple and complex movements. These theories envisage the interaction among multiple brain regions, whose cooperation leads to the execution of skilled movements. How can we test these interactions for the purpose of evaluating a theory? Our answer to this question is investigating these interactions through computational models, which provide a valuable complement to the experimental brain research, especially in evaluating the interactions within and among multiple neural systems. Based on these concepts arises our research, which addresses the questions previously pointed out and aims at understanding the computational processes performed by two neural circuits, the Basal Ganglia and Cerebellum, in motor learning. We propose a new hypothesis about the neural processes occurring during acquisition and retention of novel motor skills. According to our hypothesis, a sequence of movements is stored in the nervous system in the form of a spatial sequence of points (composing the trajectory plan associated to the motor sequence) and a sequence of motor commands. We propose that learning novel motor skills requires two phases, in which two different processes take place. Early in learning, when movements are slower, less accurate, and attention demanding, the motor sequence is performed by converting the sequence of target points into the appropriate sequence of motor commands. During this phase, the trajectory plan is acquired and the movements rely on the information provided by the visuo-proprioceptive feedback, which allows to correct the sequence of movements so that the actual trajectory plan corresponds to the desired one and the lowest energy is spent by the muscular subsystem involved. During the late learning phase, when the sequence of movements is performed faster and automatically, with little or no cognitive resources needed to complete it, and is characterized by anticipatory movements, the sequence of motor commands is acquired and thus, the sequence of movements comes to be executed as a single behavior. We suggest that the Basal Ganglia and Cerebellum are involved in learning novel motor sequences, although their role is crucial in different stages of learning. Accordingly, we propose a neural scheme for procedural motor learning, comprising the basal ganglia, cerebellum and cortex, which envisages that the basal ganglia, interacting with the cortex, select the sequence of target points to reach (composing the trajectory plan), whereas the cerebellum, interacting with the cortex, is responsible for converting the trajectory plan into the appropriate sequence of motor commands. Consequently, we suggest that early in learning, task performance is more dependent on the procedural knowledge maintained by the cortex-basal ganglia system, while after a long-term practice, when the sequence of motor commands is acquired within the cerebellum, task performance is more dependent on the motor command sequence maintained by the cortexcerebellar system. We tested the neural scheme (and the hypothesis behind it) through a computational model that incorporates the key anatomical, physiological and biological features of these brain areas in an integrated functional network. Analyzing the behavior of the network in learning novel motor tasks and executing well-known motor tasks, both in terms of the neural activations and motor response provided, we found that the results obtained fit those reported by many neuroimaging and experimental studies presented in the literature. We also carried out further experiments, simulating neurodegenerative disorders (Parkinson's and Huntington disease, which affect the basal ganglia) and cerebellar damages. Results obtained by these experiments validates the proposed hypothesis, showing that the basal ganglia play a key role during the early stage of learning, whereas the cerebellum is crucial for motor skill retention. Our model provides some insights about the learning mechanisms occurring within the cerebellum and gains further understanding of the functional dynamics of information processing within the basal ganglia and cerebellum in normal as well as in diseased brains. Therefore the model provides novel predictions about the role of basal ganglia and cerebellum in motor learning, motivating further investigations of their interactions. [edited by author]
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Babenko, Olena Mykolayivna, and University of Lethbridge Faculty of Arts and Science. "The molecular mechanisms underlying epigenetics of the stress response in the cerebellum in a rat model." Thesis, Lethbridge, Alta. : University of Lethbridge, Dept. of Biological Sciences, c2010, 2010. http://hdl.handle.net/10133/2604.
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Previous findings showed that mild chronic restraint stress causes motor impairments in rats. These behavioural impairments might be related to molecular changes in brain areas that regulate motor functions, such as the cerebellum. Little is known about the role of the cerebellum in stress-induced behavioural alteration. We hypothesized that alteration in animal behaviour after chronic restraint stress is due to brain-specific changes in miRNA and proteins encoding gene expression. Our results revealed that expression of three miRNAs and 39 mRNAs was changed significantly after two weeks of stress. Furthermore, we verified one putative target for one of the changed miRNAs and expression of four randomly selected genes. Changes in gene expression disappeared after two weeks of recovery from stress. These findings provide a novel insight into stress-related mechanisms of gene expression underlying altered behavioural performance. The observations bear implications for the prevention and treatment of stress-related disorders and disease.xii, 109 leaves. : ill. ; 29 cm
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Chintawar, Satyan. "Neural precursor cells: interaction with blood-brain barrier and neuroprotective effect in an animal model of cerebellar degeneration." Doctoral thesis, Universite Libre de Bruxelles, 2009. http://hdl.handle.net/2013/ULB-DIPOT:oai:dipot.ulb.ac.be:2013/210202.
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Adult neural precursor cells (NPCs) are a heterogeneous population of mitotically active, self-renewing multipotent cells of both adult and developing CNS. They can be expanded in vitro in the presence of mitogens. The B05 transgenic SCA1 mice, expressing human ataxin-1 with an expanded polyglutamine tract in cerebellar Purkinje cells (PCs), recapitulate many pathological and behavioral characteristics of the neurodegenerative disease spinocerebellar ataxia type 1 (SCA1), including progressive ataxia and PC loss. We transplanted neural precursor cells (NPCs) derived from the subventricular zone of GFP-expressing adult mice into the cerebellar white matter of SCA1 mice when they showed absent (5 weeks), initial (13 weeks) and significant PC loss (24 weeks). A stereological count demonstrates that mice with significant cell loss exhibit highest survival of grafted NPCs and migration to the vicinity of PCs as compared to wt and younger grafted animals. These animals showed improved motor skills as compared to sham animals. Confocal analysis and profiling shows that many of implanted cells present in the cerebellar cortex have formed gap junctions with host PCs and express connexin43. Grafted cells did not adopt characteristics of PCs, but stereological and morphometric analysis of the cerebellar cortex revealed that grafted animals had more surviving PCs and a better preserved morphology of these cells than the control groups. Perforated patch clamp recordings revealed a normalization of the PC basal membrane potential, which was abnormally depolarized in sham-treated animals. No significant increase in levels of several neurotrophic factors was observed, suggesting, along with morphological observation, that the neuroprotective effect of grafted NPCs was mediated by direct contact with the host PCs. In this study, evidence for a neuroprotective effect came, in addition to motor behavior improvement, from stereological and electrophysiological analyses and suggest that timing of stem cell delivery is important to determine its therapeutic effect.In a brain stem cell niche, NSCs reside in a complex cellular and extracellular microenvironment comprising their own progeny, ependymal cells, numerous blood vessels and various extracellular matrix molecules. Recently, it was reported that blood vessel ECs-NSCs crosstalk plays an important role in tissue homeostasis. Bloodstream offers a natural delivery vehicle especially in case of diffuse neurodegenerative diseases which require widespread distribution of exogenous cells. As NSCs are confronted with blood-brain barrier endothelial cells (BBB-ECs) before they can enter into brain parenchyma, we investigated their interaction using primary cultures in an in vitro BBB model. We isolated human fetal neural precursor cells (hfNPCs) from aborted fetal brain tissues and expanded in vitro. We showed that in an in vitro model, human BBB endothelium induces the rapid differentiation of hfNPCs and allows them to cross the endothelial monolayer, with the differentiated progeny remaining in close contact with endothelial cells. These results are not reproduced when using a non-BBB endothelium and are partly dependent on the cytokine MCP1. Our data suggest that, in the presence of attractive signals released by a damaged brain, intravascularly administered NPCs can move across an intact BBB endothelium and differentiate in its vicinity. Overall, our findings have implications for the development of cellular therapies for cerebellar degenerative diseases and understanding of the brain stem cell niche.
Doctorat en Sciences biomédicales et pharmaceutiques
info:eu-repo/semantics/nonPublished
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Takagishi, Yoshiko, 芳子 高岸, and Yoshiharu Murata. "Myosin Va mutation in rats is an animal model for the human hereditary neurological disease, Griscelli syndrome type 1." New York Academy of Sciences, 2006. http://hdl.handle.net/2237/10947.
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Hecker, David [Verfasser]. "Migration of interneuronal precursor cells in the developing cerebellum of mice : model-based cell tracking and simulation / David Hecker." Bonn : Universitäts- und Landesbibliothek Bonn, 2010. http://d-nb.info/1016155654/34.
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Klein, de Licona Hannah Washington. "Congenital LCMV virus: mechanism of brain disease in a rat model of congenital viral infection." Diss., University of Iowa, 2010. https://ir.uiowa.edu/etd/531.
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Lymphocytic choriomeningitis virus (LCMV) infection during pregnancy severely injures the human fetal brain. Neonatal rats inoculated with LCMV are an excellent model of congenital LCMV infection, as they develop neuropathology, including cerebellar injuries, similar to those seen in humans. The goal of this thesis was to determine what underlies brain injury and the differential immune response and to determine the role of T-cells in LCMV induced pathology. First, I examined whether cytokine and chemokine expression after LCMV infection was higher in the cerebellum and olfactory bulbs, which undergo destruction, compared to the hippocampus and septum, which undergo no acute destruction. Second, I used T-cell deficient and T-cell competent animals to evaluate the role of T-lymphocytes in LCMV-induced cerebellar and hippocampus pathology. Finally, I characterized the migration abnormality that develops in the cerebellum after LCMV infection. My results showed that cytokine and chemokine expression is higher in the cerebellum and olfactory bulb than in the hippocampus and septum. Using astrocyte cultures, I determined that astrocytes isolated from the cerebellum have a more robust cytokine response to infection compared to astrocytes from the hippocampus. Furthermore, inoculation of congenitally athymic (rnu/rnu) rats, which are deficient in T-lymphocytes, demonstrated that cerebellar hypoplasia is T-cell independent while cerebellar destruction and abnormal neuron migration is T-cell dependent. In the hippocampus, T-cells protect against loss of dentate granule cells. A study of the migration abnormality determined that LCMV infection disrupts radial glia fibers and extends proliferation of granule cells in a T-cell dependent manner. The findings reported here support a pivotal role of the immune system in regional brain pathology as well as in the disruption of migration.
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Balastik, Martin. "Trim2 mutant mice as a model for cerebellar ataxia." Doctoral thesis, [S.l.] : [s.n.], 2003. http://deposit.ddb.de/cgi-bin/dokserv?idn=975117025.
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MARSHALL, CRAIG ANTHONY. "QUANTITATIVE MEASUREMENT OF THE EXPRESSION OF TWO GENES IN THE CORETX AND CEREBELLUM OF A MOUSE MODEL OF JUVENILE ALZHEIMER’S." Thesis, The University of Arizona, 2016. http://hdl.handle.net/10150/613283.
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There is a continuing effort in order to connect the two neurodegenerative diseases:
Alzheimer’s Disease and Niemann-Pick Type C Disease (NPC1) “Juvenile Alzheimer’s”. Here
in this study, we attempted to determine if there was a connection through the gene expression in
inflammatory genes, CD14 and ETS-1, in a NPC1 mouse model, Npc1nmf164, using quantitative
real time PCR. Hydroxypropyl-beta-cyclodextrin (HPβCD) is reported to provide a beneficial
effect on NPC1, and there was interest in seeing if HPβCD treatment could return the expression
levels to wildtype levels. Instead, only a significant decrease of the CD14 and ETS-1 in
cerebellar tissue of untreated NPC1 affected mice (when compared to wildtype levels), and no
significant difference for the treated, affected mice was seen. CD14 p value = 0.026, and ETS-1
p value = 0.014. There was no significant difference found in cortex tissue for either CD14 or
ETS-1.
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Parnell, Scott E., Jayanth Ramadoss, Michael D. Delp, Michael W. Ramsey, Wei-Jung A. Chen, James R. West, and Timothy A. Cudd. "Chronic Ethanol Increases Fetal Cerebral Blood Flow Specific to the Ethanol-Sensitive Cerebellum Under Normoxaemic, Hypercapnic and Acidaemic Conditions: Ovine Model." Digital Commons @ East Tennessee State University, 2007. https://dc.etsu.edu/etsu-works/4134.
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Cerebral hypoxia has been proposed as a mechanism by which prenatal ethanol exposure causes fetal alcohol spectrum disorder (FASD) in children, but no study had tested this hypothesis using a chronic exposure model that mimicks a common human exposure pattern. Pregnant sheep were exposed to ethanol, 0.75 or 1.75 g kg−1 (to create blood ethanol concentrations of 85 and 185 mg dl−1, respectively), or saline 3 days per week in succession (a ‘binge drinking’ model) from gestational day (GD) 109 until GD 132. Fetuses were instrumented on GD 119–120 and studied on GD 132. The 1.75 g kg−1 dose resulted in a significant increase in fetal biventricular output (measured by radiolabelled microsphere technique) and heart rate, and a reduction of mean arterial pressure and total peripheral resistance at 1 h, the end of ethanol infusion. The arterial partial pressure of CO2 was increased, arterial pH was decreased and arterial partial pressure of O2 did not change. Fetal whole‐brain blood flow increased by 37% compared with the control group at 1 h, resulting in increased cerebral oxygen delivery. The elevation in brain blood flow was region specific, occurring preferentially in the ethanol‐sensitive cerebellum, increasing by 44% compared with the control group at 1 h. There were no changes in the lower dose group. Assessment of regional differences in the teratogenic effects of ethanol by stereological cell‐counting technique showed a reduced number of cerebellar Purkinje cells in response to the 1.75 g kg−1 dose compared with the control brains. However, no such differences in neuronal numbers were observed in the hippocampus or the olfactory bulb. We conclude that repeated exposure to moderate doses of ethanol during the third trimester alters fetal cerebral vascular function and increases blood flow in brain regions that are vulnerable to ethanol in the presence of acidaemia and hypercapnia, and in the absence of hypoxia.
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Jaeg, Tiphaine. "Exploring the mitochondrial function in muscle and molecular dysregulation in cerebellum in a mouse model for ARCA2, a recessive ataxia with coenzyme Q10 deficiency." Thesis, Strasbourg, 2017. http://www.theses.fr/2017STRAJ082/document.
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ARCA2 est une ataxie autosomique récessive rare, caractérisée par une atrophie du cervelet et un léger déficit en Coenzyme Q10 (CoQ). La majorité des patients présentent des signes neurologiques supplémentaires comme l’épilepsie ou l’intolérance à l’exercice. La maladie est due à des mutations dans le gène COQ8A qui semble encoder une protéine kinase-like atypique, impliquée dans la biosynthèse du CoQ. Pour comprendre les mécanismes physiopathologiques, une souris Coq8a knock-out (KO) constitutif a été générée et récapitule les symptômes observés chez les patients. Le but de ce travail de thèse était de mieux comprendre certains aspects, notamment l’intolérance à l’exercice et l’ataxie. Malgré un déficit en CoQ dans les muscles, aucun défaut de respiration mitochondriale n’a été détecté dans un modèle cellulaire de muscle. Néanmoins, dans le cervelet, les niveaux de transcrits de 27 gènes sont dérégulés, précocement dans l’apparition de la pathologie chez les souris KO. Les voies métaboliques vont être explorées, ce qui devrait permettre de relier la fonction de COQ8A au taux de CoQ et aux symptômes observés chez les patientsARCA2, a rare form of recessive ataxia, is characterized by early onset progressive ataxia, cerebellar atrophy and a mild Coenzyme Q10 deficiency. Most of the patients show additional neurological signs such as epilepsy and exercise intolerance. Mutations in the COQ8A gene lead to ARCA2. COQ8A is suggested as being an unorthodox protein kinase like, with a regulatory role in CoQ biosynthesis, in mammals. To better understand ARCA2, a constitutive Coq8a knock-out (KO) mouse model was generated, which recapitulates most of the patient’s symptoms. Here we report the use of cellular models and the affected tissues to uncover the molecular signature of COQ8A loss and CoQ deficit. Despite CoQ deficit in the muscle, no mitochondrial bioenergetics defect was uncovered. In parallel, we have identified, by RT-qPCR, a key set of genes that are dysregulated in cerebellum, very early on in the pathology. We are currently investigating these pathways to uncover the link with COQ8A function. Altogether, our experiments will shed light on the early molecular events that lead to ARCA2 and may help draw a link between COQ8A function, CoQ pools and the symptoms observed in patients
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Maffei, Giovanni. "Automatic and deliberate control of action: an embodied perspective of artificial and biological brains." Doctoral thesis, Universitat Pompeu Fabra, 2018. http://hdl.handle.net/10803/666954.
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Animals evolved to survive in dynamic environments by developing multiple behavioral strategies to adapt and to learn from their interaction with the world. Associative mechanisms and internal representations are at the core brain computation, however, to acquire a complete knowledge of their relevance for behavior it is necessary to take into consideration their embodied nature. In an interdisciplinary effort which integrates methods from computational modeling, robotics, and electrophysiology, this dissertation presents a series of studies that aim at advancing the understanding of the automatic and deliberate processes that regulate embodied control of action in the brain. Through the formulation of a biologically constrained control architecture engaged in a real-world foraging task, we lay the ground for modeling and analyzing complex goal-oriented behavior emerging from the interplay between the automatic cerebro-cerebellar system acquiring sensory-motor associations, and the deliberate fronto-hippocampal system providing goal-oriented navigation and planning. Following the behavioral analysis of the stimulus-response model of cerebellar learning, we later ask how could the cerebellum implement anticipatory control, which is both adaptive and resistant to uncertainty. To answer this question, we explore the properties of the automatic control system and advance a novel hypothesis on the role of the cerebellum, by recasting its computation in the perceptual domain. Finally, we ask how the automatic and deliberate systems interact during unexpected situations that require a sudden change of plans. By analyzing the neural dynamics of the human frontal cortex in the control of deliberate action switch, we support the contribution of low-frequency oscillatory dynamics within this area to orchestrate behavior, based on internal representations of goals and rules. Altogether these results contribute to our understanding of how automatic and deliberate processes control action in the brain and advance novel insights that challenge or extend current theories. Despite the main aim to understand the brain, these insights could also be applied to the development of novel control systems for a new generation of robots.Els animals van evolucionar per sobreviure en entorns dinàmics desenvolupant múltiples estratègies de comportament per adaptar-se i aprendre de la seva interacció amb el món. Els mecanismes associatius i les representacions internes estan en el nucli del càlcul del cervell, però, per adquirir un coneixement complet de la seva rellevància per a la conducta, cal tenir en compte la seva naturalesa incorporada. En un esforç interdisciplinari que integra mètodes de modelització computacional, robòtica i electrofisiologia, aquesta tesi presenta una sèrie d’estudis que pretenen avançar en la comprensió dels processos automàtics i deliberats que regulen el control de l’acció incorporat al cervell. Mitjançant la formulació d’una arquitectura de control biològicament restringida dedicada a una tasca de forjat en el món real, posem el terreny per modelar i analitzar una conducta orientada a objectius complexos que sorgeix de la interacció entre el sistema cerebrovascular cerebral automàtic que adquireix associacions sensorials motores i deliberat sistema fronto-hipocamp que proporciona una navegació i una planificació orientades a objectius. Després de l’anàlisi conductual del model d’estímul-resposta de l’aprenentatge cerebel.lari, ens preguntem més endavant com es pot aplicar el cerebel a un control anticipat que e ́s a la vegada adaptatiu i resistent a la incertesa. Per respondre a aquesta pregunta, explorem les propietats del sistema de control automàtic i avancem una nova hipòtesi sobre el paper del cerebel, tot reformant la seva computacio ́ en el domini perceptiu. Finalment, preguntem com interactuen els sistemes automa`tic i deliberat durant situacions inesperades que requereixen un canvi sobtat de plans. Analitzant la dina`mica neural de l’escorça frontal humana en el control del canvi d’acció deliberada, recolzem l’aportació de dinàmiques oscil.ladores de baixa freqüència en aquesta àrea per orquestrar el comportament, basant-se en representacions internes d’objectius i regles. Tot plegat, aquests resultats contribueixen a la nostra comprensió de com processos automàtics i deliberats controlen l’acció en el cervell i avancen noves idees que desafien o allarguen les teories actuals. Malgrat l’objectiu principal d’entendre el cervell, aquestes idees també es podrien aplicar al desenvolupament de nous sistemes de control per a una nova generació de robots.
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Šuminaite, Daumante. "Elucidating the reversibility of ataxia." Thesis, University of Edinburgh, 2017. http://hdl.handle.net/1842/28911.
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Heterozygous and recently identified homozygous mutations in the SPTBN2 gene, encoding b-III spectrin, are implicated in spinocerebellar ataxia type 5 (SCA5) and spectrin-associated autosomal recessive cerebellar ataxia type 1 (SPARCA1), respectively. Our mouse model, lacking b-III spectrin (KO), mimics the progressive human phenotype displaying motor deficiencies as well as reduced Purkinje cell firing frequency followed by dendritic tree degeneration and cell death. The aims of this study were to evaluate progression of Purkinje cell degeneration following loss of b-III spectrin function and determine whether the reintroduction of C-terminus (C-trm) of b-III spectrin to the cerebellum is enough to halt, alleviate or reverse the disease phenotype. Additionally, this study investigated whether the abnormal electrophysiological and morphological phenotypes of Purkinje cells from KO mice are re-capitulated in a primary cerebellar culture and if so, whether they could be rescued by modulating calcium signaling. Morphological and histological analyses revealed that Purkinje cell degeneration is not uniform throughout the cerebellum of KO mice with Purkinje cells from posterior cerebellar regions possessing significantly smaller dendritic trees when compared to anterior cerebellum (p=0.0003, N=4-6, n=11-29). Similarly, significant reduction in Purkinje cell density was observed in posterior, not anterior regions of KO mice when compared to WT animals (p=0.014, N=3) and reduced tonic firing is most significant in Purkinje cells from the posterior cerebellum compared to WT mice (p=0.0328, N=3-6, n=11-29), with posterior KO PCs appearing to have elevated input resistance. Two-week expression of C-trm b-III spectrin in 3-month old KO animals significantly reduced Purkinje cell input resistance when compared to non-transduced cells (p=0.0139, N=4-5, n=15), but no effect was seen 9 months after viral injection. In contrast, a difference in cell surface area was no longer detected between WT and KO animals at 12 months of age following 9-months of viral expression. Nevertheless, using the elevated beam test motor deterioration was still observed 5 months after surgery (p=0.0023, N=4). In contrast, earlier stereotaxic injections at 6-weeks of age had a positive effect on mice motor performance with no deterioration in performance detected 5 months after the surgery. Latency to stay on the rotarod at 3 rpm was also significantly extended 6 months after stereotaxic injections at 6-weeks of age with slower motor deterioration (p=0.0348, N=6). In primary cerebellar cultures, Purkinje cells from KO animals exhibit an abnormal morphology with significantly more dendritic branches (p < 0.0001, N=4-7, n=35-69) and a larger total dendritic length (p=0.0079). Chronic application of 2 μM mibefradil, a T-type calcium channel blocker, was observed to reduce total dendritic length and branching in KO animal cultures bringing these morphological measurements closer to WT Purkinje cell levels. Finally although after 14 days in vitro 40% of Purkinje cells were found to be spontaneously firing, no significant difference in firing frequency (p=0.9434) or input resistance (p=0.8434, N=4, n=6-10) was detectable between WT and KO cultures. In summary, Purkinje cells in posterior cerebellar regions of KO mice were found to be more susceptible to dendritic degeneration and cellular death than cells in the anterior cerebellum. Expression of C-trm b-III spectrin at 3 months of age had an immediate effect on cell input resistance and a modest effect on Purkinje cell morphology but no effect on motor decline. Viral injections at 6-weeks of age, however, significantly slowed motor decline. Although an abnormal KO cell morphology could be successfully recapitulated in primary cell culture, it was not possible to discern any differences in electrophysiological properties. Nevertheless, the abnormal cell morphology was successfully modified in vitro by manipulating calcium signaling via T-type calcium channels.
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El, Nagar Salsabiel. "Rôle du facteur de transcription Otx2 dans le développement normal et tumoral du cervelet." Thesis, Université Côte d'Azur (ComUE), 2017. http://www.theses.fr/2017AZUR4138.
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Les médulloblastomes (MB) sont les tumeurs cérébrales les plus fréquentes en pédiatrie. Ils apparaissent le plus souvent au niveau du cervelet. Ils peuvent être stratifiés en quatre groupes : les groupes WNT et SHH, où ces voies de signalisation sont altérées, et les groupes 3 et 4, présentant des anomalies chromosomiques et amplifications multiples, dont c-Myc (groupe 3) et N-Myc (groupe 4). L’une des altérations génétiques les plus retrouvées dans les MB est la surexpression du facteur de transcription OTX2. Ce facteur est exprimé dans les précurseurs des cellules granulaires (GCP) du cervelet, cellules d’origine de la majorité des MB. Pendant la période périnatale, les GCP subissent une phase de prolifération très intense en réponse au mitogène Sonic Hedgehog (SHH), ce qui les rendrait particulièrement sensibles à la tumorigenèse. Au cours de cette thèse, nous nous sommes intéressé à la fonction d’Otx2 dans ces GCP. Nous avons montré que l’ablation conditionnelle d’Otx2 conduit à un défaut de prolifération des ces cellules. L’analyse approfondie de ce phénotype a permis de révéler qu’Otx2 stimule la prolifération des GCP parallèlement à la voie de signalisation Shh. Par ailleurs, l’ablation d’Otx2 dans un modèle murin mimant la formation de MB Shh-dépendants a montré qu’Otx2 s’avère indispensable pour leur maintien à long terme. En parallèle, nous avons tenté de créer un nouveau modèle murin mimant la formation de MB de groupe 3 en induisant l’expression, pendant la période postnatale, d’un dominant actif de c-Myc dans les cellules exprimant Otx2. Cette approche a donné des résultats inattendus : des carcinomes de plexus choroïdes, et non des MB, ont été obtenusMedulloblastomas (MB) are the most common brain tumors in paediatrics. They appear during development in the posterior part of the brain, mainly in cerebellum. MB can be stratified in four groups: the WNT and SHH groups, where these signalling pathways are aberrantly activated, and the groups 3 and 4, which display chromosomal abnormalities and multiple amplifications, including c-Myc (group 3) and N-Myc (group 4). One of the most frequent genetic alterations in MB is the overexpression of the Otx2 transcription factor (in 75% of cases). This factor, which is essential for central nervous system development, is expressed in granule cell precursors (GCP) of the cerebellum, which represent the cell of origin of the majority of MB. During the perinatal period, GCPs undergo intense proliferation in response to Sonic Hedgegog (SHH), making them particularly susceptible to tumorigenesis. During this thesis, we were interested in examining the function of Otx2 in GCPs. We have shown that conditional ablation of Otx2 leads to a GCP proliferation defect and that Otx2 stimulates the proliferation of these cells independently of the Shh signaling pathway. Moreover, ablation of Otx2 in a mice model of Shh-dependent medulloblastomas yielded very interesting results: while Otx2 does not seem to be required for the initiation of these tumors, it is essential for their long-term maintenance. In parallel, we tried to create a new murine model for the MB group 3 by inducing the expression, during the postnatal period, of an active dominant of c-Myc in cells expressing Otx2. This approach yielded unexpected results: choroid plexus carcinomas, instead of MB, were obtained
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RIZZA, MARTINA FRANCESCA. "Parameter estimation of cerebellar stellate neuron model." Doctoral thesis, Università degli Studi di Milano-Bicocca, 2017. http://hdl.handle.net/10281/180709.
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La principale area della mia ricerca è la modellizzazione delle proprietà biofisiche dei neuroni del cervelletto. I modelli computazionali di neuroni sono descrizioni matematiche del loro funzionamento e sono importanti mezzi per lo studio di queste cellule. Saranno presentati i modelli che seguono la notazione matematica di Hodgkin e Huxley (HH) e i modelli descritti secondo la teoria degli Integrate and Fire e infine mi concentrerò sui modelli del cervelletto, essendo questa regione del sistema nervoso centrale il principale interesse della mia ricerca.
La prima parte della tesi esamina la ricostruzione di un modello multi-compartimentale di singolo neurone, e in particolare verrà approfondito lo studio dettagliato della cellula stellata del cervelletto. Il modello si basa sulla notazione matematica di HH. Il modello riproduce le principali caratteristiche elettrofisiologiche del neurone, il funzionamento delle gap junctions e la trasmissione sinpatica, raggiungendo risultati soddisfacenti.
Tuttavia, i più avanzati modelli descritti secondo HH richiedono la calibrazione di un vasto numero di parametri, che sono le conduttaze ioniche massime (Gi-max). L’assegnazione di un appropriato valore a ciascuna Gi-max, presenti nelle diverse sezioni della morfologia del modello, è un compito molto complesso. Dal momento che non possono essere determinate sperimentalmente, devono essere assegnate durante la fase di creazone del modello e accuratamente validate. La calibrazione manuale di questi parametri richiede una grande quantità di tempo e un elevato rischio di errore durante la procedura, per questo motivo sono stati studiati metodi automatici per la stima di parametri in grado di essere applicati per lo studio e la calibrazione delle Gi-max neuronali, ottenendo modelli ottimizzati in grado di riprodurre risutati ben comparabili con i risultati sperimentali. La seconda parte del lavoro, approfondisce un metodo di stima di parametri che si basa sulle tecniche di Swarm Intelligence. L’algoritmo particle swarm optimization (PSO) è appliacto per la prima volta per la calibrazione dei valori di Gi-max, portando ottimi risultati. Lo studio di questi problemi complessi è anche possibile con la parallela crescita di tecniche di high performing computing (HPC), in grado di parallelizzare i calcoli su macchine parallele e distribuite, in modo da diminuire i costi computazionali richiesti per le simuazioni. La metodologia è stata quindi implementata per potere essere usata con macchine parallele, come ad esempio computer cluster.
La terza parte del progetto prevede invece lo studio di un’importante area delle neuroscienze che si occupa dello sviluppo neurnale, dagli stadi pre-natali ai post-natali. Mi concentrerò sullo sviluppo del cervelletto e sulla creazione di un framework teorico per lo sviluppo di un modello in grado di ricostruire le diverse fasi dello sviluppo. Prenderò in rassegna i diversi modelli esistenti, che modellizzazone singoli processi, com ad esempio il differenziamento neuronale e la crescita degli assoni e dei dendriti durante lo sviluppo, e gli strumenti utilizzati per la loro modellizzazione, valutando l’applicabilità per ricostruire l’intero sviluppo cerebellare.The focus of my research is the modeling of biophysical properties of the cerebellar neurons. Computational models of neurons are mathematical descriptions used to describe and simulate biological processes of these cells and are a valuable means for the neuronal investigation. I will describe the conductance-based models, based on Hodgkin and Huxley (HH) mathematical description and spiking neuron models, based on integrate and fire (IF) theory. Then, I will focus on the models of the cerebellar neurons, being the area of interest of my research. The first part of the thesis examines the reconstruction of the multi-compartmental model of the cerebellar stellate cell (SC), modelled with the HH notation. The model reproduced the main electrophysiological properties of the SC, the gap junctions functioning and the synaptic activity, achieving satisfying results. However, the most advanced models, based on the HH theory, in order to reproduce the correct neuronal dynamics, require the fine-tuning of a large number of parameters, which are the maximum ionic conductance (Gi-max). The definition of appropriate Gi-max values, for each section of the morphology, is a complex task: they cannot be experimentally determined, so they must be assigned during the modeling phase and accurately validated. The manual calibration of Gi-max parameters for each channel is also a time-consuming and error-prone task. In order to explore the quite extensive parameter space of single-neuron models, it is possible to exploit numerical optimization techniques, able to, automatically, estimate the most fitting Gi-max values, obtaining neuron models that can reproduce the expected electro-physiological behavior, compared with the experimental results. Therefore, the second part of the thesis investigates an approach based on an automatic parameter estimation (PE) method that exploits the swarm intelligence (SI) technique known as particle swarm optimization (PSO). The investigation of this complex problem is made possible by the increase of the computational power and the high performing computing (HPC) techniques that allows scientist to develop specific procedures to calibrate automatically the parameter tuning. PSO was applied to the cerebellar SC neuron model for the first time and choosing the correct fitness functions, to quantify how well the optimization solutions compare with the target traces. The methodology proposed relies on the execution of a massive number of simulations, whose computational costs are relevant. To reduce the overall running time, the methodology was implemented on a parallel architecture. In this way, the fitness evaluations were accelerated with a computer cluster. The third part of the thesis reviews a challenging area of neuronal development, focusing on the cerebellar neuronal development. The cerebellar development is a complex biological process that requires a huge interaction between biochemical and biophysical mechanisms. Many aspects of development, such as neurons differentiation, proliferation and migration, axon and dendritic growth, synapses formation and stabilization, were extensively described with experiments in both the brain and the cerebellum, but only some of these aspects were described with computational models. Many models describe specific neurogenesis and axonal connectivity in the cerebral cortex, hippocampus, olfactory bulb and spinal cord. The frameworks, used to build these models, describe specifically several characteristics that could be applied to the cerebellum. I will review the available models and the latest tools to model the development of the cerebellar network, creating a new framework, which will explain all the specific properties of the cerebellum.
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Lu, Song, and 鲁嵩. "Phenotype analysis of Pdss2 conditional knockout mouse." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2010. http://hub.hku.hk/bib/B45552381.
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Koontz, Thadeus B. "MCMV induced cerebellar maldevelopment." Thesis, Birmingham, Ala. : University of Alabama at Birmingham, 2007. https://www.mhsl.uab.edu/dt/2007p/koontz.pdf.
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Anderson, Jennifer Louise Medical Sciences Faculty of Medicine UNSW. "Cerebellar synaptic plasticity in two animal models of muscular dystrophy." Publisher:University of New South Wales. Medical Sciences, 2008. http://handle.unsw.edu.au/1959.4/43524.
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Duchenne muscular dystrophy (DMD) and congenital muscular dystrophy 1A (MDC1A) are the two most common forms of muscular dystrophy in humans, caused by mutations in dystrophin and laminin α2 genes respectively. Both are severe forms of the disease that lead to premature death due and are both now known to have a significant effect on the central nervous system. This project investigated the role of both proteins involved in each of these diseases in cerebellar Purkinje cells of two murine models of disease: the mdx mouse a dystrophin-deficient model of DMD and the dy2J a laminin α2-deficient murine model of MDC1A. In the case of dystrophin further studies were undertaken in order to determine if increasing age had any effects on cerebellar function. It was found that there is no difference in electrophysiological characteristics (RMP, IR, eEPSP) of the cells when compared to appropriate control groups, nor was there any difference when young and aged dystrophin-deficient mdx groups were compared. Evoked IPSP characteristics were examined in young mdx cerebellar Purkinje cells and again no difference was found when compared to wildtype. There was a significant difference in response to the GABAA antagonist bicuculline, with wildtype increasing eEPSP amplitude by almost double that found in mdx. There was no difference in short term plasticity as measured by paired pulse facilitation in any of these groups. There was no difference in paired pulse depression at the inhibitory interneuron- Purkinje cell synapse of young wildtype and mdx cerebellar Purkinje cells. There a significant blunting of long term depression (LTD, (a form of long term synaptic plasticity) between young wildtype and mdx. When young wildtype animals were compared to aged wildtype animals LTD was found to be similar, when young mdx was compared to aged mdx, there was a recovery of LTD seen in the aged population. There was also significant differences in LTD found when littermate controls were compared to dy2J (laminin α2 mutants). A third of the phenotypic animals (dy2J) potentiated. Finally when rebound potentiation (a GABA-ergic form of long term synaptic plasticity in the cerebellum) was compared in young wildtype and mdx mice, mdx mice displayed depression, rather than the expected potentiation in contrast to potentiation (or no change) as seen in all wildtype cells.
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Matos, Pinto Thiago. "Computational models of intracellular signalling and synaptic plasticity induction in the cerebellum." Thesis, University of Hertfordshire, 2013. http://hdl.handle.net/2299/11560.
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Many molecules and the complex interactions between them underlie plasticity in the cerebellum. However, the exact relationship between cerebellar plasticity and the different signalling cascades remains unclear. Calcium-calmodulin dependent protein kinase II (CaMKII) regulates many forms of synaptic plasticity, but very little is known about its function during plasticity induction in the cerebellum. The aim of this thesis is to contribute to a better understanding of the molecular mechanisms that regulate the induction of synaptic plasticity in cerebellar Purkinje cells (PCs). The focus of the thesis is to investigate the role of CaMKII isoforms in the bidirectional modulation of plasticity induction at parallel fibre (PF)-PC synapses. For this investigation, computational models that represent the CaMKII activation and the signalling network that mediates plasticity induction at these synapses were constructed. The model of CaMKII activation by calcium-calmodulin developed by Dupont et al (2003) replicates the experiments by De Koninck and Schulman (1998). Both theoretical and experimental studies have argued that the phosphorylation and activation of CaMKII depends on the frequency of calcium oscillations. Using a simplified version of the Dupont model, it was demonstrated that the CaMKII phosphorylation is mostly determined by the average calcium-calmodulin concentration, and therefore depends only indirectly on the actual frequency of calcium oscillations. I have shown that a pulsed application of calcium-calmodulin is, in fact, not required at all. These findings strongly indicate that the activation of CaMKII depends on the average calcium-calmodulin concentration and not on the oscillation frequency per se as asserted in those studies. This thesis also presents the first model of AMPA receptor phosphorylation that simulates the induction of long-term depression (LTD) and potentiation (LTP) at the PF-PC synapse. The results of computer simulations of a simple mathematical model suggest that the balance of CaMKII-mediated phosphorylation and protein phosphatase 2B (PP2B)-mediated dephosphorylation of AMPA receptors determines whether LTD or LTP occurs in cerebellar PCs. This model replicates the experimental observations by Van Woerden et al (2009) that indicate that CaMKII controls the direction of plasticity at PF-PC synapses. My computer simulations support Van Woerden et al’s original suggestion that filamentous actin binding can enable CaMKII to regulate bidirectional plasticity at these synapses. The computational models of intracellular signalling constructed in this thesis advance the understanding of the mechanisms of synaptic plasticity induction in the cerebellum. These simple models are significant tools for future research by the scientific community.
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Ortiz, Abalia Jon. "Estudio de los efectos de la reducción de la expresión de Dyrk1A, mediante interferencia de RNA, sobre el fenotipo motor del model transgénico TgDyrk1A. Implantación de kis receptores glutamatérgicos de tipo NMDA." Doctoral thesis, Universitat Pompeu Fabra, 2008. http://hdl.handle.net/10803/7188.
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DYRK1A es uno de los principales genes candidatos que podrían explicar algunos de los defectos neurológicos asociados al fenotipo Síndrome de Down (SD); desde el retraso mental, rasgo común a todos los individuos con SD hasta los déficits motores, también muy frecuentes entre la población con SD. Con el fin de validar la implicación de DYRK1A en el fenotipo SD se ha desarrollado una estrategia de terapia génica basada en la reducción de la expresión del gen mediante interferencia del RNA, en el modelo transgénico TgDyrk1A, y se han evaluado los efectos en el fenotipo motor de estos animales. Además se ha estudiado la implicación de los receptores glutamatérgicos de tipo NMDA en las alteraciones motoras descritas en el modelo. Los resultados obtenidos en este trabajo ponen de manifiesto la validez de la estrategia desarrollada y apuntan a una desregulación de los receptores de NMDA como uno de los mecanismos moleculares subyacentes de las disfunción motora presente en el modelo TgDyrk1A.The are growing evidences to consider DYRK1A as a candidate gene for some of the neurological alterations present in DS phenotype such as mental retardation which is a common feature in the syndrome, or motor deficits which show a high prevalence among DS individuals. With the aim to validate the contribution of Dyrk1A to DS phenothype, we have developped a gene therapy strategy based on RNA interference to reduce gene expression in the transgenic model TgDyrk1A, and we have evaluated the effects in the motor phenotype of these animals. Moreover, we have studied the implication of the NMDA glutamate receptor in the motor alterations present in the model. The results obtained validate the strategy developped and suggest the deregulation of the NMDA receptor as one of the main causes underlying motor dysfunction in TgDyrk1A mice.
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Darka, Murat Özdemir Serhan. "The control of a manipulator using cerebellar model articulation controllers/." [s.l.]: [s.n.], 2003. http://library.iyte.edu.tr/tezler/master/makinamuh/T000251.pdf.
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Scarfe, Peter Craig. "Error minimising gradients for improving cerebellar model articulation controller performance." Thesis, Curtin University, 2009. http://hdl.handle.net/20.500.11937/1241.
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In motion control applications where the desired trajectory velocity exceeds an actuator’s maximum velocity limitations, large position errors will occur between the desired and actual trajectory responses. In these situations standard control approaches cannot predict the output saturation of the actuator and thus the associated error summation cannot be minimised.An adaptive feedforward control solution such as the Cerebellar Model Articulation Controller (CMAC) is able to provide an inherent level of prediction for these situations, moving the system output in the direction of the excessive desired velocity before actuator saturation occurs. However the pre-empting level of a CMAC is not adaptive, and thus the optimal point in time to start moving the system output in the direction of the excessive desired velocity remains unsolved. While the CMAC can adaptively minimise an actuator’s position error, the minimisation of the summation of error over time created by the divergence of the desired and actual trajectory responses requires an additional adaptive level of control.This thesis presents an improved method of training CMACs to minimise the summation of error over time created when the desired trajectory velocity exceeds the actuator’s maximum velocity limitations. This improved method called the Error Minimising Gradient Controller (EMGC) is able to adaptively modify a CMAC’s training signal so that the CMAC will start to move the output of the system in the direction of the excessive desired velocity with an optimised pre-empting level.The EMGC was originally created to minimise the loss of linguistic information conveyed through an actuated series of concatenated hand sign gestures reproducing deafblind sign language. The EMGC concept however is able to be implemented on any system where the error summation associated with excessive desired velocities needs to be minimised, with the EMGC producing an improved output approximation over using a CMAC alone.In this thesis, the EMGC was tested and benchmarked against a feedforward / feedback combined controller using a CMAC and PID controller. The EMGC was tested on an air-muscle actuator for a variety of situations comprising of a position discontinuity in a continuous desired trajectory. Tested situations included various discontinuity magnitudes together with varying approach and departure gradient profiles.Testing demonstrated that the addition of an EMGC can reduce a situation’s error summation magnitude if the base CMAC controller has not already provided a prior enough pre-empting output in the direction of the situation. The addition of an EMGC to a CMAC produces an improved approximation of reproduced motion trajectories, not only minimising position error for a single sampling instance, but also over time for periodic signals.
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Leroux, Sarah. "Etude des hypoxies périnatales : conception d'outils et effets sur le développement du cervelet chez la souris. Hypoxia is associated with a retardation of cerebellar development and long-term functional deficits in a mouse model of apnea of prematurity." Thesis, Normandie, 2019. http://www.theses.fr/2019NORMR100.
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Le cervelet est une région du système nerveux central, située à l’arrière du cerveau et impliquée dans de nombreuses fonctions motrices telles que la coordination ou encore l’équilibre. Des études plus récentes ont également permis de mettre en évidence son implication dans plusieurs fonctions cognitives comme le langage et les processus d’apprentissage. Le cervelet est constitué d’une substance blanche interne et d’une substance grise périphérique appelée cortex cérébelleux. Ce dernier est composé de 4 différentes couches cellulaires lors de la période foetale : la couche granulaire externe (CGE) dans laquelle prolifèrent les précurseurs des cellules en grain ; la couche moléculaire constituée majoritairement les fibres de Bergmann et des arbres dendritiques des cellules de Purkinje sur lesquels se connectent les fibres parallèles ; la couche des cellules de Purkinje contenant également les corps cellulaires de la glie de Bergmann ; et la couche granulaire interne dans laquelle se différencient les neurones en grain. Le cortex embryonnaire poursuit son développement jusqu’à la période postnatale. Puis la CGE disparaît peu à peu et à l’adolescence, le cervelet mature n’est plus constitué que de 3 couches corticales. Du fait de son immaturité à la naissance, cette structure est potentiellement vulnérable aux incidents périnataux, tels que des hypoxies. Les hypoxies périnatales peuvent être provoquées soit par un événement ponctuel (hypoxie continue = HC) correspondant par exemple à des retards de respiration spontanée ou à une compression du cordon ombilical, soit par des pathologies chroniques telles que l’apnée du prématuré (hypoxie intermittente = HI). Elles sont de fait relativement fréquentes et responsables d’un tiers des morts néonatales, mais entraînent également des déficits neurodéveloppementaux persistants à long terme. L’impact des hypoxies périnatales sur le cervelet a longtemps été mis de côté au profit du cortex cérébral ou de l’hippocampe, plus facilement accessibles par l’imagerie médicale. Cependant, de plus en plus de méta-analyses révèlent une corrélation entre les fonctions que contrôle le cervelet et les déficits observés chez les enfants ayant subi une hypoxie périnatale, suggérant que cette structure participe aux effets délétères induits lors d‘un manque d’oxygénation à la naissance. En se basant sur ces données, le premier objectif de cette thèse était de concevoir une enceinte capable de modéliser les différents types d’hypoxie observés chez l’Homme. Une collaboration avec l’Institut Universitaire de Technologie de l’Université de Rouen Normandie nous a permis de créer une chambre d’hypoxie avec un volume compatible avec les cycles d’HI, un contrôle automatisé des injections gazeuses d’azote, d’oxygène et d’air, mais aussi une surveillance en tempsréel des paramètres environnementaux tels que la température, la pression atmosphérique et l’hygrométrie. Les premières expérimentations in vivo ont été réalisées sur un modèle d’hypoxie continue, consistant en une hypoxie de 40 minutes à 5 % d’oxygène chez des animaux âgés de 6, 12 ou 21 jours postnataux (P6, P12, P21). Cette étude nous a permis de démontrer qu’une hypoxie périnatale aiguë induit un stress oxydatif chez les animaux âgés de 6 et 12 jours immédiatement après l’hypoxie, accompagné d’une augmentation de l’activité enzymatique des caspases pro-apoptotiques 24 heures après la fin du protocole. Les études immunohistochimiques réalisées à P12 révèlent que l’HC cible principalement les cellules en grain différenciées car les cellules apoptotiques se situent majoritairement dans la CGI. A P21, cette activité pro-apoptotique reste plus élevée chez les souris hypoxiques que chez les animaux contrôles, malgré l’absence de marqueur de stress oxydatifThe cerebellum is involved in major motor functions such as coordination and equilibrium. Recently, it has also been shown to play a role in cognitive abilities like language, attention or learning. At birth, the development of the cerebellar cortex in human is not completed and continues until the first postnatal months. Thereby, this structure appears to be particularly vulnerable to various perinatal injuries, such as hypoxic incidents. Perinatal hypoxia (HP) represents a common pathology responsible for neurodevelopmental disorders and is involved in 1/3 of neonatal deaths. It could be induced by different events such as looping of umbilical cord (continuous hypoxia) or apnea of prematurity (intermittent hypoxia) and affects many cerebral regions. However, its impact on the cerebellum has not been investigated in detail. Yet, a correlation between the functions controlled by the cerebellum and the deficits observed in children affected by an oxygen (O2) deficiency at birth has been demonstrated. Taken together, these data suggest that perinatal hypoxia may lead to modifications in the cerebellar circuit organization and induce functional alterations. Thus, this study aims to identify the effects of two types of HP on the cerebellar development; (i) an intermittent hypoxia (HI) consisting of 2-minute cycles of hypoxia and reoxygenation repeated over 6 hours on mice during 10 days from postnatal day 2 (P2), referring to apnea of prematurity, and (ii) a continuous hypoxia (HC) of 5% of O2 during 40 minutes on P6, P12 and P21 mice, mimicking a perinatal respiratory delay. Firstly, we studied the oxidative stress and showed that ROS production increases in P12 mice after both protocols, indicating that hypoxia affects the cerebellum. In HC, this oxidative stress is associated with a moderate increase in apoptosis without histological and behavioral consequences in the short or long term. However, IH induces a significant delay in histogenesis, leading to a decrease in the thickness of the cerebellar cortex layers. This disorganization of the cerebellum is accompanied by deficits in reflex acquisition. Our results suggest that IH may induce a long-term protective mechanism via, at least, an anti-apoptotic effect which compensates histological alterations from P21. However, this compensatory process is insufficient and defaults in motor coordination and cognition persist in adult mice. In order to study more precisely hypoxia and report its effects in vivo in real time, we also characterized 7 probes derived from sulforhodamine-101 and sensitive to a lack of oxygen. The emission and excitation spectra obtained demonstrate that 5 of these molecules are excitable in the infrared, and can thus be detectable by two-photon microscopy. In addition, we demonstrated that they are not degraded, confirming that they are usable for in vivo imaging. Thus, this work validates our two hypoxia models but shows that each type of hypoxia has specific effects on the developing cerebellum: continuous hypoxia acts in the short-term while intermittent hypoxia leads to profound structural and functional impacts. In the long term, our data aim to determine the precise mechanisms underlying the deleterious effects of HP with fluorescent dies sensitive to hypoxia, and to correlate the functional deficits observed in children who have suffered from perinatal hypoxia with cerebellum alterations to improve their health care
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ROMANO, FAUSTO. "Evaluation of acute alcohol intoxication as a model of cerebellar disease." Doctoral thesis, Università degli studi di Pavia, 2017. http://hdl.handle.net/11571/1203377.
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The cerebellum is one of the most sensible regions to alcohol effect, since ethanol directly interacts with the functioning of synapses in the cerebellar cortex. Cerebellar patients manifest deficits of cerebellar functions comparable, although stronger, to those experienced by alcohol-intoxicated subjects. Based on such similarities, my work aimed at exploiting the transient cerebellar impairment caused by alcohol in order to model cerebellar diseases, and get new insights on its role in motor control. To achieve this goal, the research activity described in this thesis has concerned the study of the effects induced by alcohol on the control of eye movements in humans and zebrafish, focusing on the gaze-holding mechanism. The gaze-holding mechanism is fundamental and is “implemented” in our CNS by means of two actors: the neural integrator and the cerebellum. Both cerebellar patients and alcohol-intoxicated subjects manifest a typical clinical ocular motor sign called gaze-evoked nystagmus (GEN): an abnormal centripetal eye drift with centrifugal correcting saccades while at eccentric gaze. Despite GEN has been extensively investigated in cerebellar patients, a detailed analysis of the influence of alcohol on gaze-dependent eye drift is still missing. Thus, as a first aim of my research, we examined gaze-holding in two groups of healthy human subjects recorded before and 30 minutes after intake of the estimated alcohol amount needed to reach a blood alcohol content (BAC) of 0.06 and 0.10%, respectively. The results presented here showed that alcohol intoxication caused a linear increase of drift velocity for all gaze eccentricities. A secondary effect, instead, was found in a subgroup of subjects, which showed an additional nonlinear increase of drift velocity at large gaze angles. Considering that similar linear and nonlinear transformations were described in patients affected by cerebellar degenerations, our results suggest that alcohol-induced GEN could provide a model of GEN in cerebellar pathology. The second part of my research aimed at understanding whether the results found in alcohol intoxicated human subjects, could be generalized to zebrafish, which has been frequently considered as potential candidate for modeling cerebellar diseases in the scientific literature. To pursue such aim, we exploited the advantages of using a simpler vertebrate as a model organism and the analogies between alcohol-induced and cerebellar-induced ocular motor abnormalities. Despite the zebrafish cerebellum shares relevant functions with the human one, the involvement of the cerebellum in the gaze-holding mechanism of the fish has not been explicitly tested yet. Thus, my study was designed to face two purposes: quantifying ethanol effects on the zebrafish ocular motor system for the first time, and elucidating the role of the cerebellum on the gaze-holding mechanism at two developmental stages, i.e. larval and juvenile.The study on larvae did not reveal any macroscopic effect on their ocular motor system, showing only a nonhomogeneous effect of ethanol on their eye movements. In juvenile zebrafish, instead, ethanol-dependent abnormalities were induced both in gaze-holding and in the saccadic system. In the former system, a nonlinear a transformation of the position-drift velocity relationship was observed, although any reduction in the time constant of the neural integrator was not statistically significant. In the latter, instead, only a reduction of saccade peak velocity and amplitude was found. Despite the observed saccadic abnormalities are partially comparable to those documented in intoxicated humans, the dissimilar alteration found in gaze-holding system after alcohol exposure suggests that cerebellar involvement in eye movement control may be limited in zebrafish. Such limitation pointed out that zebrafish may not be a suitable model organism for cerebellar diseases, although it is widely used in ophthalmic research.
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Steuber, Volker. "Computational models of intracellular signalling in cerebellar Purkinje cells." Thesis, University of Edinburgh, 1999. http://hdl.handle.net/1842/21550.
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The aim of this thesis is to contribute to an understanding of the intracellular signalling network that is linked to the activation of metabotropic glutamate receptors (mGluRs) in a cerebellar Purkinje cell. In the thesis, ten different computational models of the mGluR signalling network are mathematically analysed and numerically integrated. The main result of this thesis is that the mGluR signalling network can implement an adaptive time delay between the activation of the mGluRs by glutamate and the release of calcium from intracellular stores. The adaptation of the time delay has at least three different computational functions. Based on the delay adjustment, a single Purkinje cell can learn the adaptive timing of the classically conditioned eye-blink response. A more general function of the adaptive time delay is that it enables a Purkinje cell to learn a radial basis function (RBF)-like response to temporal parallel fibre input patterns. Furthermore, different Purkinje cells in a group can discover different clusters in a temporal parallel fibre input space. The adaptation of a synaptic delay as opposed to a synaptic weight is a novel non-Hebbian learning mechanism. By systematically simplifying the original model, it is shown that the delay learning can be produced by a very limited set of intracellular processes. Two antagonistic phosphorylations can adjust the concentration of available mGluRs and implement the adaptation of the time delay. A delayed as opposed to an immediate response can be generated by the combination of calcium of dependent negative feedback and autocatalytic release of calcium from intracellular stores.
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Al-Gonaiah, Majed A. "Investigating xanthine oxidase toxicity models in cultured cerebellar granule neurons." Thesis, University of Glasgow, 2009. http://theses.gla.ac.uk/1057/.
Full textAbstract:
In the last few decades, evidence has been accumulating for a role for xanthine oxidoreductase (XOR)-generated toxic reactive oxygen species (ROS) in a variety of pathological conditions that affect different organ systems. This enzyme in mammals exists in two inter-convertible forms: xanthine dehydrogenase (XDH) (the predominant intracellular form under physiological conditions) and xanthine oxidase (XO). A combination of XO and its oxidizable substrate xanthine (X) (or hypoxanthine (HX)) is widely used as a model to produce ROS and to study their effects in a variety of cell culture studies. However, the effect of the combination of XOR and the reduced nicotinamide adenine dinucleotide (NADH) in cell cultures is much less studied. NADH is another oxidizable substrate for XOR that binds to a different site on the enzyme from that of X binding. The aim of this project was to investigate some aspects of the in vitro toxicity of XOR, which might provide more insights into its in vivo toxicity. The main investigation was a comparison between the well studied X / XO and the much less studied NADH / XO toxicity models. Also, secondary studies were undertaken to investigate those aspects of X / XO toxicity where there are uncertainties about them. These studies were performed using primary cell cultures. Cell cultures are now widely used to study different diseases, and although they have their drawbacks, they have their advantages over the in vivo studies. For this project, primary cultures of cerebellar granule neurons (CGNs) were used. In the beginning, some problems were encountered with CGNs. The main problem was the immediate damage induced to the neurons (including those in the control groups) at the intervention/experiments day (i.e. day 8 or 9 after plating) by manipulating the cultures (i.e. aspirating the culture medium, adding treatment and control vehicles, and adding the restoration medium). After several months of investigation, it was serendipitously discovered that the immediate damage seen in the neurons (including those in the control groups) when they are manipulated at the experiments/intervention day was due to glutamate excitotoxicity (through activating its N-methyl-D-aspartate (NMDA) receptors). The source of glutamate was the fresh serum which is present at 10% V/V in the fresh culture medium that is added to the cultures at that day. After solving this problem, it was possible to conduct reliable experiments to investigate XO toxicity models. Regarding investigating XO toxicity, it was found that both of the X / XO and NADH / XO combinations were toxic to cultures of CGNs. However, the concentration of NADH needed to cause the toxicity was much higher than that of the other substrate, X, which is in agreement with previous cell-free experiments that showed that NADH is a much weaker substrate than X for the bovine milk XO used here. Blocking the site of X binding on XO prevented X / XO toxicity, but did not prevent NADH / XO toxicity. On the other hand, blocking the site of NADH binding prevented both X / XO and NADH /XO toxicities. Another difference between the two systems was that deactivating either superoxide or hydrogen peroxide (both are ROS) generated by XO prevented NADH / XO toxicity, whereas although deactivating hydrogen peroxide prevented X / XO toxicity, deactivating superoxide generated from this combination did not. In the NADH / XO system, an extracellular metal contaminant (likely contaminating XO powder/preparation) seemed to be involved in the toxicity. The two toxicity models were similar in the mediation of toxicity by intracellular iron ion. In X / XO toxicity, although superoxide generated extracellularly from the combination has no role in the toxicity, intracellularly produced superoxide seemed to play a role. Conclusions: 1. Culturing/experimental conditions have been optimised for viability studies in CGNs cultures. 2. The combination of NADH and XO induces damage to CGNs, where although blocking the NADH binding site prevents this damage, blocking the X binding site does not. It is feasible that the oxidation of NADH by some forms of XOR (other than the one used here) that are known to be very efficient in oxidizing NADH might produce in vivo toxicity. 3. A possibility raised by this study is that a metal (like the metal contaminant proposed to play a role in NADH / XO toxicity in this study) might contribute to XOR toxicity in vivo. 4. Intracellular superoxide often mediates XOR toxicity. 5. The results add support to many previous studies which suggested that intracellular hydroxyl radical (or a similar species) is involved in XOR toxicity.
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Anderle, Marica. "Human cerebellar organoids as an in vitro 3D model of Group 3 Medulloblastoma." Doctoral thesis, Università degli studi di Trento, 2020. http://hdl.handle.net/11572/262782.
Full textAbstract:
Medulloblastoma (MB) is a heterogeneous tumor that represents the most common malignant brain tumor of childhood. It stands as a cause for a high percentage of morbidity and mortality among cancer patients. Thanks to genome-wide analyses, MB can be divided into four significant subgroups, different from each other for diagnosis, prognosis, and metastatic recurrence. WNT subtype has the best prognosis; SHH subtype has an intermediate prognosis; Group 3 subtype is characterized by a high percentage of metastases and worst prognosis; Group 4 MB is the most common subtype, but the less understood.
Willing to increase the knowledge about the aggressiveness of the Group3 subtype, this work will focus on developing a reliable Human Group 3 MB model based on cerebellar organoids derived from human induced pluripotent stem cells (iPSC).
Three-dimensional (3D) cell culture systems have gained increasing interest in modeling, drug discovery, and tissue engineering due to their evident advantages in providing more reliable information and more predictive data before in vivo tests. The field of cell development, differentiation, and cell organization was the first to make use of cerebellar organoids, but these 3D structures are starting to be a novelty in the cancer field.
One of the innovative points of this work is the setup of a new way to modify wild type human cerebellar organoids, electroporating them with strong Group 3 MB inducers, derived from in vivo patient-specific NGS data screen. We validate that Gfi1/c-Myc and Otx2/c-Myc oncogenes give rise to MB-like organoids, which (in nude mice) can develop tumors harboring a DNA methylation signature that clusters specifically with human patient Group 3 tumors. Moreover, we identify Smarca4 as an oncosuppressor gene and discover that treatment with an EZH2 specific inhibitor, called Tazemetostat, reduces Otx2/c-Myc tumorigenicity in human organoids.
We speculate that our Medulloblastoma 3D culture system holds great promises for applications in infant tumor research, cancer cell biology, and drug discovery, being a novel human 3D reliable tool for developing personalized therapies.
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Jo, Sungho 1974. "Application of a model of cerebellar function to the maintenance of human upright posture." Thesis, Massachusetts Institute of Technology, 2001. http://hdl.handle.net/1721.1/34345.
Full textAbstract:
Thesis (S.M.)--Massachusetts Institute of Technology, Dept. of Mechanical Engineering, 2001.Includes bibliographical references (leaves 82-87).
In this thesis a simple human postural control model is suggested and analyzed based on hypothesized neurophysiology of the cerebellar function and the musculoskeletal system. The cerebellum model is made up of simple linear filters such as differentiator and integrator. The simple linear filters implement a linear feedback control scheme including a phase lead compensator. The neural feedback signal represents the action of the cerebellum in the processing of angular position and angular velocity error signals. The goal of the investigation is to indicate whether the simple linear filters can describe neurophysiological functions of the cerebellum to compensate for the neural delays and coordinate the postural strategies that make possible human upright posture in gravity. Performance of the model is investigated with regard to disturbance rejection after adjustment of the parameters representing the cerebellum and the muscle. Whether the combination of the cerebellar and musculoskeletal control systems can realistically model human posture balance recovery is evaluated by simulating human postural maintenance during backward translation of a support surface. The simulation is compared with actual human postures and movements. The simulation realizes the ankle and hip strategy that prevails in human posture, and suggests the functions of the cerebellum.
by Sungho Jo.
S.M.
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Kalia, Lokeshvar Nath. "An investigation of the behaviour of the granular layer of the cerebellum using neuronal and network models." Thesis, Imperial College London, 1999. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.312830.
Full text
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Kaslin, Jan, and Michael Brand. "Cerebellar Development and Neurogenesis in Zebrafish." Springer, 2013. https://tud.qucosa.de/id/qucosa%3A33555.
Full textAbstract:
Cerebellar organization and function have been studied in numerous species of fish. Fish models such as goldfish and weakly electric fish have led to important findings about the cerebellar architecture, cerebellar circuit physiology and brain evolution. However, most of the studied fish models are not well suited for developmental and genetic studies of the cerebellum. The rapid transparent ex utero development in zebrafish allows direct access and precise visualization of all the major events in cerebellar development. The superficial position of the cerebellar primordium and cerebellum further facilitates in vivo imaging of cerebellar structures and developmental events at single cell resolution. Furthermore, zebrafish is amenable to high-throughput screening techniques and forward genetics because of its fecundity and easy keeping. Forward genetics screens in zebrafish have resulted in several isolated cerebellar mutants and substantially contributed to the understanding of the genetic networks involved in hindbrain development (Bae et al. 2009; Brand et al. 1996). Recent developments in genetic tools, including the use of site specific recombinases, efficient transgenesis, inducible gene expression systems, and the targeted genome lesioning technologies TALEN and Cas9/CRISPR has opened up new avenues to manipulate and edit the genome of zebrafish (Hans et al. 2009; Scott 2009; Housden et al. 2016; Li et al. 2016)}. These tools enable the use of genome-wide genetic approaches, such as enhancer/exon traps and cell specific temporal control of gene expression in zebrafish. Several seminal papers have used these technologies to successfully elucidate mechanisms involved in the morphogenesis, neurogenesis and cell migration in the cerebellum (Bae et al. 2009; Chaplin et al. ; Hans et al. 2009; Volkmann et al. ; Volkmann et al. 2008). In addition, the use of genetically encoded sensors and probes that allows detection and manipulation of neuronal activity using optical methods have open up new means to study the physiology and function of the cerebellum (Simmich et al. 2012; Matsui et al. 2014). Taken together, these features have allowed zebrafish to emerge as a complete model for studies of molecular, cellular and physiological mechanisms involved in cerebellar development and function at both cell and circuit level.
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Ramadoss, Jayanth. "Mechanisms underlying fetal alcohol spectrum disorders: ovine model." 2008. http://hdl.handle.net/1969.1/ETD-TAMU-2660.
Full textAbstract:
Maternal alcohol abuse during pregnancy can result in a range of structural and
functional abnormalities that include lifelong physical, mental, behavioral and learning
disabilities, now collectively termed as Fetal Alcohol Spectrum Disorders (FASD). The
incidence of FASD is now estimated be as high as 10 per 1000 live births. Each year,
40,000 babies are born with FASD in the United States at an estimated cost of $1.4
million per individual and total cost of $6 billion. Because of the magnitude of this
problem and because the incidence has not decreased in spite intensive efforts to educate
women to not abuse alcohol during pregnancy, ways to prevent or mitigate the effects of
prenatal alcohol exposure must be explored in addition to education. Therefore, we
wished to identify the precise mechanisms by which alcohol mediates the
neurodevelopmental damage in order to develop intervention/amelioration strategies.
The present study was conducted using an ovine model system. The large body
mass of the ovine fetus, the longer gestation that is more similar to that of humans, and
that all three trimester equivalents occur in utero, make the sheep an excellent model to
study the effects of alcohol on the developing fetus. Our study establishes that maternal alcohol exposure does not result in fetal cerebral hypoxia. Instead, alcohol results in
hypercapnea and acidemia leading to a cascade of events in the maternal and fetal
compartments that include deficits in the levels of glutamine and glutamine-related
amino acids, alterations in endocrine axes, oxidative stress, alteration in cardiovascular
homeostasis and fetal neuronal loss. Further, we demonstrate that inhibiting the novel
two-pore domain acid sensitive potassium channel (TASK) expressed in the cerebellar
granule cells and the peripheral and central chemoreceptors may prove to a be potential
therapeutic strategy. Preventive strategies that are safe to use in pregnant women and
that involve glutamine-related pathways are also suggested. Finally, the study also
establishes the beneficial effects of moderate alcohol consumption on the fetal skeletal
system.
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(8755629), Laura E. Hawley. "Quantifying DYRK1A during perinatal development in the hippocampus, cerebral cortex, and cerebellum of the Ts65Dn mouse model." Thesis, 2020.
Find full textAbstract:
The relationship between gene copy number and protein expression levels has not thoroughly been examined in humans or mouse models of Down syndrome (DS) in relationship to developmental changes in the trisomic brain. Found on human chromosome 21 (Hsa21) and triplicated in DS, Dual-specificity tyrosine-phosphorylated regulated kinase 1A (DYRK1A) has been linked in DS to neurological deficits by restricting cell growth and proliferation. Little information exists regarding DYRK1A during perinatal development and how its expression may lead to cognitive deficits, and none exists that explores the gene-to-protein relationship during these critical time periods. This study aims to 1) Quantify variable DYRK1A expression across development as a function of age, sex, and brain region in trisomic Ts65Dn mice compared to euploid counterparts and 2) establish that the spatiotemporal pattern of developmental DYRK1A in the brain is not influenced solely by gene copy number, and that reduction of Dyrk1a in euploid and trisomic mice does not result in a corresponding global reduction of DYRK1A expression. DYRK1A was quantified in three areas of the postnatal brain at seven ages using the Ts65Dn mouse, the most studied model of DS, and found that trisomic expression is significantly increased on postnatal day ([P]6), declining by the third week to near euploid levels. We also uncovered a sexual dimorphic expression of DYRK1A when comparing animals of different sexes within the same genotype. Data from Dyrk1a knockdown mice indicated that reducing only Dyrk1a in euploid and in otherwise trisomic animals yields highly variable levels of DYRK1A, dependent on sex and tissue type, supporting the non-intuitive relationship between gene dosage and protein expression. These data emphasize the need to understand the age-dependent regulation of antecedent conditions that are causing changes in Dyrk1a expression in the brain.
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BRUNO, FRANCESCO. "Morphofunctional impairment of neuronal and glial cells in the developing cerebellum of a mouse model of Niemann-Pick type C1 disease." Doctoral thesis, 2017. http://hdl.handle.net/11573/986527.
Full textAbstract:
La malattia di Niemann-Pick di tipo C è un disturbo da accumulo lisosomiale ereditario, causata da mutazioni a carico del gene NPC1 (~95% dei casi) e NPC2 (~5% dei casi).
La genetica di tale malattia è molto complessa; attualmente sono state identificate 380 mutazioni a carico del gene NPC1 e 22 a carico del gene NP2. Questi geni codificano per le proteine Npc1 e Npc2 coinvolte nel trasporto intracellulare del colesterolo e di altri lipidi. Infatti, la loro ridotta funzionalità causa un accumulo di colesterolo e altri lipidi, quali sfingosina e i gangliosidi GM2 e GM3, nei compartimenti endosomiali/lisosomiali tardivi, portando a morte cellulare.
Anche da un punto di vista clinico la Malattia di Niemann-Pick di tipo C è molto eterogenea e si manifesta mediante un ampio spettro di sintomi sistemici, neurologici, psichiatrici e declino cognitivo che, a seconda dell’età d’esordio, assumono caratteristiche peculiari diverse. In ogni caso, oltre alla splenomegalia e alla paralisi sopranucleare dello sguardo verticale, il sintomo più prominente è l’atassia cerebellare che presente nel 76% dei pazienti ed è causata dalla degenerazione delle Cellule del Purkinje del cervelletto.
Tra i principali modelli murini sviluppati per poter studiare tale patologia, vi sono il modello knock-out Npc1-/- e del modello ipomorfo Npc1nmf164. Mentre il primo modello mima le forme più gravi e precoci del disturbo, il modello Npc1nmf164 è utile per lo studio delle forme a tarda insorgenza e più lentamente progressive, dal momento che la perdita di funzione della proteina Npc1 è solo parziale.
Attualmente, fra i trattamenti di nuova generazione quello più promettente è la somministrazione dell’oligosaccaride triciclico 2-idrossipropil-β-ciclodestrina (CD). È stato dimostrato che tale farmaco è in grado di contrastare l’accumulo di colesterolo e, di conseguenza il fenotipo NPC-like, aumentando del 50% l’aspettativa di vita sia in modelli murini che felini della NP-C.
L’obiettivo di questo lavoro sperimentale è stato quello di caratterizzare le anomalie morfo-funzionali, sia gliali che neuronali, del cervelletto in via di sviluppo e lo sviluppo motorio nel modello murino Npc1nmf164 , nonché la valutazione dell’efficacia del trattamento con CD nel contrastare tali deficit. Tramite l’utilizzo di tecniche istologiche, immunoistochimica e Western Blot è emerso che, così come riscontrato nel modello knock-out, la ridotta disponibilità di Shh causa una disorganizzazione generale della citoarchitettura corteccia cerebellare. Rispetto ai topi wt, i topi Npc1nmf164 mostrano una minore differenziazione morfologica della Glia di Bergmann (BG), come indicato da un maggiore spessore degli assi radiali e da un meno elaborato modello reticolare dei processi radiali. Anche BG sviluppo funzionale è deficitario, come indicato dalla significativa riduzione di espressione di GLAST e glutammina sintetasi. La ridotta espressione di VGlut2 e GAD65 indicano la presenza di un generale squilibrio della stimolazione glutammatergica/GABAergica che le cellule del Purkinje ricevono rispettivamente dalle fibre rampicanti/parallele e dalle cellule Basket/Stellate. Anche il differenziamento degli oligodendrociti è colpito, come indicato dalla forte riduzione nei livelli di espressione della proteina basica della mielina.
Poiché la microglia attiva gioca un ruolo chiave nella regolazione dello sviluppo e dell’omeostasi del cervello, fagocitando i neuroni apoptotici, mediando il pruning sinaptico e secernendo molecole segnale che promuovono la neurogenesi, la crescita e la sopravvivenza neuronale e l’oligodendritogenesi, ho investigato la presenza di un deficit a carico di questa tipologia gliale nei topi Npc1nmf164. Sebbene non ho riscontrato differenze tra topi wt e Npc1nmf164 nei livelli di espressione della proteina CD11b, un marker “prototipo”, della microglia attiva, è emersa la presenza di ridotti livelli della glicoproteina di membrana endosomiale/lisosomiale CD68, suggerendo la presenza di una ridotta fagocitosi mediata dalla microglia.
È stato dimostrato che Shh promuove l’espressione del BDNF mediante un meccanismo post-trascrizionale. In linea con tale scoperta, ho documentato la presenza di un’alterazione generale nella via di segnalazione del BDNF, che durante lo sviluppo del cervelletto regola il metabolismo del colesterolo per la formazione delle sinapsi ed è indispensabile per lo sviluppo delle arborizzazioni dendritiche delle cellule del Purkinje, la migrazione e la crescita assonale dei neuroni granulari.
Infine, mediante la somministrazione di test di sviluppo motorio è emerso che tale generale disorganizzazione della citoarchitettura cerebellare causa nei topi Npc1nmf164 un ritardo di 2,5 giorni nell’acquisizione delle abilità motorie complesse che richiedono coordinazione motoria fina e equilibrio.
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Izzo, Mariapaola. "The KCASH2KO mice: a new mouse model with mild cerebellar Hedgehog-dependent phenotype and spermatozoa abnormalities." Doctoral thesis, 2019. http://hdl.handle.net/11573/1269209.
Full textAbstract:
KCASH2 gene participates in the modulation of the Hedgehog (Hh) pathway, which plays a role in development, embryogenesis and tumorigenesis. In particular, KCASH2 protein prevents the transcriptional Gli1 activity, interacting with the E3 ubiquitin Ligase Cullin 3, mediating histone-deacetylase 1 (HDAC1) ubiquitin-dependent degradation, which would otherwise deacetylate Gli1 enhancing their transcriptional activity.
In the present work, we generated KCASH2 knockout mice (KCASH2KO) to evaluate in vivo effect of KCASH2 deletion on the Shh pathway and cerebellar development.
KCASH2 expression was present in differentiated cerebellar granule cells, and histological analysis highlighted a larger thickness of the internal granule layer (IGL) in the IV-V cerebellar lobules in the adult KCASH2KO mice cerebellum, confirming the KCASH2 loss determines a prolonged proliferation of granule cells precursors (GCP) during post natal development.
Behavioural experiments have highlighted a significant alteration in cerebellum functions; indeed that the loss of KCASH2 induces in male KCASH2KO a delayed learning and in female KCASH2KO a diversity in procedural navigational strategy compared to WT siblings. Our observations demonstrate that KCASH2 acts in vivo as negative regulator of Hh pathway and suggest, for the fist time, the role of the Hh pathway alteration in such behavioural disorders related to cerebellar function.
During the characterization of the KCASH2KO mouse, we unveiled a potential physiological role of KCASH2 in spermatozoa development and function. We have demonstrated that KCASH2 is expressed in Leydig cells and in Epididymal Epithelium cells and we have observed anomalies in KCASH2KO mice spermatozoa morphology (increased atipicity) and sperm mobility (dyskinesia).
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Teles, Magda. "Adult neurogenesis in a new model specie, the cichlid fish Oreochromis mossambicus." Master's thesis, 2010. http://hdl.handle.net/10400.12/4045.
Full textAbstract:
Dissertação de Mestrado apresentada ao ISPA - Instituto UniversitárioEm comparação com outros vertebrados, os peixes teleósteos têm um enorme potencial para produzir células novas no cérebro de animais adultos. Em contraste com os mamíferos, onde o processo de neurogénese adulta encontra-se restrito a duas áreas cerebrais, a zona subventricular (SVZ) e a zona subgranular parte do giro dentado do hipocampo, em peixes teleósteos foram descritas mais de 10 regiões neurogénicas. Através da marcação de células mitóticas com 5-bromo-2’-deoxiuridina (BrdU), foram caracterizadas as zonas proliferativas da Tilapia de Moçambique (Oreochromis mossanbicus). Nesta espécies, foram encontradas zonas proliferativas em regiões específicas do bolbos olfactivo, telecéfalo, região pré-optica, hipotálamo, tálamo, tecto óptico, torus longitudinalis, nas três divisões do cerebelo, valvula cerebelli, corpus cerebelli, e lobus caudalis e na região da medula, abrangendo assim toda a extensão cerebral. A localização destas zonas proliferativas parece ser extremamente conservada ao longo da taxonomia e até o número total de células produzidas parece ser mantido com pouca variação. Com um tempo de sobrevivência de 2 horas, foram encontrados na tilapia um total de 80.000 células novas em comparação com as 100.000 descritas para o peixe eléctrico Apteronotus leptorhynchus. Os nossos resultados sugerem que a actividade mitótica em regiões discretas do cérebro adulto são uma característica primitiva que tem sido conservada ao longo da evolução.
ABSTRACT: Compared to other vertebrate species, fish exhibit an enormous potential to produce new cells in the adult brain. In contrast to mammals, where proliferation zones are restricted to two brain areas, the sub ventricular zone (SVZ), and the subgranular zone (SGZ), part of the dentate gyrus of hippocampus, in teleost species more than 10 neurogenic regions have been described. By labeling mitotically dividing cells with 5-bromo-2'-deoxyuridine (BrdU), we have characterized the proliferation zones in the Mozambique tilapia (Oreochromis mossambicus). Proliferation zones were located in specific brain regions of the olfactory bulb, telencephalon, preoptic area, hypothalamus, thalamus, optic tectum, torus longitudinalis, in all three subdivisions of the cerebellum, the valvula cerebelli, the corpus cerebelli, and the lobus caudalis cerebelli and in the region of the medulla oblongata. These proliferation zones appeared to be extremely conserved across taxonomy and even the total number of new generated cells seems to be preserved. After 2 hours survival time we found a total of approximately 80.000 new cells for tilapia compared to 100.000 new cells described for Apteronotus leptorhynchus. Our results suggest that the presence of mitotic activity in specific brain regions is a primitive feature that has been conserved through evolution.
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Yu-Ju, Liu. "Fault Accommodation Using Cerebellar-Model Articulation Controller." 2004. http://www.cetd.com.tw/ec/thesisdetail.aspx?etdun=U0009-0112200611330190.
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Liu, Yu-Ju, and 劉郁汝. "Fault Accommodation Using Cerebellar-Model Articulation Controller." Thesis, 2004. http://ndltd.ncl.edu.tw/handle/05841755424482700783.
Full textAbstract:
碩士元智大學
電機工程學系
92
This thesis presents the fault accommodation using Cerebellar-Model Articulation Controller and recurrent Cerebellar-Model Articulation Controller. These controllers are applied to a three-tank system and two engine systems to illustrate their effectiveness. First, a learning architecture, with CMAC network as on-line approximator of the off-nominal system behavior, is used for the accommodation control of two engine systems and a three-tank system. Simulation results show that this method can effectively achieve the fault accommodation. Furthermore, a robust fault accommodation scheme used recurrent Cerebellar-Model Articulation Controller approach, is used for two engine system faults. Simulation results show that the fault accommodation performance can be further improved.
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Chuang, Chih-Ying, and 莊智穎. "STUDY OF PARAMETRIC CEREBELLAR MODEL ARTICULATION CONTROLLER." Thesis, 2012. http://ndltd.ncl.edu.tw/handle/99899097621827012510.
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Lin, Tzu-Hua, and 林子華. "A Study on Cerebellar Model Articulation Controller." Thesis, 2007. http://ndltd.ncl.edu.tw/handle/2m53up.
Full textAbstract:
碩士國立臺北科技大學
電機工程系研究所
95
The PID controller is the longest standing and the most popular controller that has ever been used in the industry because it is convenient and has a simple structure. However, the PID controller can not be used for every system. If the PID controller is used in a more complicated system or in a system where it is not possible to estimate the mathematical model of the plant, then the control performance could be very poor and the plant may not be able to be controlled. In addition, if the parameters of the plant are changed due to external factors, the parameters for the PID controller cannot be immediately modified online, thus the robustness of the PID controller may be deteriorated. In recent years, the development of control theories shows a trend towards intelligent controllers. Among them, artificial neural network (NN), fuzzy controls, and cerebellar model articulation controllers (CMAC), etc., are the most popular. CMAC is a branch of traditional artificial neural networks, and has advantages over traditional artificial neural networks, with less computation required, high computation speed, intelligent learning capability, simple structure, and the ability to adjust the parameters on-line. In view of the disadvantages of PID controllers, the CMAC PID controller, which allows real-time parameter adjustment, is studied specifically and implemented in this thesis. In this study, the C++ programming language is used for the implementation of the CMAC algorithm. Meanwhile, Matlab/Simulink is used as well to simulate the following systems: the second-order systems with steady-state errors and with/without delay, and the second-order unstable systems with/without delay. As the simulation result shows, the CMAC PID controller can effectively control the above systems and the performance is improved significantly.
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Hsu, Julie Yong. "The relationship between posterior cerebellum volume and cross-modal divided attention in Autism Spectrum Disorders." Thesis, 2011. http://hdl.handle.net/2152/ETD-UT-2011-12-4431.
Full textAbstract:
The purpose of the current study is to understand the relationship between the volume of the posterior cerebellar hemispheres and cross-modality divided attention in ASD and control participants. Abnormalities in shifting, orienting, and selective attention are well reported in ASD, but few studies have examined divided attention. Furthermore,
there is evidence of volumetric reduction of the posterior cerebellum in ASD. However,
few studies have examined the relationship between the posterior cerebellum and behavioral performance. The current study addresses this gap in the literature through structural MRI and a neuropsychological attention task. It is hypothesized that the ASD group will have impaired divided attention abilities compared to the control group.
Furthermore, within the ASD group, reduced posterior cerebellar volume is expected to
be associated with impaired divided attention. The study will use multiple regression analyses. As ASD is a neurodevelopmental disability with considerable heterogeneity and unknown etiology, the current study seeks to contribute to the understanding of neural and behavioral markers of ASD.text
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Šalomová, Martina. "Změny motorických funkcí u myšího modelu cerebelární degenerace v průběhu ontogeneze." Master's thesis, 2017. http://www.nusl.cz/ntk/nusl-367899.
Full textAbstract:
The cerebellum affects a number of important and complex processes in the organism. It ensures coordination, motor learning and plays an important role in cognitive and affective functions. In the case of cerebellar degeneration, we find not only the movement disorders but also behavioral abnormalities, collectively referred to as cognitive-affective syndrome. The aim of this work was to investigate motor functions during ontogenesis in animal models of hereditary cerebellar degeneration - mutant mice Lurcher and Purkinje cell degeneration using the device for quantitative gait analysis and rotarod. In addition, the effect of physical activity on the extent of ataxia and manifestations in classical behavioral tests was monitored. The results confirmed significant differences in motor skills between mutant and healthy mice; differences were also observed in some gait parameters, especially in walking speed and parameters that correlate with it. The motor functions of most groups of mice did not change during ontogenesis, pcd mice deteriorated their performance on the rotarod. The effect of physical activity was not found, with the exception of Forced swimming test. Physical activity of set intensity did not have any beneficial effect on the motoric manifestations of the mice.
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Lu, Wei-Ting, and 呂韋廷. "Deadzone compensation based on Cerebellar Model Articulation Controller." Thesis, 2012. http://ndltd.ncl.edu.tw/handle/82472173577771948228.
Full textAbstract:
碩士龍華科技大學
工程技術研究所
100
In this paper, the utilization of adaptive control and Cerebellar Model Articulation Controller is the compensation of the phenomenon of Non-Linear Deadzone which is in Servo-Hydraulic System. In addition, the controlled-dynamical model is separated into Non-Linear Deadzone System and Linear Time-Invariant System. In the systems, there are two Cerebellar Model Articulation Controller; One is for identifying the parameters of Deadzone, then the result is used to train the other one which is used for the inverse compensation of Deadzone that is employed to eliminate the phenomenon of Non-Linear Deadzone. The parameters of Liner System in the theory of Recursive identification are utilized to identify the systems, and the parameters from the end of the testament are used model reference adaptive pole placement to design the controller. According to these simulations, it can be obtained good results.
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Chi-Jui, Kao. "Intelligent Car-Following Control Using Cerebellar Model Articulation Controller." 2004. http://www.cetd.com.tw/ec/thesisdetail.aspx?etdun=U0009-0112200611330076.
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Lin, Ming-Hung, and 林明宏. "Design and Applications of Robust Cerebellar Model Articulation Controller." Thesis, 2006. http://ndltd.ncl.edu.tw/handle/57069450746764653910.
Full textAbstract:
碩士清雲科技大學
電機工程研究所
94
In this thesis the cerebellar model articulation controller (CMAC) is the main controller. First , since the dynamic characteristics of the linear piezoelectric ceramic motor (LPCM) are highly nonlinear and time varying, it is difficult to design a suitable motor position controller to achieve high-precision position control at all time. An robust cerebellar model articulation controller (CMAC) via the backstepping control technique is proposed. In the robust CMAC backstepping control system, an adaptive CMAC is used to mimic an ideal backstepping control law and a robust controller is designed to compensate for the difference between the ideal backstepping control law and the adaptive CMAC. The adaptation laws of the control system are derived in the sense of Lyapunov stability analysis, so that the stability of the system can be guaranteed. the controlled LPCM possesses the advantages of good tracking control performance and robustness to uncertainties under wide operating ranges. The effectiveness of the proposed control system is verified with hardware experiments under the occurrence of uncertainties. Then, an adaptive recurrent cerebellar model articulation controller (RCMAC) with a guaranteed performance is proposed for the car-following collision prevention systems to track periodic reference trajectories. In this control scheme, the proposed dynamic structure of RCMAC has superior capability to the conventional static cerebellar model articulation controller (CMAC) in efficient learning mechanism and dynamic response. The control laws for the robust RCMAC control system are derived based on the control technique and the Lyapunov stability analysis, so that system-tracking stability can be guaranteed in the closed-loop system. Finally, the proposed robust RCMAC control system is applied for the car-following collision prevention control. Simulation results show that this method can achieve favorable tracking performance for a safe car-following control.
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Kao, Chi-Jui, and 高啟瑞. "Intelligent Car-Following Control Using Cerebellar Model Articulation Controller." Thesis, 2004. http://ndltd.ncl.edu.tw/handle/41258903770963265558.
Full textAbstract:
碩士元智大學
電機工程學系
92
The application of new technologies of computer and communications on the transportation vehicle can improve the vehicle safety and accelerate the vehicle performance dramatically. Also, the vehicle can communicate with all other information suppliers at any time. This is called the Intelligent Vehicle (IV). This thesis focuses on the design of the cerebellar model articulation controller (CMAC) based on adaptive control, supervisory control and recursive control, which attempt to provide a comprehensive treatment of CMACs in closed-loop control applications. For supervisory recurrent cerebellar-model articulation controller (SRCMAC), the car-following control system is formulated as a tracking problem. The SRCMAC is designed to achieve satisfactory tracking performance for car-following control system. Finally, a design method of recurrent CMAC for multi-input multi-output nonlinear systems is developed and is applied to lane-change control system. From the simulation results, the proposed intelligent control techniques have been shown to achieve satisfactory control performance for the considered nonlinear systems. In addition to use matlab’s simulations, the virtual reality (VR) simulations are also carried out. In the VR system, we use 3D Studio MAX to construct the scenes, and use the 3D animation development tool MATFOR VR to program the entire playing process. Moreover, we add dynamic motion equation and control method into the scenes, and use virtual reality technique to show the motion of translation and rotation of vehicles.
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Lan, Shih-Wei, and 藍世緯. "Adaptive Echo Cancellation Using Deep Cerebellar Model Articulation Controller." Thesis, 2017. http://ndltd.ncl.edu.tw/handle/80404587248894079955.
Full textAbstract:
碩士元智大學
電機工程學系
105
ABSTRACT It had the very big breakthrough in the machine learning development in recent years. No matter the Watson which developed by IBM or Google’s AlphaGo, they both are based on depth of neural networks. And the cerebellar model articulation controller (CMAC) has been widely used in various applications of neural networks, such as: inverted pendulum, nonlinear channel equalization and robot control. It has great generalization and learning fast characteristics enough to deal with the basic applications of neural network. But if the complexity of the higher non-linear task, there will be learning learning-difficulty situation. And the CMAC was originally designed for simple control applications, so high-dimensional input processing, such as: speech recognition which can’t be used by normal CMAC, so it need to improved. This paper proposed the deep cerebellar model articulation controller(DCMAC) for echo cancellation and the MIMO-DCMAC with the Softmax function for speech recognition. We stack the conventional single-layered CMAC models into multiple layers to form a DCMAC model, and re-modify the back propagation algorithm to get the update of DCMAC’s parameter. Due to the deep structure, DCMAC can have a better generalization error than the normal CMAC. The experimental results also show that DCMAC can build model more effectively than CMAC in signal processing.
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Lin, Shou-Chuang, and 林首壯. "High Performance PID-type Cerebellar Model Articulation Controller Design." Thesis, 2006. http://ndltd.ncl.edu.tw/handle/t6rks5.
Full textAbstract:
碩士國立臺北科技大學
電機工程系所
94
As modeling the physical systems to meet the need of control purpose, finding mathematical models of these systems is a challenging work, and there are many approaches proposed to solve this problem. To reduce the complexity of analysis, model reduction and linearization techniques are frequently adopted. Also, insignificant parameters or inferences are sometimes neglected during the modeling process. Though using the forgoing obtained mathematical models can easily and quickly calculate the control force, in some circumstances, the control behavior of simulation is deviated from that of implementation because of too many unpractical assumptions and oversimplification. Consequently, the controller designed based on the mathematical model did not work properly. Due to the increasing complexity of modern controlled objects, accurate mathematical models are getting difficult to obtain. Mathematical models used in conventional control system analysis and design are established by way of experiments. From the frequency responses of experiments, the simplified models of the control system are then built by zero-pole matching and then the transfer function of the derived model to can be used to describe the dynamic characteristics. Motivated by Ziegler and Nichols PID tuning method, there are various PID controller design methods suggested. When the mathematical model is of order 1 or order 2, the designed PID controller performs well. However, for the high order systems, the performance of designed controller based on the second order system deteriorates and the closed-loop system is even out of control in the worst case. Moreover, when the parameters of plant fluctuate due to the environmental or artificial factors, PID parameters can not on-line and real-time self adjust. As a result, the robustness of closed-loop system is affected. To overcome the aforementioned disadvantages and implement the high performance PID controller with real-time parameter tuning ability, this thesis proposes a new Credit Assignment Cerebellar Model Articulation Controller (CA-CMAC), which is widely investigated in the intelligent control field. The research result of this thesis, the on-line CA-CMAC algorithm, is programmed by C++ language and accompanied with Matlab/Simulink to simulate the following plants: induction motor, aircraft, second-order system with steady-state error, and second-order unstable system. From the simulation results, it is seen that the proposed PID CA-CMAC can effectively control these plants and the performances of dynamic behaviors are improved dramatically.
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龔書暉. "The cerebella model articulation controller based on CAM architecture." Thesis, 2001. http://ndltd.ncl.edu.tw/handle/97458667971351984150.
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Snow, Wanda Mae. "Cerebellar pathophysiology in a mouse model of Duchenne muscular dystrophy." 2012. http://hdl.handle.net/1993/11296.
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This series of experiments investigated dystrophin localization in the normal cerebellum and examined Purkinje neuron function in normal and dystrophin-deficient mice to better understand the physiological basis for cognitive deficits associated with Duchenne muscular dystrophy (DMD), a common genetic disorder among children. Cognitive impairments are consistently reported in DMD, yet precise mechanisms for their occurrence are unknown. Dystrophin protein, which is absent in DMD, is normally localized to muscles and specific neurons in the brain. Purkinje neurons are rich in dystrophin, specifically in somatic and dendritic membranes. Studies demonstrate perturbed cerebellar function in the absence of dystrophin, suggesting that DMD should be regarded as a cerebellar disorder in addition to being considered a neuromuscular disorder. However, theory and evidence are not generated from overlapping information: research investigating cerebellar involvement in DMD has focused on the vermal region, associated with motor function. The lateral region, implicated in cognition, has not been explicitly examined in DMD. The first experiment revisited the issue of dystrophin distribution in the mouse cerebellum using immunohistochemistry to investigate qualitative and quantitative differences between cerebellar regions. Both regions showed dystrophin localized to Purkinje neuron somatic and dendritic membranes, but dystrophin density was 30% greater in the lateral than the vermal region. The second experiment examined intrinsic electrophysiological properties of vermal and lateral Purkinje neurons from wild-type (WT) mice and from the mdx mouse model of DMD which lack dystrophin. Significant differences in action potential firing frequency, regularity, and shape were found between cerebellar regions. Purkinje neurons from mdx mouse cerebellum exhibited membrane hyperpolarization and irregular action potential firing, regardless of region. Spontaneous action potential firing frequency was reduced in Purkinje neurons from lateral cerebellum in mdx mice relative to controls, demonstrating that a loss of dystrophin causes a potent dysregulation of Purkinje neuron function in the region associated with cognition. This research extends our understanding of cerebellar pathology in DMD and its potential relevance to cognitive deficits in the disorder. Moreover, this research further supports the role of the cerebellum as a structure important for cognition and contributes to our understanding of dystrophin’s role in the brain.
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Peng, Yen-Jui, and 彭彥瑞. "Dynamic Petri Cerebellar Model Articulation Controller for Magnetic Levitation System." Thesis, 2011. http://ndltd.ncl.edu.tw/handle/48571506368131012507.
Full textAbstract:
碩士元智大學
電機工程學系
99
In this thesis, the control of the magnetic levitation system is achieved by the proposed intelligent controller, which is based on the cerebellar model articulation controller (CMAC). The magnetic levitation system is a complicated and tough problem for the conventional controller, because the system is a highly nonlinear system. Since the magnetic levitation system is without mechanical contact, friction and noise, it can be used for precise positioning. These advantages make it a wide range of applications on the maglev train, magnetic bearing, wind tunnel, and conveyor system, etc. The proposed intelligent controller is composed of a novel dynamic Petri CMAC controller which is utilized to approximate an ideal controller. The dynamic Petri is used to determine the passing of the Gaussian function value. Finally, the proposed intelligent control system is applied to the magnetic levitation system, and its performance is verified through simulation and experiments based on the field programmable gate array (FPGA) chip. From the simulation and experimental results for the magnetic levitation system, the system stability and desired control performance can be achieved by the proposed intelligent controller.