Dissertationen: „Granular neuron“

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Mortessagne, Pierre. „Characterization of the different populations of granular neurons in the dentate gyrus of the hippocampus : from morphology to function“. Electronic Thesis or Diss., Bordeaux, 2024. http://www.theses.fr/2024BORD0402.

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Dans le gyrus denté (GD) de la formation hippocampique, la génération des neurones granulaires (NGs) commence vers la fin de l'embryogenèse, atteint un pic autour de la naissance, puis se poursuit à un faible niveau à l'âge adulte. Cette neurogénèse continue fait du GD une structure cérébrale unique, composée de NGs d'origines temporelles distinctes qui forment des sous-populations potentiellement dotées de caractéristiques anatomiques et fonctionnelles spécifiques dans l'hippocampe. Étonnamment, cette hypothèse a reçu peu d'attention. Dans ce contexte, ce travail de thèse a visé à élucider les caractéristiques morphologiques, électrophysiologiques et comportementales des sous-populations de NGs en fonction de leur origine temporelle. S’appuyant sur des découvertes antérieures de notre équipe qui avaient mis en évidence des différences dendritiques entre ces populations, nous avons centré nos investigations sur leurs axones, appelés fibres moussues. En utilisant des stratégies de marquage épars — l'électroporation pour cibler les NGs nés durant la période embryonnaire(E14.5) et néonatale (P0), ainsi que des injections rétrovirales pour les NGs nés à l’adolescence(P21) et à l’âge adulte (P84) — nous avons mis en évidence que les NGs générés à des périodes plus tardives développent des boutons plus larges avec davantage de filopodes et présentent un segment initial axonal plus court. De plus, en utilisant les lignées de souris Osteocalcin-Cre etAscl1CreERT2 pour marquer de larges cohortes de NGs générés durant la période embryonnaire et à l’âge adulte, respectivement, nous avons observé que les neurones nés précocement projettent davantage vers le CA2 comparativement aux neurones générés plus tardivement au cours de la vie. Suite à ces découvertes, nous avons étudié les caractéristiques fonctionnelles des NGs d’origines temporelles différentes, au niveau électrophysiologique et comportemental.Les études électrophysiologiques ont révélé que les NGs nés en période néonatale partagent des propriétés intrinsèques similaires à celles des NGs nés en période adulte, mais possèdent une transmission basale plus élevée, reflétant potentiellement un nombre plus important de sites actifs. Enfin, nous avons examiné le rôle des NGs nés en période embryonnaire dans le comportement de type social et montré qu’une inhibition aiguë de ces neurones retardait l’expression de la préférence sociale. Cependant, ces données fonctionnelles restent préliminaires et nécessitent des investigations supplémentaires.En conclusion, ce travail de thèse met en évidence l'impact significatif de l'origine temporelle des NGs sur leurs caractéristiques anatomiques et potentiellement fonctionnelles, soulignant l’importance de prendre en compte l’origine temporelle des NGs dans toute étude s’intéressant à l’aspect structurel ou fonctionnel du DG
In the dentate gyrus (DG) of the hippocampus, the generation of dentate granule neurons(DGNs) starts during late embryogenesis, peaks around birth and continues at low levels during adulthood. This continuous neurogenesis makes the DG a unique structure, composed of DGNs from distinct temporal origins, which form subpopulations potentially bearing unique anatomical characteristics and functional roles in hippocampal physiology. Surprisingly, this hypothesis has received limited attention. In this context, our research aimed to elucidate the morphological, electrophysiological, and behavioral characteristics of DGNs subpopulations based on their temporal origin. Building on prior findings from our team that high lighted dendritic differences between these populations, we focused on examining the features of their axons, called mossy fibers (MFs). Using sparse labeling strategies — electroporation to targetembryonically-born (E14.5) and neonatally-born (P0) DGNs, and retroviral injections foradolescent-born (P21) and adult-born (P84) DGNs — we uncovered that DGNs generated laterin life develop larger MF boutons with more filopodia, and exhibit a shorter axon initialsegment. Additionally, using the Osteocalcin-Cre and Ascl1CreERT2 mouse lines to selectivelylabel large cohorts of embryonically-born and adult-born DGNs, respectively, we found thatearlier-born neurons project further onto the CA2 compared to later-born neurons. Following these morphological findings, we further investigated the functional characteristics of temporally distinct DGNs at both the electrophysiological and behavioral levels. The electrophysiological studies revealed similar intrinsic properties between neonatally- and adult born DGNs, and higher basal transmission in neonatally-born DGNs, potentially reflecting alarger number of active sites. Finally, we examined the role of embryonic-born DGNs in socialbehavior, and showed that acute inhibition of these neurons delayed the expression of social preference. However, these functional data remain preliminary and need further investigation.Altogether, this PhD work highlights the significant impact of the birthdate of DGNs on their anatomical and potentially functional characteristics, and emphasizes the importance of considering their precise temporal origin in any structural or functional analysis of the DG

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Čurilla, Matej. „Neuronové sítě a hrubé množiny“. Master's thesis, Vysoké učení technické v Brně. Fakulta informačních technologií, 2015. http://www.nusl.cz/ntk/nusl-264945.

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Rough sets and neural networks both offer good theoretical background for data processing and analysis. However, both of them suffer from few issues. This thesis will investigate methods by which these two concepts are merged, and few such solutions will be implemented and compared with conventional algorithm to study the benefits of this approach.

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Leite, Daniel Furtado. „Evolving granular systems = Sistemas granulares evolutivos“. [s.n.], 2012. http://repositorio.unicamp.br/jspui/handle/REPOSIP/260761.

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Orientador: Fernando Antonio Campos Gomide
Tese (doutorado) - Universidade Estadual de Campinas, Faculdade de Engenharia Elétrica e de Computação
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Resumo: Recentemente tem-se observado um crescente interesse em abordagens de modelagem computacional para lidar com fluxos de dados do mundo real. Métodos e algoritmos têm sido propostos para obtenção de conhecimento a partir de conjuntos de dados muito grandes e, a princípio, sem valor aparente. Este trabalho apresenta uma plataforma computacional para modelagem granular evolutiva de fluxos de dados incertos. Sistemas granulares evolutivos abrangem uma variedade de abordagens para modelagem on-line inspiradas na forma com que os humanos lidam com a complexidade. Esses sistemas exploram o fluxo de informação em ambiente dinâmico e extrai disso modelos que podem ser linguisticamente entendidos. Particularmente, a granulação da informação é uma técnica natural para dispensar atenção a detalhes desnecessários e enfatizar transparência, interpretabilidade e escalabilidade de sistemas de informação. Dados incertos (granulares) surgem a partir de percepções ou descrições imprecisas do valor de uma variável. De maneira geral, vários fatores podem afetar a escolha da representação dos dados tal que o objeto representativo reflita o significado do conceito que ele está sendo usado para representar. Neste trabalho são considerados dados numéricos, intervalares e fuzzy; e modelos intervalares, fuzzy e neuro-fuzzy. A aprendizagem de sistemas granulares é baseada em algoritmos incrementais que constroem a estrutura do modelo sem conhecimento anterior sobre o processo e adapta os parâmetros do modelo sempre que necessário. Este paradigma de aprendizagem é particularmente importante uma vez que ele evita a reconstrução e o retreinamento do modelo quando o ambiente muda. Exemplos de aplicação em classificação, aproximação de função, predição de séries temporais e controle usando dados sintéticos e reais ilustram a utilidade das abordagens de modelagem granular propostas. O comportamento de fluxos de dados não-estacionários com mudanças graduais e abruptas de regime é também analisado dentro do paradigma de computação granular evolutiva. Realçamos o papel da computação intervalar, fuzzy e neuro-fuzzy em processar dados incertos e prover soluções aproximadas de alta qualidade e sumário de regras de conjuntos de dados de entrada e saída. As abordagens e o paradigma introduzidos constituem uma extensão natural de sistemas inteligentes evolutivos para processamento de dados numéricos a sistemas granulares evolutivos para processamento de dados granulares
Abstract: In recent years there has been increasing interest in computational modeling approaches to deal with real-world data streams. Methods and algorithms have been proposed to uncover meaningful knowledge from very large (often unbounded) data sets in principle with no apparent value. This thesis introduces a framework for evolving granular modeling of uncertain data streams. Evolving granular systems comprise an array of online modeling approaches inspired by the way in which humans deal with complexity. These systems explore the information flow in dynamic environments and derive from it models that can be linguistically understood. Particularly, information granulation is a natural technique to dispense unnecessary details and emphasize transparency, interpretability and scalability of information systems. Uncertain (granular) data arise from imprecise perception or description of the value of a variable. Broadly stated, various factors can affect one's choice of data representation such that the representing object conveys the meaning of the concept it is being used to represent. Of particular concern to this work are numerical, interval, and fuzzy types of granular data; and interval, fuzzy, and neurofuzzy modeling frameworks. Learning in evolving granular systems is based on incremental algorithms that build model structure from scratch on a per-sample basis and adapt model parameters whenever necessary. This learning paradigm is meaningful once it avoids redesigning and retraining models all along if the system changes. Application examples in classification, function approximation, time-series prediction and control using real and synthetic data illustrate the usefulness of the granular approaches and framework proposed. The behavior of nonstationary data streams with gradual and abrupt regime shifts is also analyzed in the realm of evolving granular computing. We shed light upon the role of interval, fuzzy, and neurofuzzy computing in processing uncertain data and providing high-quality approximate solutions and rule summary of input-output data sets. The approaches and framework introduced constitute a natural extension of evolving intelligent systems over numeric data streams to evolving granular systems over granular data streams
Doutorado
Automação
Doutor em Engenharia Elétrica

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Mahoney, Sally-Ann. „A role for tissue transglutaminase in neuron / glial interaction and development of cerebellar granule neurons“. Thesis, University of Bristol, 1997. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.361111.

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Pushpalatha, Kavya Vinayan. „Remodelage des condensats RNP neuronaux au cours du vieillissement chez la drosophile“. Electronic Thesis or Diss., Université Côte d'Azur, 2021. http://theses.univ-cotedazur.fr/2021COAZ6007.

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Dans la cellule, les molécules d’ARN s’assemblent avec des protéines de liaison aux ARNs pour former des assemblages macromoléculaires très dynamiques appelés granules ribonucléoprotéiques (RNP). Ces assemblages régulent l’expression génique en contrôlant le transport, la stabilité et/ou la traduction des ARNs associés. Des travaux réalisés in vitro ont montré que la formation et la composition des granules RNP reposent sur l’établissement de réseaux denses d’interactions établis entre protéines et ARN, ainsi que sur leur stoechiométrie. Comment les propriétés des granules RNP sont régulées en contexte physiologique, et en particulier lors du vieillissement, est cependant actuellement peu connu. Mon projet de thèse visait à répondre à cette question par une étude in vivo des granules RNP présents dans les cellules neuronales du cerveau de drosophile.A cette fin, j’ai analysé dans des cerveaux d’âge croissant des granules RNP caractérisés par la présence de la protéine de liaison aux ARNs Imp/ZBP1 et de la DEAD-box hélicase Me31B/DDX6. Mes travaux ont révélé une augmentation progressive de la condensation de Imp et Me31B en larges granules au cours du vieillissement. Ces granules sont dynamiques et ne co-localisent pas avec des marqueurs d’agrégation, suggérant qu’ils ne correspondent pas à des agrégats protéiques statiques. Remarquablement, la condensation de Imp et Me31B est associée à la perte des granules Me31B+ Imp- observées dans les cerveaux jeunes, et à la coalescence de Me31B et Imp pour former des granules uniques Me31B+ Imp+. De plus, ce processus est accompagné d’une inhibition spécifique de la traduction des ARNms associés aux granules, parmi lesquels profilin. Par une analyse fonctionnelle, j’ai mis en évidence qu’une modification de la concentration en Me31B est responsable de la condensation de Me31B dans les cerveaux âgés. Alors qu’une augmentation de la quantité de Me31B est observée au cours du vieillissement, enlever une copie de me31B supprime la condensation age-dépendante de ce composant. Étant donné que la condensation de Imp n’est que partiellement affectée dans ce contexte, j’ai réalisé un crible génétique afin d’identifier des régulateurs de ce processus. Ceci m’a permis de montrer que l’activité de la kinase PKA est essentielle d’une part à la condensation de Imp chez les drosophiles âgées, et d’autre part à la répression traductionnelle des ARNms associés aux granules.En conclusion, mon travail a montré pour la première fois que les propriétés des granules RNP neuronaux sont modifiées au cours du vieillissement, un phénomène qui ne reflète pas une altération générale de l’homéostasie des ARNs, mais plutôt une modulation spécifique de la concentration en composants RNP combinée à l’activité de kinase conservée. Ces résultats démontrent comment les systèmes biologiques peuvent moduler des paramètres clés initialement identifiés dans des contextes in vitro, et ouvrent de nouvelles perspectives dans le domaine de la régulation de l’expression génique au cours du vieillissement
Nascent mRNAs complex with RNA binding proteins (RBPs) to form highly dynamic, phase-separated organelles termed ribonucleoprotein (RNP) granules. These macromolecular assemblies can regulate gene expression by controlling the transport, decay and/or translation of associated RNA molecules. As mostly shown in vitro, RNP granule assembly and function rely on the interaction networks established by individual components and on their stoichiometry. To date, how the properties of constitutive RNP granules are regulated in different physiological context is unclear. In particular, the impact of physiological aging is unclear. My PhD project aimed at addressing this question by analyzing in vivo in long-lived neuronal cells the properties of RNP granules. To this end, I have analysed in flies of increasing age RNP granules characterized by the presence of the conserved RBP Imp/ZBP1 and DEAD-box RNA helicase Me31B/DDX6. Strikingly, a progressive increase in the condensation of Imp and Me31B into granules was observed upon aging. The large granules observed in aged flies were dynamic, contained profilin mRNA, and did not colocalize with Ubiquitin or aggregation markers, suggesting that they do not correspond to static protein aggregates. Increased condensation also associated with the loss of Me31B+ Imp- granules observed in young brains and the collapse of RNP component into a unique class of Me31B+ Imp+ granule. Furthermore, it was accompanied by a specific inhibition of the translation of granule-associated mRNAs, among which the Imp RNA target profilin. Through functional analysis, I uncovered that changes in Me31B stoichiometry trigger Me31B condensation in aged flies. While an increase in Me31B protein levels was observed upon aging, decreasing the dosage of Me31B suppressed its age-dependent condensation. As Imp condensation was only partially suppressed in this context, I performed a selective screen to identify regulators of this process. This revealed that downregulating PKA activity by different genetic means both drastically reduced Imp recruitment and prevented the age-dependent translational repression of granule-associated mRNAs. Taken together, my work thus showed for the first time in vivo that the properties of neuronal RNP granules change upon aging, a phenomenon that does not reflect general alterations in RNA homeostasis but rather specific modulation of RNP component stoichiometry and kinase activity. These results demonstrate how biological systems can modulate key parameters initially defined based on in vitro framework, and also open new perspectives in the field of age-dependent regulation of gene expression

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Kerloch, Thomas. „Etude du développement des neurones granulaires du gyrus denté : morphogénèse et régulation par Rnd2“. Thesis, Bordeaux, 2018. http://www.theses.fr/2018BORD0254.

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Dans la plupart des régions cérébrales, les neurones sont générés pendant l’embryogénèse. A l’inverse, dans le gyrus denté (DG) de l'hippocampe, la majorité des neurones granulaires (NGs) est générée en période postnatale et cette production neuronale se poursuit tout au long de l'âge adulte. Cette découverte selon laquelle de nouveaux neurones sont générés dans le cerveau des mammifères adultes a ouvert de nouvelles perspectives pour réparer le cerveau et a conduit de nombreuses recherches, au cours des 20 dernières années, à caractériser comment les nouveaux neurones se différencient et s'intègrent aux circuits neuronaux adultes. Cependant, d'autres études sont nécessaires pour mieux comprendre les mécanismes et les cascades de signalisation impliqués dans ce processus. Dans ce contexte, nous nous sommes concentrés sur Rnd2, une RhoGTPase particulièrement enrichie dans le DG adulte et décrite comme une actrice clé dans la régulation de la neurogenèse corticale embryonnaire. Nous avons montré, in vivo, que la suppression de Rnd2 spécifiquement dans les néo-neurones hippocampiques diminue la survie de ces cellules, et dans les cellules survivantes, conduit à une hypertrophie du soma, augmente l'arborisation dendritique et induit un mauvais positionnement. De façon intéressante cette suppression augmente également le comportement anxiogène des souris, identifiant ainsi Rnd2 comme un régulateur critique de la neurogénèse adulte hippocampique. De plus, nos données montrent que Rnd2 ne joue pas les mêmes fonctions dans les NGs nés à P0, mettant en évidence une régulation différentielle de la neurogenèse développementale et adulte dans la DG. Dans le même ordre d'idées, nous démontrons également que les NGs nés en période périnatale, en particulier les neurones embryonnaires, sont morphologiquement distincts par rapport aux NGs nés plus tard. L'ensemble de ces travaux de thèse apporte donc de nouvelles connaissances sur le développement des différentes populations de NGs dans la DG, soulignant davantage la particularité de cette structure cérébrale
In most areas of the brain, neurons are born during embryogenesis. In contrast, the majority of granule neurons in the dentate gyrus (DG) of the hippocampus are born postnatally and their generation continues throughout adulthood. This finding that new neurons are generated in the adult mammalian brain has opened novel avenues for brain repair and has initiated, in the last 20 years, tremendous efforts to characterize how new neurons differentiate and integrate into adult neural circuitries. However, further studies are needed to better understand the mechanisms and signaling cascades involved in this process. In this context, we focused on Rnd2, a RhoGTPase particularly enriched in the adult neurogenic DG and described as a key player in the regulation of embryonic cortical neurogenesis. We found, in vivo, that the deletion of Rnd2 specifically in adult-born hippocampal neurons decreases the survival of these cells, and in the surviving ones, leads to soma hypertrophy, increases dendritic arborization and induces mispositioning. Importantly, this deletion also increases anxiety-like behavior in mice, thus identifying Rnd2 as a critical regulator of adult newborn neuron development and function. In addition, our data show that Rnd2 does not play the same functions in granule neurons born at P0, highlighting a differential regulation of developmental and adult neurogenesis in the DG. In the same vein, we also demonstrate that perinatally-born granule neurons, especially the embryonic ones, are morphologically distinct compared with later-born neurons. Altogether, this PhD work provides new insights into the development of the different populations of granule neurons in the DG, further emphasizing the peculiarity of this brain structure

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Landeira, Bruna Soares. „Elimina??o de neur?nios infragranulares afeta a especifica??o de neur?nios granulares e supragranulares do c?rtex cerebral em desenvolvimento“. PROGRAMA DE P?S-GRADUA??O EM NEUROCI?NCIAS, 2017. https://repositorio.ufrn.br/jspui/handle/123456789/23364.

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O c?rtex cerebral de mam?feros ? histologicamente organizado em diferentes camadas de neur?nios excitat?rios que possuem diversos padr?es de conex?o com alvos corticais e subcorticais. Durante o desenvolvimento, essas camadas corticais se estabelecem sequencialmente atrav?s de uma intrincada combina??o de especifica??o neuronal e migra??o em um padr?o radial conhecida como ?de dentro para fora?: neur?nios infragranulares s?o gerados primeiro do que os neur?nios granulares e supragranulares. Nas ?ltimas d?cadas, diversos genes codificando fatores de transcri??o envolvidos na especifica??o de neur?nios destinados a diferentes camadas corticais foram identificados. Todavia, a influ?ncia dos neur?nios infragranulares sobre a especifica??o das coortes neuronais subsequentes permanece pouco entendida. Para investigar os poss?veis efeitos da abla??o de neur?nios infragranulares sobre a especifica??o de neur?nios supragranulares, n?s induzimos a morte seletiva de neur?nios corticais das camadas V e VI antes da gera??o dos neur?nios destinados ?s camadas II-IV. Nossos dados revelam que um dia ap?s a abla??o, progenitores continuaram a gerar neur?nios destinados a camada VI que expressam o fator de transcri??o TBR1, enquanto praticamente nenhum neur?nio expressando TBR1 foi gerado na mesma etapa do desenvolvimento em controles com a mesma idade. Curiosamente, alguns neur?nios TBR1-positivos gerados ap?s a abla??o de neur?nios infragranulares se estabeleceram em camadas corticais superficiais, como esperado para neur?nios supragranulares gerados neste est?gio, sugerindo que a migra??o de neur?nios corticais pode ser controlada independentemente da sua especifica??o molecular. Al?m disso, n?s observamos um aumento em neur?nios de camada V que expressam CTIP2 e neur?nios calosos que expressam SATB2 ? custa da diminui??o neur?nios de camada IV em animais P0. Quando estes animais se tornam adultos jovens (P30) o aumento de neur?nios SATB2 e CTIP2 n?o existe mais, todavia encontramos esses neur?nios distribu?dos de forma diferente na ?rea somatossensorial dos animais que sofreram abla??o. Experimentos in vitro revelaram que a organiza??o citoarquitet?nica laminar do c?rtex ? necess?ria para gerar novamente os neur?nios TBR1+ que foram eliminados anteriormente. Al?m disso, experimentos in vitro indicam que em condi??o de baixa densidade celular os neur?nios tem seu fen?tipo alterado, expressando v?rios fatores de transcri??o ao mesmo tempo. Em conjunto, nossos dados indicam a exist?ncia de um mecanismo regulat?rio entre neur?nios infragranulares e progenitores envolvidos na gera??o de neur?nios supragranulares e/ou entre neur?nios infragranulares e neur?nios p?s-mit?ticos gerados em seguida. Este mecanismo poderia ajudar a controlar o n?mero de neur?nios em diferentes camadas e contribuir para o estabelecimento de diferentes ?reas corticais.
The cerebral cortex of mammals is histologically organized into in different layers of excitatory neurons that have distinct patterns of connections with cortical or subcortical targets. During development, these cortical layers are sequentially established through an intricate combination of neuronal specification and migration in a radial pattern known as "inside-out": deep-layer neurons are generated prior to upper-layer neurons. In the last few decades, several genes encoding transcription factors involved in the specification of neurons destined to different cortical layers have been identified. However, the influence of early-generated neurons in to the specification of subsequent neuronal cohorts remains unclear. To investigate the possible effects early born neurons ablation on the specification of late born neurons, we induced the selective death of cortical neurons from layers V and VI neurons before the generation of neurons destined to layers II, III and IV. Our data shows that oneday after ablation, progenitors resumed generation of layer VI neurons expressing the transcription factor TBR1, whereas virtually no TBR1-expressing neuron was generated at the same developmental stage in age-matched controls. Interestingly, many TBR1-positive neurons generated after deep-layer ablation settled within superficial cortical layers, as expected for upper-layer neurons generated at that stage, suggesting that migration post-mitotic neurons is independent of fate-specification. Furthermore, we observed an increase in layer V neurons expressing CTIP2 and cortico-cortical neurons expressing SATB2 at the expense of layer IV neurons in P0 animals. When these animals became young adults (P30) the increase os SATB2 and CTIP2 neurons is no longer observed, however these neurons are distributed in a different way in somatosensory areas from ablated animals. In vitro experiments show that the laminar cytoarchitectural organization of the cortex is necessary to regenerate the previously deleted TBR1 + neurons. In addition, in vitro experiments indicate that in a condition of low cell density the neurons phnotype is altered, they express several transcription factors at the same time. Together, our data indicate the existence of feedback mechanism either from early-generated neurons to progenitors involved in the generation of upper-layer neurons or from deep-layer neurons to postmitotic neurons generated subsequently. This mechanism could help to control the number of neurons in different layers and contribute to the establishment of different cortical areas.

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Al-Shammaa, Mohammed. „Granular computing approach for intelligent classifier design“. Thesis, Brunel University, 2016. http://bura.brunel.ac.uk/handle/2438/13686.

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Granular computing facilitates dealing with information by providing a theoretical framework to deal with information as granules at different levels of granularity (different levels of specificity/abstraction). It aims to provide an abstract explainable description of the data by forming granules that represent the features or the underlying structure of corresponding subsets of the data. In this thesis, a granular computing approach to the design of intelligent classification systems is proposed. The proposed approach is employed for different classification systems to investigate its efficiency. Fuzzy inference systems, neural networks, neuro-fuzzy systems and classifier ensembles are considered to evaluate the efficiency of the proposed approach. Each of the considered systems is designed using the proposed approach and classification performance is evaluated and compared to that of the standard system. The proposed approach is based on constructing information granules from data at multiple levels of granularity. The granulation process is performed using a modified fuzzy c-means algorithm that takes classification problem into account. Clustering is followed by a coarsening process that involves merging small clusters into large ones to form a lower granularity level. The resulted granules are used to build each of the considered binary classifiers in different settings and approaches. Granules produced by the proposed granulation method are used to build a fuzzy classifier for each granulation level or set of levels. The performance of the classifiers is evaluated using real life data sets and measured by two classification performance measures: accuracy and area under receiver operating characteristic curve. Experimental results show that fuzzy systems constructed using the proposed method achieved better classification performance. In addition, the proposed approach is used for the design of neural network classifiers. Resulted granules from one or more granulation levels are used to train the classifiers at different levels of specificity/abstraction. Using this approach, the classification problem is broken down into the modelling of classification rules represented by the information granules resulting in more interpretable system. Experimental results show that neural network classifiers trained using the proposed approach have better classification performance for most of the data sets. In a similar manner, the proposed approach is used for the training of neuro-fuzzy systems resulting in similar improvement in classification performance. Lastly, neural networks built using the proposed approach are used to construct a classifier ensemble. Information granules are used to generate and train the base classifiers. The final ensemble output is produced by a weighted sum combiner. Based on the experimental results, the proposed approach has improved the classification performance of the base classifiers for most of the data sets. Furthermore, a genetic algorithm is used to determine the combiner weights automatically.

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Pekanovic, Ana. „Aging of cerebellar granule neurons in vitro“. [S.l. : s.n.], 2006.

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Lee, Bongjoon. „Analysis of the Kinetics of Filler Segregation in Granular Block copolymer Microstructure“. Research Showcase @ CMU, 2016. http://repository.cmu.edu/dissertations/705.

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Block copolymers have attracted interests for potential application ranging from dynamic photonic sensors to solid-state ion conductors. However, due to nucleation and growth mechanism, block copolymer inherently forms granular microstructure with defects such as grain boundaries. Understanding the microstructure of block copolymer is thus crucial in many applications because the microstructure determines the transport property of functional fillers such as ions in block copolymer template. Previous research has shown that athermal filler segregated to grain boundary of lamellae block copolymer and retards the grain coarsening. However, the kinetics of this grain boundary segregation during thermal annealing has not been revealed. Polystyrene-b-polyisoprene blended with deuterated polystyrene is used for neutron scattering study on studying the kinetics of grain boundary segregation. Deuterated polystyrene will segregate to grain boundaries, therefore, decorate grain boundary. The filler segregation behavior will be studied by comparing neutron scattering of polystyrene-b-polyisoprene/deuterated polystyrene with different annealing times (at T=130 deg C, duration of 0hr, 3hr, 1day, 3day and 7day, respectively). Invariant (Q) analysis along with grain mapping is conducted to quantitatively analyze the kinetics of grain boundary segregation. This kinetic was in good agreement with the McLean’s kinetic model for grain boundary segregation in metals. By applying Langmuir-Mclean’s segregation isotherm equation, we have predicted the equilibrium concentration of filler in grain boundary by calculating the strain energy stored in grain boundary.

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Goodwin, Laura Rose. „The Chromatin Remodelling Contributions of Snf2l in Cerebellar Granule Neuron Differentiation“. Thesis, Université d'Ottawa / University of Ottawa, 2018. http://hdl.handle.net/10393/38201.

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Recent studies have uncovered de novo mutations of the gene encoding the chromatin remodelling protein Snf2l in patients with schizophrenia, Rett-like syndrome and intellectual disability. Snf2l and its closely related protein, Snf2h, play a critical role in embryonic and post-natal brain development. Murine models lacking functional Snf2h or Snf2l point to complementary activities of these remodelers; Snf2h cKO mice present with a significantly reduced cerebellum, while Snf2l Ex6DEL (exon 6 deleted) cerebella are larger than their wild-type counterparts. Granule neuron progenitors (GNPs) isolated from Ex6DEL cerebella display delayed cell cycle exit and hindered terminal differentiation compared to wild-type controls. Moreover, loss of Snf2l activity results in widespread transcriptome shifts which underlie the Ex6DEL GNP differentiation phenotype. In particular, key transcription factors are differentially expressed without Snf2l remodelling activity. We confirm that ERK pathway activation is misregulated in Ex6DEL GNPs, possibly in response to elevated fibroblast growth factor 8 (Fgf8) expression in these cultures. We find that Snf2l activity maintains the chromatin landscape throughout GNP differentiation, as Ex6DEL cultures have a global increase in chromatin accessibility. We suggest that Snf2l-mediated chromatin condensation is responsible for proper regulation of gene expression programs in GNP differentiation.

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Li, Jun. „Genetic Granular Cognitive Fuzzy Neural Networks and Human Brains for Comparative Cognition“. Digital Archive @ GSU, 2005. http://digitalarchive.gsu.edu/cs_theses/7.

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In this thesis, Genetic Granular Cognitive Fuzzy Neural Networks (GGCFNN), combining genetic algorithms (GA) and granular cognitive fuzzy neural networks (GCFNN), is proposed for pattern recognition problems. According to cognitive patterns, biological neural networks in the human brain can recognize different patterns. Since GA and neural networks represent two learning methods based on biological science, it is indispensable and valuable to investigate how biological neural networks and artificial neural networks recognize different patterns. The new GGCFNN, based on granular computing, soft computing and cognitive science, is used in the pattern recognition problems. The hybrid forward-wave-backward-wave learning algorithm, as a main learning technology in GCFNN, is used to enhance learning quality. GA optimizes parameters to make GGCFNN get better learning results. Both pattern recognition results generated by human persons and those by GGCFNN are analyzed in terms of computer science and cognitive science.

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Jenkins, Paul James. „X-ray and neutron scattering studies of starch granule structure“. Thesis, University of Cambridge, 1994. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.362925.

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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/.

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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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Corbière, Auriane. „Etude du peptidome du cervelet de rat au cours du développement et identification des effets neurotrophiques de la nociceptine dans la mise en place des neurones en grain“. Thesis, Normandie, 2017. http://www.theses.fr/2017NORMR063/document.

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Le cervelet est une structure cérébrale impliquée dans de multiples fonctions motrices mais aussi cognitives et dont le développement postnatal est sous le contrôle de divers types de facteurs dont les neuropeptides. Les peptides capables d’agir sur le développement du cortex cérébelleux présentent généralement un profil d’expression particulier, avec chez le rongeur un pic d’expression au cours des 2 premières semaines postnatales. L’objectif de cette étude était d’identifier d’autres peptides présentant ce même type d’expression et de caractériser leurs potentiels effets au cours du développement du cortex cérébelleux, et plus particulièrement dans la mise en place des neurones en grain qui sont les plus abondants de cette structure. Pour cela, des cervelets de rats âgés de 8 à 90 jours ont été analysés par spectrométrie de masse. Parmi les 33 peptides identifiés, 4 présentent le profil recherché et nous avons choisi d’étudier l’un d’entre eux, la nociceptine. La mesure de l’expression du gène de la nociceptine et de son récepteur montre un profil d’expression similaire à celui observé en peptidomique. De plus, ces 2 gènes sont retrouvés principalement exprimés dans la couche granulaire interne du cortex cérébelleux par microdissection et qPcr. La recherche de la fonction de la nociceptine montre qu’elle exerce un effet neurotrophique en augmentant la survie et la différenciation des neurones en grain, sans affecter la motilité de ces cellules. Des tests préliminaires réalisés in vivo indiquent que la nociceptine est aussi capable de bloquer la toxicité induite par l’alcool. La dernière partie de l’étude avait pour but d’identifier de nouveaux neuropeptides exprimés dans le cervelet en utilisant une approche par séquençage de novo. L’application de filtres comme la récurrence des séquences peptidiques ou leur régulation au cours du développement a permis de ne retenir que 6 séquences pour la suite de l’analyse. Des études génomiques permettront de restreindre encore ce nombre afin de focaliser les tests d’activité biologique sur la ou les cibles qui ont la plus grande probabilité de correspondre à des peptides biologiquement actifs
The cerebellum is a structure involved in many motor and cognitive functions whose development occurs after birth under the control of various factors, including neuropeptides. Peptides acting on cerebellar cortex development often exhibit a specific pattern of expression with in rodents a high expression over the 2 first postnatal weeks which then decreases at adulthood. The aim of this study was to identify additional peptides with such expression profile and to characterize their putative functions in the development of the cerebellar cortex and more particularly, in the establishment of cerebellar granule neurons which are the most abundant cells of the cerebellum. To address this, cerebella of rats aged from 8 to 90 days-old were analyzed by mass spectrometry. Among the 33 peptides identified in the cerebellum, 4 had the particular expression profile we were looking for. We choose to study further one of them, i.e. the nociceptin, and confirmed peptidomic results by measuring the expression of its gene precursor and of its receptor. Combining laser microdissection and qPCR approaches revealed that both nociceptin and its receptor genes were expressed in the internal granular layer of the cerebellar cortex. Functional studies showed that nociceptin exerts a neurotrophic effect on granule neurons by increasing their survival and differentiation, but had no effect on their motility. Preliminary in vivo experiments indicate that nociceptin can also counteract ethanol-induced toxicity. The last part of the present study aimed to identify new neuropeptides expressed in the rat cerebellum by using de novo sequencing. The large amount of peptide sequences initially found was then reduced to only 6 candidates for further analysis, by using filters such as recurrence of the sequences and their differential expression in between the four developmental stages considered. Additional genomic studies will help to decrease even further this number, in order to focus the biological tests on the targets which are most likely to code for biological active peptides

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Haddad, Katia. „Evolution de l'expression des trois sous-unités des neurofilaments in situ et en cultures primaires : induction d'autoanticorps dirigés contre les neurofilaments par des greffes intracérébrales“. Angers, 1994. http://www.theses.fr/1994ANGE0009.

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Les neurofilaments (NF) sont constitués de trois sous-unités : NF-H, NF-M et NF-L, de poids moléculaires apparents 200,150 et 70 kda. Ils déterminent le diamètre axonal ; cependant, un grand nombre d'inconnues subsistent quant aux fonctions cellulaires des NF, dont l'accumulation accompagne un ensemble de situations neurodégénératives. La première partie de ce travail aborde l'organisation en polymères des sous-unités des NF au cours du développement pré- et post-natal. Des formes solubles phosphorylées des NF-H et NF-M sont régulièrement détectées pendant cette période. Elles pourraient être associées aux microtubules labiles et persistent pendant le développement postnatal, pour disparaitre chez l'adulte. L'étude de l'expression des NF dans divers types de cultures de neurones primaires a été abordée dans une seconde partie. Des formes solubles de NF-H et NF-M sont également détectées dans ces conditions. L'expression des sous-unités de NF en culture de neurones est régulable par divers agents extracellulaires ; l'expression de NF-H est induite par le naftidrofuryl, une drogue affectant la survie et le métabolisme neuronal in situ et en culture. Par ailleurs, la mise en culture de cellules granulaires de cervelet de rat démontré que les NF sont exprimés progressivement dans ces conditions, alors qu'in situ, les mêmes cellules contiennent au mieux de faibles proportions de NF immatures, soulevant l'hypothèse d'un contrôle direct de l'expression des NF in situ par l'environnement tissulaire. La dernière partie explore la participation des NF-H et NF-M au répertoire auto-immun. La greffe intracérébrale de cellules pc12 induit la production d'autoanticorps diriges contre NF-H, NF-M et contre des molécules de cellules pc12 de poids moléculaire de 60-65 kda, ainsi que des protéines d'autres tissus dont les kératines. Les sérums des rats greffes réagissent avec les NF et d'autres structures exclusivement neuronales en cultures mixtes de neurones et de cellules gliales.

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Millar, Julie Anne. „Characterisation of a novel potassium conductance in rat cerebellar granule neurons“. Thesis, University College London (University of London), 2000. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.392110.

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Hatami, Maryam [Verfasser], und Thomas [Akademischer Betreuer] Skutella. „Combination of Prox1/NeuroD1 Transcription Factor Overexpression Boosts Generation of Dentate Gyrus Granule Neurons from Pluripotent Stem Cells / Maryam Hatami ; Betreuer: Thomas Skutella“. Heidelberg : Universitätsbibliothek Heidelberg, 2018. http://d-nb.info/1177386011/34.

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Díaz, Rudas José Rafael. „Histomorfometría de la capa granular órbitofrontal murina sometida a administración crónica de bebidas alcohólicas adulteradas“. Bachelor's thesis, Universidad Nacional Mayor de San Marcos, 2015. https://hdl.handle.net/20.500.12672/4143.

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OBJETIVO GENERAL: Determinar las alteraciones histomorfométricas de la capa granular de la corteza órbitofrontal de Rattus norvegicus, a nivel de las neuronas granulares y glías de la serie astrocítica sometidas a administración crónica de bebidas alcohólicas adulteradas. MATERIAL Y MÉTODOS: Estudio experimental, prospectivo, comparativo y longitudinal. Se utilizaron cuarenta y cinco ratas de laboratorio Rattus norvegicus, variedad albina, obtenidos de los bioterios del CENAN y trasladados al bioterio de la Facultad de Medicina Humana de la UNMSM. Fueron divididos en 3 grupos de trabajo: el grupo control (Grupo O) y los grupos experimentales (Grupo A y Grupo B), el Grupo A recibió la bebida alcohólica denominada “Tumbaloco” (mezcla de pisco, anisado y cognac adulterado) y el Grupo B la bebida alcohólica denominada “Penal” (mezcla de pisco, anisado y cognac adulterado más cerveza). Se enviaron dichas bebidas alcohólicas al Centro de Información, Control Toxicológico y Apoyo a la Gestión Ambiental (CICOTOX) para el análisis cuantitativo de etanol y metanol por el método de espectrofotometría de absorción atómica. Se les administró de manera crónica, por un tiempo de 12 semanas, bebidas alcohólicas adulteradas al grupo experimental y agua al grupo control mediante el uso de una sonda orogástrica. Luego de las 12 semanas se procedió al sacrificio del animal mediante la decapitación, se procedió a la extracción del encéfalo murino en un tiempo no mayor de 4 minutos luego del cual fue colocado en una solución de formol neutro al 10%. Se hizo un corte coronal del encéfalo a nivel de la corteza prefrontal, una parte del tejido fue incluido en parafina para la realización de láminas histológicas con la coloración Hematoxilina & Eosina e inmunohistoquímica con GFAP (marcador específico para astrocitos) la otra parte del tejido fue llevada a congelación para la elaboración de láminas histológicas con la coloración Argéntica del Río Ortega impregnación simple. Dichas láminas histológicas fueron fotografiadas y posteriormente analizadas mediante el procesador de imágenes JMicrovision 1.2.5. RESULTADOS: No existió diferencia estadísticamente significativa en el peso de los animales al inicio y al final del experimento. El área determinada por las neuronas necróticas de la capa granular fue menor en los grupos que recibieron bebidas alcohólicas adulteradas a predominio del grupo que recibió la bebida “Penal”. El mayor porcentaje de neuronas necróticas se observó en el grupo que recibió bebidas alcohólicas adulteradas más cerveza el cual fue estadísticamente superior que el grupo control, el porcentaje de neuronas necróticas en el grupo que recibió sólo bebidas alcohólicas adulteradas también fue estadísticamente superior que el grupo control pero menor que el grupo que recibió bebidas alcohólicas adulteradas más cerveza. Se observó gliosis de la serie astrocítica en los grupos que recibieron bebidas alcohólicas adulteradas también a predominio del grupo que recibió la bebida “Penal”. CONCLUSIONES: El consumo crónico de bebidas alcohólicas adulteradas produce una disminución de las neuronas granulares y un aumento de las glías de la serie astrocítica a nivel de la capa granular de la corteza órbitofrontal. Las alteraciones fueron mayores en el grupo que recibió la bebida alcohólica “Penal”, mezcla de 3 bebidas alcohólicas adulteradas más cerveza.
Tesis

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Boyd, David Frank. „Potassium current regulation and intracellular calcium stores in rat cerebellar granule neurons“. Thesis, University College London (University of London), 2001. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.368093.

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Weeranantanapan, Oratai. „The role of L1-CNTNs in controlling SHH-induced proliferation of cerebellar granule neuron progenitors“. Thesis, University of Sheffield, 2014. http://etheses.whiterose.ac.uk/6180/.

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Singh, Shweta. „Mechanisms of cell death in cerebellar granule neurones“. Thesis, University of Kent, 2001. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.344143.

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Vijayakumar, Jeshlee Cyril. „Rôle du domaine de type prion de Imp dans la régulation des granules RNP neuronaux“. Thesis, Université Côte d'Azur (ComUE), 2018. http://www.theses.fr/2018AZUR4099/document.

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Les ARNms des cellules eucaryotes sont liés à des protéines de liaison aux ARNs (RBPs) et empaquetés au sein d’assemblages macro-moléculaires appelés granules RNP. Dans les cellules neuronales, les granules RNP de transport sont impliqués dans le transport d’ARNms spécifiques jusqu’aux axones et dendrites, ainsi que dans leur traduction locale en réponse à des signaux externes. Bien que peu de choses soient connues sur l’assemblage et la régulation de ces granules in vivo, des résultats récents ont indiqué que la présence de domaines de type prion (PLDs) dans les RBPs facilite les interactions protéines-protéines et protéines-ARN, favorisant ainsi la condensation de complexes solubles en granules RNP. La RBP conservée Imp est un composant central de granules RNP qui sont transportés dans les axones lors du remodelage neuronal chez la drosophile. De plus, la fonction de Imp est nécessaire au remodelage des axones lors de la maturation du système nerveux de drosophile. Une analyse de la séquence de la protéine Imp a révélé qu’en plus de quatre domaines de liaison aux ARNs, Imp contient un domaine C-terminal désordonné enrichi en Glutamines et Serines, deux propriétés caractéristiques des domaines PLDs. Lors de ma thèse, j’ai étudié la fonction de ce PLD dans le contexte de l’assemblage et du transport des granules RNP. J’ai observé en culture de cellules que les granules Imp s’assemblent en absence de PLD, bien que leur nombre et leur taille soient augmentés. Des protéines présentant une séquence PLD mélangée, au contraire, s’accumulent dans des granules au nombre et à la taille normale, indiquant que l’état désordonné de ce domaine, et non sa séquence primaire, est essentiel à l’homéostasie des granules. De plus, des expériences de FRAP réalisées en culture de cellule et in vivo ont révélé que le domaine PLD de Imp favorise la dynamique des granules. In vivo, ce domaine est nécessaire et suffisant à l’accumulation axonale de Imp. Comme montré par une analyse en temps réel, l’absence de domaine PLD aboutit également à une diminution du nombre de granules axonaux motiles. Fonctionnellement, le domaine PLD de Imp est essentiel au remodelage neuronal car des protéines sans ce domaine ne sont pas capables de supprimer les défauts de repousse axonale observés après inactivation de imp. Enfin, la génération d’un variant de Imp dans lequel le domaine PLD a été déplacé en N-terminus a montré que les fonctions du PLD dans le transport des granules et dans leur assemblage sont découplées, et que la modulation des propriétés des granules Imp médiée par le domaine PLD n’est pas nécessaire au remodelage neuronal in vivo. En conclusion, mes résultats ont montré que le domaine PLD de Imp n’est pas nécessaire à l’assemblage des granules RNP Imp, mais régule leur nombre et leur dynamique. De plus, mon travail a mis en évidence une fonction inattendue pour un domaine PLD dans le transport axonal et le remodelage des neurones lors de la maturation du système nerveux
Eukaryotic mRNAs are bound by RNA Binding Proteins (RBP) and packaged into diverse range of macromolecular assemblies named RNP granules. In neurons, transport RNP granules are implicated in the transport of specific mRNAs to axons or dendrites, and in their local translation in response to external cues. Although little is known about the assembly and regulation of these granules in vivo, growing evidence indicates that the presence of Prion Like domains (PLD) within RBPs favours multivalent protein–protein and protein-RNA interactions, promoting the transition of soluble complexes into RNP granules. The conserved RBP Imp is as a core component of RNP granules that are actively transported to axons upon neuronal remodelling in Drosophila. Furthermore, Imp function was shown to be required for axonal remodelling during Drosophila nervous system maturation. Analyses of the domain architecture of the Imp protein revealed that, in addition to four RNA binding domains (RBD), Imp contains a Cterminal domain showing a striking enrichment in Glutamines and Serines, which is one of the characteristics of a PLD. During my PhD, I explored the function of the PLD in the context of granule assembly and transport. In cultured cells, I observed that Imp granules assembled in the absence of the PLD, however their number and size were increased. Proteins with scrambled PLD sequence accumulated in granules of normal size and number, implying that the degree of disorder of this domain, and not its sequence, is essential for granule homeostasis. Moreover, FRAP experiments, performed on cultured cells and in vivo, revealed that Imp PLD is important to maintain the turnover of these granules. In vivo, this domain is both necessary and sufficient for efficient transport of Imp granules to axons. These defects are associated with a reduction on the number of motile granules in axons. Furthermore, mutant forms lacking the PLD do not rescue the axon remodelling defects observed upon imp loss of function. Finally, a swapping experiment in which I moved Imp PLD from the C-terminus to the N-terminus of the protein revealed that the functions of Imp PLD in granule transport and homeostasis are uncoupled, and that PLD-dependent modulation of Imp granule properties is dispensable in vivo. Together, my results show that Imp PLD of is not required for the assembly of RNP granules, but rather regulates granule number and dynamics. Furthermore, my work uncovered an unexpected in vivo function for a PLD in axonal transport and remodelling during nervous system maturation

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Xie, Fang. „Neuregulin Signaling and GABA_A Receptor Expression in Cerebellar Granule Neurons“. Connect to text online, 2006. http://rave.ohiolink.edu/etdc/view?acc%5Fnum=case1125415656.

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Ulin, Samuel. „Digging deep : A data-driven approach to model reduction in a granular bulldozing scenario“. Thesis, Umeå universitet, Institutionen för fysik, 2018. http://urn.kb.se/resolve?urn=urn:nbn:se:umu:diva-152498.

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The current simulation method for granular dynamics used by the physics engine AGX Dynamics is a nonsmooth variant of the popular Discrete Element Method (DEM). While powerful, there is a need for close to real time simulations of a higher spatial resolution than currently possible. In this thesis a data-driven model reduction approach using machine learning was considered. A data-driven simulation pipeline was presented and partially implemented. The method consists of sampling the velocity and density field of the granular particles and teaching a machine learning algorithm to predict the particles' interaction with a bulldozer blade as well as predicting the time evolution of its velocity field. A procedure for producing training scenarios and training data for the machine learning algorithm was implemented as well as several machine learning algorithms; a linear regressor, a multilayer perceptron and a convolutional neural network. The results showed that the method is promising, however further work will need to show whether or not the pipeline is feasible to implement in a simulation.

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Formicola, Nadia. „Remodelage des granules ARN en réponse à l’activité neuronale“. Electronic Thesis or Diss., Université Côte d'Azur (ComUE), 2019. http://theses.univ-cotedazur.fr/2019AZUR6008.

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Une des questions les plus fascinantes – et les plus ouvertes – en neuroscience est de comprendre comment les cellules neuronales contribuent à la formation, le maintien puis le rappel des souvenirs. Des travaux antérieurs ont montré que la formation de la mémoire à long-terme (MLT) requiert la synthèse de novo de protéines, impliquant non seulement la traduction d’ARNs nouvellement transcrits, mais aussi la traduction locale, induite par l’expérience, d’ARNms latents transportés et stockés dans les synapses. En vue de leur transport et du contrôle de leur traduction, les ARNms sont empaquetés avec des protéines de liaison aux ARNs (RBP), qui sont majoritairement des répresseurs de traduction, dans des granules ribonucléoprotéiques (RNP). La manière dont les granules RNP neuronaux sont remodelés en réponse à l’activité neuronale pour lever la répression traductionelle des ARNms est pour l’instant peu claire. En outre, l’impact fonctionnel d’un tel remodelage sur l’établissement de la MLT reste à démontrer in vivo. L’objectif de mon doctorat était 1) d’étudier les mécanismes in vivo qui sous-tendent le remodelage des granules RNP neuronaux ; 2) de tester l’hypothèse que les granules RNP pourraient être impliqués dans les mécanismes de renforcement de la MLT en régulant l’expression génétique. Dans cette optique, j’ai utilisé comme modèle des granules RNP contenant la RBP conservée Imp chez la drosophile. Tout d’abord, j’ai étudié l’impact de l’activité neuronale sur les propriétés des granules RNP Imp, en traitant des explants de cerveau soit avec du KCl, soit avec le neuromodulateur Tyramine. Dans les deux cas, un désassemblage des granules RNP Imp - caractérisé par une dé-granulation à la fois de Imp et d’autres composants – est observé. Le désassemblage des granules RNP est réversible après retrait de la tyramine, et n’a pas été observé dans les neurones hyperpolarisés. Il ne dépend pas strictement du domaine de type prion qui se trouve à l’extrémité carboxy-terminale de Imp, un domaine connu pour être impliqué dans l’homéostasie des granules RNP. De plus, mes données suggèrent que ce désassemblage soit lié à une augmentation de la traduction des ARNms associés, ce qui est cohérent avec un modèle dans lequel le remodelage des granules RNP induit par l’activité des neurones induit une dé-répression de la traduction. Ensuite, j’ai recherché les mécanismes contrôlant le remodelage des granules RNP. Un candidat pour cette régulation était CamkII, une kinase conservée activée par le calcium, et identifiée comme partenaire de Imp dans une analyse d’immunoprécipitation-spectrométrie de masse. Au cours de mon doctorat, j’ai pu valider l’intéraction Imp-CamkII et montrer qu’elle n’est pas médiée par l’ARN, mais dépend de l’activité de CamkII. De plus, j’ai montré qu’inhiber l’activité de CamkII empêche le désassemblage des granules RNP Imp observé lors de l’activation neuronale, suggérant que CamkII pourrait être impliquée dans le remodelage des granules RNP Imp induit par l’activité neuronale. Ces résutats sont particulièrement intéressants dans le contexte de l’établissement de la MLT, car CamkII est depuis longtemps reconnue comme y étant essentielle. Plus encore, nous avons récemment démontré chez la drosophile qu’inactiver la fonction de Imp dans une population de neurones du cerveau central impliquée dans l’apprentissage et la mémoire – les neurones du Mushroom Body – altère radicalement la MLT. En conclusion, mes résultats sont cohérents avec un modèle où le remodelage des granules RNP Imp en réponse à l’activation neuronale dépend de CamkII, et pourrait contribuer à la formation de la MLT in vivo
One of the most fascinating – and still open – questions in neuroscience is how neuronal cells can form, store and then recall memories. Previous work has shown that Long-term memory (LTM) formation requires de novo protein synthesis, involving not only translation of newly transcribed RNAs, but also local, experience-induced translation of quiescent mRNAs carried and stored at synapses. For their transport and translational control, mRNAs are packaged with regulatory RNA binding proteins (RBPs), mainly translational repressors, into ribonucleoprotein (RNP) granules. To date, how neuronal RNP granules are remodelled in response to neuronal activity to relieve translation repression of mRNAs is unclear. Furthermore, the functional impact of such a remodelling in the establishment of long-term memories remains to be demonstrated in vivo. The objective of my PhD was to 1) investigate the in vivo mechanisms underlying activity-dependent remodelling of neuronal RNP granules; 2) test the hypothesis that RNPs could be involved in LTM-underlying mechanisms by regulating gene expression. To this end, I used as paradigm RNPs containing the conserved RBP Imp in Drosophila. First, I studied the impact of neuronal activity on Imp RNP properties by treating Drosophila brain explants with either KCl or the tyramine neuropeptide. In both cases, a disassembly of Imp RNPs was observed, characterized by a loss of both Imp and other RNP-component granular patterns, and a de-clustering of RNP-associated mRNA molecules. RNP disassembly could be reverted upon Tyramine withdrawal and was not observed in hyperpolarized neurons. Furthermore, my data suggest that RNP-disassembly is linked to increased translation of associated mRNAs, consistent with a model in which activity-induced RNP remodelling would lead to translational de-repression. Second, I investigated the mechanisms controlling RNP remodelling. A candidate regulator was CamkII, a conserved Ca2+ -activated kinase identified as a partner of Imp in an IP-Mass Spectrometry analysis. During my PhD, I could validate the Imp-CamkII interaction and showed that it is not mediated by RNA but depends on CamkII activity. Furthermore, I showed that inactivating CamkII function prevents the disassembly of Imp RNPs observed upon neuronal activation of brain explants, suggesting that CamkII may be involved in the activity-dependent remodelling of Imp RNP granules. These results are particularly interesting in the context of establishment of LTM, as CamkII has long been recognized as essential for LTM. Moreover, we recently showed in Drosophila that interfering with Imp function in a population of CNS neurons involved in learning and memory – the Mushroom Body γ neurons -, dramatically impairs LTM and that this effect relies on Imp C-terminal Prion-like domain, a domain known to be involved in RNP homeostasis. Altogether, my thesis work suggests a model where CamkII-dependent remodelling of Imp RNPs in response to neuronal activation might underlie LTM formation in vivo

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Vijayakumar, Jeshlee Cyril. „Rôle du domaine de type prion de Imp dans la régulation des granules RNP neuronaux“. Electronic Thesis or Diss., Université Côte d'Azur (ComUE), 2018. http://www.theses.fr/2018AZUR4099.

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Les ARNms des cellules eucaryotes sont liés à des protéines de liaison aux ARNs (RBPs) et empaquetés au sein d’assemblages macro-moléculaires appelés granules RNP. Dans les cellules neuronales, les granules RNP de transport sont impliqués dans le transport d’ARNms spécifiques jusqu’aux axones et dendrites, ainsi que dans leur traduction locale en réponse à des signaux externes. Bien que peu de choses soient connues sur l’assemblage et la régulation de ces granules in vivo, des résultats récents ont indiqué que la présence de domaines de type prion (PLDs) dans les RBPs facilite les interactions protéines-protéines et protéines-ARN, favorisant ainsi la condensation de complexes solubles en granules RNP. La RBP conservée Imp est un composant central de granules RNP qui sont transportés dans les axones lors du remodelage neuronal chez la drosophile. De plus, la fonction de Imp est nécessaire au remodelage des axones lors de la maturation du système nerveux de drosophile. Une analyse de la séquence de la protéine Imp a révélé qu’en plus de quatre domaines de liaison aux ARNs, Imp contient un domaine C-terminal désordonné enrichi en Glutamines et Serines, deux propriétés caractéristiques des domaines PLDs. Lors de ma thèse, j’ai étudié la fonction de ce PLD dans le contexte de l’assemblage et du transport des granules RNP. J’ai observé en culture de cellules que les granules Imp s’assemblent en absence de PLD, bien que leur nombre et leur taille soient augmentés. Des protéines présentant une séquence PLD mélangée, au contraire, s’accumulent dans des granules au nombre et à la taille normale, indiquant que l’état désordonné de ce domaine, et non sa séquence primaire, est essentiel à l’homéostasie des granules. De plus, des expériences de FRAP réalisées en culture de cellule et in vivo ont révélé que le domaine PLD de Imp favorise la dynamique des granules. In vivo, ce domaine est nécessaire et suffisant à l’accumulation axonale de Imp. Comme montré par une analyse en temps réel, l’absence de domaine PLD aboutit également à une diminution du nombre de granules axonaux motiles. Fonctionnellement, le domaine PLD de Imp est essentiel au remodelage neuronal car des protéines sans ce domaine ne sont pas capables de supprimer les défauts de repousse axonale observés après inactivation de imp. Enfin, la génération d’un variant de Imp dans lequel le domaine PLD a été déplacé en N-terminus a montré que les fonctions du PLD dans le transport des granules et dans leur assemblage sont découplées, et que la modulation des propriétés des granules Imp médiée par le domaine PLD n’est pas nécessaire au remodelage neuronal in vivo. En conclusion, mes résultats ont montré que le domaine PLD de Imp n’est pas nécessaire à l’assemblage des granules RNP Imp, mais régule leur nombre et leur dynamique. De plus, mon travail a mis en évidence une fonction inattendue pour un domaine PLD dans le transport axonal et le remodelage des neurones lors de la maturation du système nerveux
Eukaryotic mRNAs are bound by RNA Binding Proteins (RBP) and packaged into diverse range of macromolecular assemblies named RNP granules. In neurons, transport RNP granules are implicated in the transport of specific mRNAs to axons or dendrites, and in their local translation in response to external cues. Although little is known about the assembly and regulation of these granules in vivo, growing evidence indicates that the presence of Prion Like domains (PLD) within RBPs favours multivalent protein–protein and protein-RNA interactions, promoting the transition of soluble complexes into RNP granules. The conserved RBP Imp is as a core component of RNP granules that are actively transported to axons upon neuronal remodelling in Drosophila. Furthermore, Imp function was shown to be required for axonal remodelling during Drosophila nervous system maturation. Analyses of the domain architecture of the Imp protein revealed that, in addition to four RNA binding domains (RBD), Imp contains a Cterminal domain showing a striking enrichment in Glutamines and Serines, which is one of the characteristics of a PLD. During my PhD, I explored the function of the PLD in the context of granule assembly and transport. In cultured cells, I observed that Imp granules assembled in the absence of the PLD, however their number and size were increased. Proteins with scrambled PLD sequence accumulated in granules of normal size and number, implying that the degree of disorder of this domain, and not its sequence, is essential for granule homeostasis. Moreover, FRAP experiments, performed on cultured cells and in vivo, revealed that Imp PLD is important to maintain the turnover of these granules. In vivo, this domain is both necessary and sufficient for efficient transport of Imp granules to axons. These defects are associated with a reduction on the number of motile granules in axons. Furthermore, mutant forms lacking the PLD do not rescue the axon remodelling defects observed upon imp loss of function. Finally, a swapping experiment in which I moved Imp PLD from the C-terminus to the N-terminus of the protein revealed that the functions of Imp PLD in granule transport and homeostasis are uncoupled, and that PLD-dependent modulation of Imp granule properties is dispensable in vivo. Together, my results show that Imp PLD of is not required for the assembly of RNP granules, but rather regulates granule number and dynamics. Furthermore, my work uncovered an unexpected in vivo function for a PLD in axonal transport and remodelling during nervous system maturation

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Barneda, Zahonero Bruna. „BMP-6 i NMDA com a moduladors de la supervivència de les neurones granulars de cerebel: mecanismes implicats“. Doctoral thesis, Universitat Autònoma de Barcelona, 2009. http://hdl.handle.net/10803/3622.

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Les neurones granulars de cerebel es generen a la capa granular externa i es diferencien i migren a traves de la capa molecular per donar lloc a la capa granular interna durant el desenvolupament postnatal del cerebel. Durant aquest procés de maduració,aquestes neurones necessiten l'aportació constant d'estímuls tròfics. Si no és el cas, moren per apoptosi. Aquesta situació que es dóna in vivo és mimetitzable en un cultiu de CGCs. Aquestes neurones són sensibles a les concentracions extracel·lulars de potassi i moren per apoptosi quan són exposades a 5mM de KCl (K5). Per contra, si s'addiciona al medi factors que s'han descrit que participen del seu manteniment in vivo com IGF-1, BDNF, PACAP, l'estimulació amb l'agonista glutamatèrgic NMDA o KCl 25 mM (K25) aquestes es desenvolupen i sobreviuen durant el cultiu.
Les BMPs tenen un paper important en la regulació de la diferenciació de les CGCs i se'ls hi ha atribuït efectes anti-apoptòtics en diferents sistemes. En aquest treball ens varem plantejar l'estudi de les BMPs com a possibles factors tròfics per les CGCs. BMP-6 protegeix les CGCs en front de K5 en estadis madurs del cultiu, mentre que BMP-2 i BMP-7 no. Les BMPs senyalitzen a traves de tetràmers de receptors tipus I i II i l'activació d'aquests promou l'activació i translocació al nucli de les proteïnes Smads. La maquinària de resposta a les BMPs s'expressa en les CGCs in vitro. Tot i així, no detectarem diferències en l'estat d'activació de les Smads en les diferents condicions testades. La supervivència d'aquestes neurones s'ha relacionat principalment a l'activació de tres vies de cinases com són la PI3K-Akt, la via de MEK/ERK i la de JNK. Varem estudiar el grau d'activació d'aquestes en K5 i la possible modulació pel tractament amb BMP-6. Mentre que el tractament amb BMP-6 no produeix diferències en l'activació de les vies PI3K-Akt i JNK, sí que indueix una forta activació a temps curts de la via MEK/ERK quan es compara amb K5. Mitjançant l'ús d'inhibidors de la via hem observat com aquesta és la principal mediadora de l'efecte de BMP-6. En aprofundir en la senyalització que es desencadena per sota l'activació de MEK/ERK hem identificat a CREB com a factor de transcripció involucrat en l'efecte. La seva activació resulta en la regulació a l'alça dels nivells de la proteïna anti-apoptòtica Bcl-2 que resulta en la inhibició de l'activació de la caspasa-3 per K5 i la reducció dels nuclis apoptótics. Per altre banda, en la recerca del nexe d'unió entre l'activació del receptor i l'activació de la via MEK/ERK també hem descrit com BMP-6 és capaç d'activar a Rap-1 deixant la porta oberta a la participació d'aquesta proteïna G monomèrica en l'efecte de BMP-6. Així doncs, les nostres dades suggereixen un paper nou de BMP-6 com a factor tròfic en el desenvolupament de les CGCs i que realitzaria aquesta funció a través de l'activació de la via MEK/ERK/CREB.
El tractament amb NMDA promou la supervivència de les CGCs en cultiu. Estudis previs en el nostre laboratori i en altres han relacionat l'activació de la via de PI3K-Akt i la inhibició de JNK amb l'efecte protector del NMDA. L'activació o inhibició de vies de cinases cursa en la modulació de l'activitat de factors de transcripció que resulta en canvis en el transcriptoma. Així, varem estudiar els canvis en l'expressió gènica induïts pel tractament amb NMDA.. Varem observar una inducció de gens corresponents a programes de desenvolupament neuronal, neurogènesi i anti-apoptosi. Mitjançant estudi comparatiu amb el treball de Zhang i cols. obtinguérem una llista de candidats a mediar l'efecte del NMDA: atf3, bdnf, cdp, Crem, Fos, Homer1, Nfil3, Pcsk1, Plagl1, Rem2, Snf1lk, vgf i NR4A1-3(Nur77, Nurr1 i NOR-1). Tot i que tots ells presentaven funcions relacionables amb supervivència cel·lular, ens varem centrar en l'estudi dels membres de la família de NR4a pel seu paper desconegut en el desenvolupament del cerebel. Encara que l'expressió dels missatgers de Nur77, Nurr1 i NOR-1 es correspon amb les dades del array, a nivell proteic només Nurr1 presenta una pujada en els seus nivells després del tractament amb NMDA. La reducció dels nivells de Nurr1 mitjançant shRNA resulta en una reducció de l'efecte de NMDA. Tanmateix, hem descrit que CREB és el responsable de la inducció de Nurr1 en resposta a NMDA i que la reducció en l'efecte del NMDA en presència del shRNA de Nurr1 ve acompanyat per una reducció en els nivells de BDNF. A més a més, Nurr1 i BDNF presenten un patró d'expressió correlatiu en el cerebel durant els dies postnatals que s'atribueixen a la migració de les CGCs des de la EGL a la IGL. Donant força a Nurr1 com a mediador de l'efecte supervivència de l'estimulació del NMDAR durant el desenvolupament del cerebel.
Cerebellar granule neurons (CGCs) are generated in the external granule layer (EGL) and they differentiate and migrate trough the molecular layer to form the internal granule layer (IGL) during the postnatal development of the cerebellum. During its maturation they need trophic support to survive. Otherwise, they die by apoptosis. That situation that occurs in vivo can be mimicked in a culture of CGCs. These neurons are sensitive to extracellular potassium concentrations and they die by apoptosis when they are exposed to low potassium concentrations (5 mM KCl, K5). In contrast, the presence in the media of molecules that have been described to participate in hte maintenance of these neurons in vivo like IGF-1, BDNF, PACAP, glutamatergic stimulation with the agonist NMDA or depolarizing concentrations of potassium promote the survival of CGCs during the days in vitro.
BMPs have an important role in the regulation of CGCs differentiation and they have been described to promote survival against some pro-apoptotic paradigms. In these work we planned to study the eventual effect of BMPs on CGCs survival. BMP-6 protects from K5 induced apoptosis while BMP-2 and -7 do not. We analyzed the presence of the cannonical signaling machinery associated to BMPs in the CGCs in vitro and we observed that all the elements where expressed. However, they do not participate in BMP-6 effect as we do not observe an increase in the nuclear localization of smads in presence of BMP-6. The survival of CGCs have been closely related with the activation status of some signaling pathways like JNK, PI3K/Akt and MEK/ERK. In order to see if they where involved in BMP-6 effect we analyzed their activation. We didn't detect any difference in the JNK and PI3K/Akt pathways in presence or absence of BMP-6. By contrast MEK/ERK pathway was activated in BMP-6 treated cells. We Took in advance of inhibitors to determine the participation in BMP-6 effect and we observed that BMP-6 was mediate by MEK/ERK pathway. We went further in the study of the signaling involved in BMP-6 effect and we have described that CREB is downstream of MEK/ERK pathway activation and that its activation promotes an increase in Bcl-2 levels that results in the inhibition of caspase-3 induced activation of K5 and the reduction of apoptotic nuclei. Moreover, we show that Rap-1 can be a good candidate to be mediating MEK/ERK activation after BMP-6 treatment. Taking together, our data suggest that BMP-6 could be participating in CGCs maintenance during their development in vivo an that this function would be performed by the activation of MEK/ERK/CREB pathway.
NMDA treatment promotes CGCs survival in culture. Previous studies in our laboratory have related the activation of PI3K/Akt and the inhibition of JNK with NMDA protective effect. The activation and inhibition of these pathways results in changes in the activation status of transcription factors that promote changes in the transcriptome. In order to analyze the expression changes after NMDA treatment we performed an array with the Genechip® Rat genome 230 Affymetrix platform. We found an enrichment of neuronal development, neurogenesis and anti-apoptotic programs. Moreover, we performed a comparative analysis with the work of Zhang and cols (Zhang et al., 2007) and we obtained a list o f candidates to mediate NMDA effect: atf3, bdnf, cdp, Crem, Fos, Homer1, Nfil3, Pcsk1, Plagl1, Rem2, Snf1lk, vgf i NR4A1-3(Nur77, Nurr1 i NOR-1). All of them are involved in cellular processes that could be related to CGCs survival. However, we focused our attention in Nr4a subfamily members as their role in cerebellum development haven't been explored. We detected the increase in the expression of Nur77, Nurr1 i NOR-1, although only Nurr1 protein levels were increased in presence of NMDA. Reduction of Nurr1 levels by shRNA revealed its participation in NMDA neuroprotection. Additionally, we described that Nurr1, regulated by CREB in NMDA treated cells, promotes an increase in BDNF levels to develop its function in NMDA effect. We also performed a translation to the in vivo situation and as a first approach we studied the expression of Nurr1 and BDNF in the cerebellum during the postnatal development. Both proteins present a similar kinetic and they are induced in the time that is believed to be when CGCs migrate from the EGL to the IGL. In conclusion, this is the first time that Nurr1 have been described as a mediator of NMDA neuroprotection and our results suggest that this situation could be also occurring in vivo.

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Arakawa, Yoshiki. „Control of axon elongation via an SDF-1α/Rho/mDia pathway in cultured cerebellar granule neurons“. Kyoto University, 2003. http://hdl.handle.net/2433/148487.

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Kyoto University (京都大学)
0048
新制・課程博士
博士(医学)
甲第10450号
医博第2649号
新制||医||844(附属図書館)
UT51-2003-T276
京都大学大学院医学研究科脳統御医科学系専攻
(主査)教授大森治紀, 教授井出千束, 教授金子武嗣, 教授橋本信夫
学位規則第4条第1項該当

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Berliocchi, Laura. „Neurodegeneration induced by clostridial neurotoxins in cerebellar granule neurons a novel in vitro model for neurodegenerative disease /“. [S.l.] : [s.n.], 2000. http://deposit.ddb.de/cgi-bin/dokserv?idn=961250100.

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Berliocchi, Laura. „Neurodegeneration induced by clostridial neurtoxins in cerebellar granule neurons : a novel in vitro model for neurodegenerative disease /“. [S.l. : s.n.], 2000. http://www.bsz-bw.de/cgi-bin/xvms.cgi?SWB9038454.

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Chan, Hugh Hiu Nam. „Neuroprotective effects and mechanisms of Bis(12)-hupyridone on the glutamate-induced apoptosis in cerebellar granule neurons /“. View abstract or full-text, 2004. http://library.ust.hk/cgi/db/thesis.pl?BICH%202004%20CHAN.

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Thesis (M. Phil.)--Hong Kong University of Science and Technology, 2004.
Includes bibliographical references (leaves 84-94). Also available in electronic version. Access restricted to campus users.

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Dorgans, Kevin. „Ultrastructural, molecular and functional heterogeneities of cerebellar granule cell presynaptic terminals“. Thesis, Strasbourg, 2017. http://www.theses.fr/2017STRAJ083/document.

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Le cervelet est une structure cérébrale impliquée dans la régulation motrice. Dans le cortex cerebelleux, les informations sensorimotrices sont transmises par les cellules en grain. Mon travail de thèse démontre que les connections synaptiques de ces neurones ont des propriétés hétérogènes. D’une synapse à l’autre, j’ai pu observer des variations d’ultrastructure, de composition moléculaire et de fonctionnement au cours de trains de potentiels d’action à haute fréquence. Plus particulièrement, j’ai caractérisé les propriétés de « plasticité à court terme » des synapses unitaires des cellules en grain : 1) Elles sont très différentes d’une synapse à l’autre et peuvent être classées en différentes sous-catégories. 2) Certaines catégories de fonctionnement synaptique reposent sur l’expression de molécules telles que la Synapsine2. 3) La réponse d’un neurone post-synaptique à de hautes fréquences de stimulation dépend de la nature de la synapse activée
Cerebellum is a brain structure involved in motor regulation and motor learning. In the cerebellar cortex, sensorimotor information is transmitted by granule cells. During my PhD, I demonstrated that the properties of individual granule cell synaptic connections are highly heterogeneous. From one synapse to another, I observed ultrastructural, molecular and functional variability at unitary contacts. More precisely, I assessed the properties of short term plasticity at individual synapses during high frequency trains of stimulation :1) Short term plasticities are highly heterogeneous from one synapse to another and can be classified in sub-categories.2) Some categories of short-term plasticity profiles relie on the expression of molecules such as Synapsin2.3) The response of post-synaptic neuron to high-frequency inputs is dependent on the nature of the activated synaptic contact

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Stock, Rachel E. „DNA binding activities in cerebellar granule cell neurons recognizing the promoter for the GABA(A)-alpha6 receptor subunit“. Link to electronic thesis, 2002. http://www.wpi.edu/Pubs/ETD/Available/etd-0822102-175859.

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Masgrau, Juanola Roser. „Activació de la fosfolipasa C per receptors acoblats a proteïnes G en cultius de neurones granulars de cerebel. Paper modulador del calci“. Doctoral thesis, Universitat Autònoma de Barcelona, 2000. http://hdl.handle.net/10803/3620.

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Grangeray-Vilmint, Anais. „Modulation of cerebellar Purkinje cell discharge by subthreshold granule cell inputs“. Thesis, Strasbourg, 2016. http://www.theses.fr/2016STRAJ023/document.

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La décharge des cellules de Purkinje (CP), neurone de sortie du cortex cérébelleux, joue un rôle majeur dans le contrôle moteur. Les CP reçoivent des entrées excitatrices provenant des cellules des grains (CG), lesquelles génèrent également une inhibition antérograde sur les CP via l’activation d’interneurones de la couche moléculaire (IN). Lors de ma thèse, j’ai étudié l’influence simultanée de la balance excitation-inhibition (E/I) et des plasticités à court terme aux synapses CG-IN-CP sur la décharge des CP, par des techniques d’électrophysiologie, d’optogénétique et de simulation. Ces travaux démontrent l’existence d’une hétérogénéité d’E/I dans le cortex cérébelleux ainsi qu’une grande diversité de modulation des CP en réponse à la stimulation de CG. Le nombre de stimulation des CG influence fortement la direction et l’intensité de la modulation observée. Enfin, la combinaison de plasticités à court terme et d’E/I génère dans la décharge des CP des motifs de réponses complexes mais reproductibles, ayant sans doute un rôle essentiel dans l’encodage sensoriel
Rate and temporal coding in Purkinje cells (PC), the sole output of the cerebellar cortex, play a major role in motor control. PC receives excitatory inputs from granule cells (GC) which also provide feedforward inhibition on PC through the activation of molecular layer interneurons (MLI). In this thesis, I studied the influence of the combined action of excitation/inhibition (E/I) balance and short-term plasticity of GC-MLI-PC synapses on PC discharge, by using electrophysiological recordings, optogenetic stimulation and modelling. This work demonstrates that E/I balances are not equalized in the cerebellar cortex and showed a wide distribution of PC discharge modulation in response to GC inputs, from an increase to a shut down of the discharge. The number of stims in GC bursts strongly controls the strength and sign of PC modulation. Lastly, the interplay between short-term plasticity and E/I balance implements complex but reproducible output patterns of PC responses to GC inputs that should play a key role in stimulus encoding by the cerebellar cortex

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Safiulina, Dzahmilja. „The studies of mitochondria in cultured cerebellar granule neurons : characterization of mitochondrial function, volume homeostasis and interaction with neurosteroids /“. Online version, 2006. http://dspace.utlib.ee/dspace/bitstream/10062/1136/5/safiulina.pdf.

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Bauer, Karl Emory [Verfasser], und Michael [Akademischer Betreuer] Kiebler. „Live microscopy of RNA granule sorting in hippocampal neurons in space and time / Karl Emory Bauer ; Betreuer: Michael Kiebler“. München : Universitätsbibliothek der Ludwig-Maximilians-Universität, 2019. http://d-nb.info/1196529094/34.

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Lassus, Benjamin. „Exploitation des systèmes microfluidiques pour l'étude de la physiopathologie des maladies neurodéveloppementales et neurodégénératives : perturbation de DISC-1, impact sur les réseaux de neurones“. Thesis, Paris 6, 2016. http://www.theses.fr/2016PA066455.

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L'étude de la dynamique des circuits neuronaux est primordiale pour la compréhension des troubles neurologiques et psychiatriques. Ces processus, classiquement étudiés in vivo ou ex vivo, peuvent être appréhender in vitro grâce à des micro-technologies. Les technologies microfluidiques offrent la possibilité de reconstruire des réseaux de neurones orientés et de manipuler indépendamment les deux populations neuronales ainsi connectées. Dans cette étude, une caractérisation de la mise en place et de la rythmogénèse des réseaux cortico-striataux a été entreprise par imagerie calcique. Par la suite, nous avons démontré que des modifications chroniques des rythmes pré-synaptiques corticaux conduisaient à des phénomènes d¿excitotoxicité trans-synaptique. L'avancée des recherches a montré que les maladies neurodégénératives et psychiatriques pouvaient partager des points communs, notamment des altérations de la transmission synaptique et de l'activité des réseaux de neurones. Pour évaluer ces effets, une modulation de l'expression de Disrupted-In-Schizophrenia-1 a été réalisée dans nos réseaux cortico-striataux. Une altération de la différenciation des neurones striataux a été objectivée mais sans impact sur l'activité rythmique des réseaux neuronaux. Cependant, les expériences de surexpression ont montré la capacité de DISC-1 à participer à la formation des granules de stress, et à recruter dans celles-ci des protéines impliquées dans la transmission synaptique. Au final, ce projet démontre que les réseaux reconstruits in vitro possèdent des caractéristiques similaires aux réseaux in vivo et permettent l'étude de pathologies du système nerveux central
Neural circuit dynamics need to be elucidated for understanding neurological and psychiatric disorders such as Parkinson's disease and schizophrenia. While this is classically studied in vivo or ex vivo, micro-technological approaches permit “brain-on-chip” models recapitulating some intrinsic neuronal network properties. In this study, parameters of cortico-striatal connection were monitored. Glutamatergic neuronal network activity was monitored using calcium imaging. Dopamine and Dopaminergic receptor 2 agonist decreased firing frequency and disrupted striato-striatal synchrony. Then, we demonstrated that both acute and chronic alterations of cortical neurons activity led to impairment of striatal survival through trans-synaptic degeneration. In psychiatric diseases, network rhythm alterations do not lead to neuronal death but to behavior disorders. To study how those alterations appeared, we investigated the impact of DISC-1 expression modulation on the establishment of cortico-striatal network and its activity. Alteration of DISC-1 expression led to deficits in striatal differentiation processes and seemingly did not drive network rhythms variation. Interestingly, DISC-1 overexpression experiments showed its aggregation in stress granules concomitant with an ability to recruit others proteins involved in synaptic transmission and neuronal plasticity. These results seem to show that DISC-1 could be involved in degenerative processes and not only in psychiatric diseases. The present data demonstrate that cortico-striatal networks reconstructed in a microfluidic environment present characteristics similar to in vivo cortico-striatal networks

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Miñano, Molina Alfredo Jesús. „El 17-?-estradiol frente a la muerte apoptótica en neuronas granulares de cerebelo: efectos sobre la supervivencia y modulación de la plasticidad neuronal“. Doctoral thesis, Universitat Autònoma de Barcelona, 2006. http://hdl.handle.net/10803/3559.

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Durant el desenvolupament de les malalties neurodegeneratives les neurones moren. Una de les conseqüències més comuns del desenvolupament de malalties neurodegeneratives és l'activació en la majoria d'elles del programa de mort cel·lular, conegut com apoptosi. El coneixement exhaustiu d'aquest programa apoptòtic és clau per poder abordar estratègies terapèutiques que puguin aturar l'avanç d'aquestes malalties.
L'apoptosi és un procés fisiològic important durant el desenvolupament del SNC mantenint la homeòstasi cel·lular. El cerebel és una de les regions del cervell en la que aquest fenomen és especialment dramàtic. Durant el desenvolupament de les neurones granulars de cerebel (CGCs) pràcticament la meitat es perden durant el procés apoptòtic. Aquest fenomen pot mimetitzar-se in vitro, a partir d'un cultiu pur d'aquestes neurones. El cultiu primari de les CGCs és un model àmpliament utilitzat per a l'estudi de l'apoptosi, induint-la per deprivació de potassi. En aquest procés es pot produir un increment en les concentracions intracel·lulars de ceramida, implicada en aquest procés de mort.
La ceramida és una molècula senyalitzadora implicada en diferents processos cel·lulars com la proliferació, senescència, diferenciació i aturada del cicle cel·lular. Durant els últims anys s'ha proposat que la ceramida podria tenir un paper més important com a regulador de la mort apoptòtica. Un dels nostres objectius va ser, mitjançant la utilització d'aquest model, caracteritzar el procés de mort apoptòtica per ceramida.
Durant els últims anys s'han acumulat evidències suggerint que la exposició a estrògens disminueix el risc i retarda el principi de malalties neurodegeneratives com l'Alzheimer i el Parkinson, així com potencien la recuperació front a danys neurològics traumàtics com la isquèmia cerebral. Aquestes hormones poden realitzar aquestes funcions implicant diferents processos com la supervivència cel·lular, respostes regeneratives, creixement axonal, potenciació de la senyal sinàptica i neurogènesi.
Els resultats de les nostres investigacions indiquen que: (1) la ceramida indueix apoptosi en CGCs activant tant la caspasa-9 com la caspasa-2; dues vies a priori paral·leles i que en aquesta mort apoptòtica, (2) la inhibició d'Akt i l'activació de les MAPK estan implicades. (3) L'estradiol (E2) no protegeix front l'apoptosi en les CGCs i l'absència d'activació d'Akt pot ser clau en aquesta falta de neuroprotecció. (4) L'absència de neuroprotecció podria deure's a que el receptor d'estrògens ER-? no interacciona amb el receptor d'IGF-I. (5) ER-? està localitzat en la membrana plasmàtica de les CGCs i media l'activació de ERK1/2 per E2. L'activació de la via clàssica de les MAPKs per E2 implica un mecanisme diferent d'acció per a E2 en el model de les CGCs. (6) L'E2 exerceix un efecte neuroprotector en les CGCs degut a les seves propietats com a molècula antioxidant. (7) L'activació de la via Src/Ras/ERK/CREB estaria relacionada amb fenòmens de plasticitat sinàptica i el manteniment de connexions entre neurones de les CGCs tot i que no seria suficient per protegir les CGCs de la mort apoptòtica.
Malgrat que l'E2 no protegeix les CGCs de la mort apoptòtica, podria tenir gran rellevància el fet de conèixer com l'E2 posa en marxa mecanismes que desencadenin fenòmens de manteniment dendrític i disminució potencial de la vulnerabilitat de les neurones front a estímuls adversos, permetent poder incidir en un futur sobre models de malalties neurodegeneratives com l'Alzheimer o processos isquèmics, on el manteniment de les connexions dendrítiques existents i la generació de noves sinapsis, a més de mantenir la seva estructura, poden ser processos clau.
A lo largo del desarrollo de las enfermedades neurodegenerativas las neuronas mueren. Una de las consecuencias más comunes del desarrollo de enfermedades neurodegenerativas es la activación en la mayoría de ellas del programa de muerte celular, conocido como apoptosis. El conocimiento exhaustivo de este programa apoptótico es clave para poder abordar estrategias terapéuticas que puedan frenar el avance de estas enfermedades.
La apoptosis es un proceso fisiológico importante durante el desarrollo del SNC manteniendo la homeóstasis celular. El cerebelo es una de las regiones del cerebro en la cual este fenómeno es especialmente dramático. Durante el desarrollo de las neuronas granulares de cerebelo (CGCs) prácticamente la mitad se pierden durante el proceso apoptótico. Este fenómeno puede mimetizarse in vitro, a partir de un cultivo puro de estas neuronas. El cultivo primario de las CGCs es un modelo ampliamente utilizado para el estudio de la apoptosis, induciéndola por deprivación de potasio. En este proceso se puede producir un incremento en las concentraciones intracelulares de ceramida, implicada en este proceso de muerte.
La ceramida es una molécula señalizadora implicada en diferentes procesos celulares como la proliferación, senescencia, diferenciación y paro del ciclo celular. Durante los últimos años se ha propuesto que la ceramida podría tener un papel más importante como regulador de la muerte apoptótica. Uno de nuestros objetivos fue, mediante la utilización de este modelo, caracterizar el proceso de muerte apoptótica por ceramida.
Durante los últimos años se han acumulado evidencias sugiriendo que la exposición a estrógenos disminuye el riesgo y retrasa el principio y desarrollo de enfermedades neurodegenerativas como el Alzheimer y el Parkinson, así como potencian la recuperación frente a daños neurológicos traumáticos como la isquemia cerebral. Estas hormonas pueden desempeñar estas funciones implicando diferentes procesos como la supervivencia celular, respuestas regenerativas, crecimiento axonal, potenciación de la señal sináptica y neurogénesis.
Los resultados de nuestras investigaciones indican que: (1) la ceramida induce apoptosis en CGCs activando tanto la caspasa-9 como la caspasa-2; dos vías de muerte a priori paralelas y que en esta muerte apotótica, (2) la inhibición de Akt y la activación de las MAPKs están implicadas. (3) El estradiol (E2) no protege frente a la apoptosis en las CGCs y la ausencia de activación de Akt puede ser clave en esta falta de neuroprotección. (4) La ausencia de neuroprotección podría deberse a que el receptor de estrógenos ER-? no interacciona con el receptor de IGF-I. (5) ER-? está localizado en la membrana plasmática de las CGCs y media la activación de ERK1/2 por E2. La activación de la vía clásica de las MAPKs por E2 implica un mecanismo diferente de acción para E2 en el modelo de las CGCs. (6) El E2 ejerce un efecto neuroprotector en las CGCs debido a sus propiedades como molécula antioxidante. (7) La activación de la vía Src/Ras/ERK/CREB estaría relacionada con fenómenos de plasticidad sináptica y el matenimiento de conexiones entre neuronas de las CGCs aunque no sería suficiente para proteger las CGCs de la muerte apoptótica.
A pesar de que el E2 no protege a las CGCs de la muerte apoptótica, podría tener gran relevancia el hecho de conocer cómo el E2 pone en marcha mecanismos que desencadenan fenómenos de mantenimiento dendrítico y disminución potencial de la vulnerabilidad de las neuronas frente a estímulos adversos, permitiendo poder incidir en un futuro sobre modelos de enfermedades neurodegenerativas como el Alzheimer o procesos isquémicos, donde el mantenimiento de las conexiones dendríticas existentes y la generación de nuevas sinapsis, además de mantener su estructura, pueden ser procesos clave.
Along neurodegenerative disease development, neurons die. One of the most common consequences of the development of neurodegenerative diseases is the activation, in the majority of them, of the cellular death program, known as apoptosis. The exhaustive knowledge of apoptotic programme is a key to approach new therapeutical strategies to slow down the advance of these diseases.
Apoptosis is an important physiological process during development of CNS maintaining cellular homeostasis. Cerebellum is one of the cerebral regions in which this phenomenon is especially dramatic. During development of cerebellar granule neurons (CGNs) practically a half are removed during apoptotic process. This phenomenon is able to mimic in vitro from pure culture of these neurons. Primary cultures of CGNs are an extensively used model to study apoptosis, inducing it by potassium deprivation. In this process is able to produce an increase of intracellular concentrations of ceramide, implied in the process of cell death.
Ceramide is a signalling molecule implied in different cellular processes like proliferation, senescence, differentiation and control of cellular cycle. During the last years authors suggest ceramide with an important role like a regulator of apoptotic death. One of our objectives was, by means of using this model; characterize apoptotic death process by ceramide.
During the last years diverse accumulating evidences have suggested that estrogens exposition reduce risk and delay the onset and development of neurodegenerative diseases like Alzheimer and Parkinson, the same way as promote recovery from neurological shocks like cerebral ischemia. These hormones are able to carry out these functions implying different processes as cellular survival, regenerative responses, axonal growth, synaptic signal potentiation and neurogenesis.
Results of ours investigation shows that: (1) ceramide induce apoptosis in CGNs activating as caspase-9 as caspase-2; two death pathways beforehand parallels and that in this apoptotic death, (2) inhibition of Akt and activation of MAPKs are implicated. (3) Estradiol (E2) does not protect from apoptosis in CGNs and the absence of Akt activation can be key in this absence of neuroprotection. (4) The absence of neuroprotection could be due to estrogen receptor ER-? does not interact with IGF-IR. (5) ER-? is located in plasmatic membrane of the CGNs and mediates the ERK1/2 activation by E2. Activation of classic pathway MAPKs by E2 implies a different action mechanism to E2 in CGNs model. (6) E2 exerts a neuroprotective effect in CGNs due to proprieties as an antioxidant molecule. (7) Activation of Src/Ras/ERK/CREB pathway would be related with phenomena of synaptic plasticity and the maintenance of connexions between neurons of CGNs although it would not be enough to protect CGNs of apoptotic death.
In spite of E2 does not protect CGNs from apoptotic death, it could have great relevance the fact of known how E2 switch on mechanisms that triggers phenomena of dendrite maintenance and potential decrease of vulnerability of neurons in front of adverse stimuli, making possible to influence in the future on neurodegenerative disease models as Alzheimer or ischemic processes, where the maintenance of dendrite connexions existing and generating news, moreover of maintenance of structure can be key processes.

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Hunt, Philip Duncan. „Analysis of roughness deterioration of bitumen sealed unbound granular pavements for use in road asset management modeling“. Thesis, Queensland University of Technology, 2002. https://eprints.qut.edu.au/36178/1/36178_Hunt_2002.pdf.

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The road system under the care and control of the State of Queensland, Australia has an estimated replacement value of $23 Billion (US$12 billion), excluding structures. Pavement management systems for recording, rating, and predicting a pavement's condition are used to prudently manage this large asset. Tne of the fundamental components of a pavement management system is the method of determining a pavement's rate of deterioration over time. Throughout the world, "pavement roughness" is one of the most widely used methods of measuring the performance of a pavement. Queensland is a large State, having an approximate area of 1.7 million square kilometres, and incorporates many small communities separated by vast distances. The majority of bitumen sealed pavements exist in low traffic volume rural areas, and consist of either a flexible unbound granular pavement or a semi-rigid modified granular pavement. This study has focussed on the roughness progression of these pavement types. Roughness data has been collected at varying frequencies since 1987, across the State's road network. In order to understand roughness progression behaviour, this research has considered 16,000 pavement segments (each lkm) from all parts of the State. This number is significant, as many previous research efforts, which form the basis of the current roughness progression models, have been based on the study of typically between forty and several hundred pavement segments. This extensive database has been used in this study to investigate trends in roughness pogression over time (~R). Traditionally, roughness progression has been represented in many road asset management models as an exponential relationship, providing rapidly increasing roughness values as the pavement approaches the end of its theoretical life. However, this relationship has not been commonly observed in the State's pavement asset. Investigations revealed that a linear relationship, termed the Linear Roughness Progression Rate (LRPR), represented the roughness progression of the pavement segments very well, and thereby assists in the identification of poor performing pavement segments. Pavement maintenance costs can also be used to identify poor performing pavement segments, based on excessive use of pavement maintenance funds to maintain functionality. This information assists in 'unmasking' pavements that may possess an umepresentative LRPR. For this reason, the effects of pavement maintenance costs (~PMC) on roughness progression have also been examined. Independent variables which are typically considered to affect roughness progression, have been examined with LRPR in this study. These variables include traffic volume, traffic loading, pavement type, subgrade soil classification, climate (rainfall, temperature, Thomthwaite Index), pavement age, and width of bitumen surface (seal width). It has been established that the roughness progression of each individual pavement segment is unique. No particular formula or model has been identified, which can accurately predict the roughness progression of any particular pavement segment from a population, based upon known values of the independent variables. In order to develop an understanding of the effects of these variables on pavement performance, a means of rating a pavement's condition using a combination of LRPR and excessive pavement maintenance expenditure has been established. Subsequently, a discrete rating scale from "Good", "Fair" to "Poor" has been used. The effects of the independent variables on pavement rating have been examined across the population of study pavement segments, using summary charts. This has enabled the proportions of pavement rated within each category to be examined with changes in each independent variable, to establish whether that variable has a global influence on pavement rating. For instance, whether the proportion of pavements rated "Poor" varies with Annual Average Daily Traffic. These summary charts provide the basis of a Network Performance Profile, which has yielded a better understanding of the variables globally influencing pavement rating across the State's road network. Further, the Network Performance Profile provides insight into the inbuilt risk of the past and current pavement design and delivery system. The knowledge gained from a whole of network analysis of condition may form a catalyst for the assessment of material quality, design methods, construction technology, and contract delivery, to ensure that pavements have the best chance of performing well. Currently, road network performance is commonly defined only by a measure of the road network's 'Absolute Condition'. The Network Performance Profile developed in this study will add new measures of pavement performance to the current definition. By including a Current Network Profile, and a more robust method for predicting mid term (five year) roughness values, asset managers will have a suite of information on historic, current, and estimated future road network condition, to use in evaluating the impact of previous and current management decisions. Pavement roughness prediction analysis, based on site-specific extrapolation of LRPR, has shown that at least six time-series roughness data points are required if an accurate short term prediction (4 to 6 year) is to be achieved. It is believed that the research of roughness progression has highlighted the unique nature of pavement segment deterioration. It is interesting to note that all categories of pavements suffer from a range of good to poor performance, and this finding is considered to be one of the keys in understanding pavement behaviour. At a network level, the study of performance has been considered very successful and has not only provided a robust methodology for quantifying road network performance, but also provides information for input into the improvement of technical policies and funding distribution decisions.

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Ko, Hae Kyung. „Exploring the Role of FUS Mutants from Stress Granule Incorporation to Nucleopathy in Amyotrophic Lateral Sclerosis: A Dissertation“. eScholarship@UMMS, 2015. https://escholarship.umassmed.edu/gsbs_diss/799.

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Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease characterized by preferential motor neuron death in the brain and spinal cord. The rapid disease progression results in death due to respiratory failure, typically within 3-5 years after disease onset. While ~90% of cases occur sporadically, remaining 10% of ALS cases show familial inheritance, and the number of genes linked to ALS has increased dramatically over the past decade. FUS/TLS (Fused in Sarcoma/ Translocated to liposarcoma) is a nucleic acid binding protein that may regulate several cellular functions, including RNA splicing, transcription, DNA damage repair and microRNA biogenesis. More than 50 mutations in the FUS gene are linked to 4% of familial ALS, and many of these may disrupt the nuclear localization signal, leading to variable amounts of FUS accumulation in the cytoplasm. However, the mechanism by which FUS mutants cause motor neuron death is still unknown. The studies presented in this dissertation focused on investigating the properties of FUS mutants in the absence and presence of stress conditions. We first examined how ALS-linked FUS mutants behaved in response to imposed stresses in both cell culture and zebrafish models of ALS. We found that FUS mutants were prone to accumulate in stress granules in proportion to their degree of cytoplasmic mislocalization under conditions of oxidative stress, ER stress, and heat shock. However, many FUS missense mutants are retained predominantly in the nucleus, and this suggested the possibility that these mutants might also perturb one or more nuclear functions. In a human cell line expressing FUS variants and in human fibroblasts from an ALS patient, mutant FUS expression was associated with enlarged promyelocytic leukemia nuclear bodies (PML-NBs) under basal condition. Upon oxidative insult with arsenic trioxide (ATO), PML-NBs in control cells increased acutely in size and were turned over within 12-24 h, as expected. However, PML-NBs in FUS mutant cells did not progress through the expected turnover but instead continued to enlarge over 24 h. We also observed a persistent accumulation of the transcriptional repressor Daxx and the 11S proteasome regulator in association with these enlarged PML-NBs. Furthermore, the peptidase activities of the 26S proteasome were decreased in FUS mutant cells without any changes in the expression of proteasome subunits. These results demonstrate that FUS mutant expression may alter cellular stress responses as manifested by (i) accumulation of mutant FUS into stress granules and (ii) inhibition of PML-NB dynamics. These findings suggest a novel nuclear pathology specific to mutant FUS expression that may perturb nuclear homeostasis and thereby contribute to ALS pathogenesis.

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Ko, Hae Kyung. „Exploring the Role of FUS Mutants from Stress Granule Incorporation to Nucleopathy in Amyotrophic Lateral Sclerosis: A Dissertation“. eScholarship@UMMS, 2009. http://escholarship.umassmed.edu/gsbs_diss/799.

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Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease characterized by preferential motor neuron death in the brain and spinal cord. The rapid disease progression results in death due to respiratory failure, typically within 3-5 years after disease onset. While ~90% of cases occur sporadically, remaining 10% of ALS cases show familial inheritance, and the number of genes linked to ALS has increased dramatically over the past decade. FUS/TLS (Fused in Sarcoma/ Translocated to liposarcoma) is a nucleic acid binding protein that may regulate several cellular functions, including RNA splicing, transcription, DNA damage repair and microRNA biogenesis. More than 50 mutations in the FUS gene are linked to 4% of familial ALS, and many of these may disrupt the nuclear localization signal, leading to variable amounts of FUS accumulation in the cytoplasm. However, the mechanism by which FUS mutants cause motor neuron death is still unknown. The studies presented in this dissertation focused on investigating the properties of FUS mutants in the absence and presence of stress conditions. We first examined how ALS-linked FUS mutants behaved in response to imposed stresses in both cell culture and zebrafish models of ALS. We found that FUS mutants were prone to accumulate in stress granules in proportion to their degree of cytoplasmic mislocalization under conditions of oxidative stress, ER stress, and heat shock. However, many FUS missense mutants are retained predominantly in the nucleus, and this suggested the possibility that these mutants might also perturb one or more nuclear functions. In a human cell line expressing FUS variants and in human fibroblasts from an ALS patient, mutant FUS expression was associated with enlarged promyelocytic leukemia nuclear bodies (PML-NBs) under basal condition. Upon oxidative insult with arsenic trioxide (ATO), PML-NBs in control cells increased acutely in size and were turned over within 12-24 h, as expected. However, PML-NBs in FUS mutant cells did not progress through the expected turnover but instead continued to enlarge over 24 h. We also observed a persistent accumulation of the transcriptional repressor Daxx and the 11S proteasome regulator in association with these enlarged PML-NBs. Furthermore, the peptidase activities of the 26S proteasome were decreased in FUS mutant cells without any changes in the expression of proteasome subunits. These results demonstrate that FUS mutant expression may alter cellular stress responses as manifested by (i) accumulation of mutant FUS into stress granules and (ii) inhibition of PML-NB dynamics. These findings suggest a novel nuclear pathology specific to mutant FUS expression that may perturb nuclear homeostasis and thereby contribute to ALS pathogenesis.

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Imoto, Yuki. „Activity-dependent bidirectional regulation of terminal neuronal maturation in the adult hippocampus“. 京都大学 (Kyoto University), 2015. http://hdl.handle.net/2433/199491.

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Stewart, Robyn. „17beta estradiol, but not estrone, increases hippocampal neurogenesis and activation of new granule neurons in response to spatial memory in adult female rats“. Thesis, University of British Columbia, 2012. http://hdl.handle.net/2429/42872.

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Estrogens fluctuate across the lifespan in women, with circulating 17β-estradiol levels higher pre-menopause than estrone and circulating estrone levels higher postmenopause than 17β- estradiol. Estrone is a common component of hormone replacement therapies, but research shows that 17β-estradiol may have a greater positive impact on cognition. Previous studies show that acute estrone and 17β-estradiol impact hippocampus-dependent learning and cell proliferation in the dentate gyrus in a dose-dependent manner in adult female rats. The current study explores how chronic treatment with estrone and 17β-estradiol differentially influences spatial learning, hippocampal neurogenesis and activation of new neurons in response to spatial memory. Adult female rats received daily injections of vehicle (sesame oil), or a 10μg dose of either 17β-estradiol or estrone for 20 days. One day following the first hormone injection all rats were injected with the DNA synthesis marker, bromodeoxyuridine. On days 11-15 after BrdU injection rats were trained on a spatial reference version of the Morris water maze, and five days later (day 20 of estrogens treatment) were given a probe trial to assess memory retention. There were no significant differences between groups in acquisition or retention of Morris water maze. However, the 17β-estradiol group had significantly higher, while the estrone group had significantly lower, levels of neurogenesis in the dentate gyrus compared to controls. Furthermore, rats injected with 17β-estradiol showed significantly higher levels of activation of new neurons in response to spatial memory compared to controls. These results provide insight into how estrogens differentially influence the brain and behaviour, and may provide insight into the development of hormone replacement therapies for women.

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LEDDA, MARIO. „Studio dell'effetto delle radiazioni non ionizzanti sul processo di maturazione e differenziamento dei granuli cerebellari di ratto neonato: studi in vitro e in vivo“. Doctoral thesis, Università degli Studi di Roma "Tor Vergata", 2009. http://hdl.handle.net/2108/774.

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The purpose of this study is to examine the effect of Extremely Low Frequency electromagnetic Fields (ELF) on the differentiation of cerebellar granule neurons. These cells represent the main population of the rat cerebellum and is one of the most widespread models for the study of numerous neuronal parameters(Balazs et al.,1988; Gallo et al.,1987; Contestabile 2002). In this research I studied cerebellar granule neurons, in experiments in vitro and in vivo. In the first case I analyzed the effects induced by the exposure to electromagnetic fields on primary cerebellar granule neurons of newborn rats, which were eight days old. In the second case I exposed pregnant rats, for the entire duration of the gestation and I sacrified the newborn rat after eight days of exposure. In both cases the cells exposed to the electromagnet fields of 50 Hz, 1 mT showed one premature reaction to Glutamate toxicity test. Moreover the Patch clamp technique showed an increase of the currents of the KAINATO in the exposed cells. These two techniques showed a premature and greater activity of glutamate receptors in the exposed cells. The study of expression of ionotropic glutamate receptors confirmed, by means of Western blotting and RT-PCR, their precocius expression in the exposed cells. These receptors represent an index of maturation of the cerebellar granule neurons (Hack and Balazs 1994), therefore I studied another important neuronal marker, the protein NF-200, one of the three proteins of the neurofilament. Immunofluorescence assay and Western blotting showed one greater expression of this marker in the exposed cells compared to control cells. All these results indicate that the electromagnetic fields of 50Hz and 1 mT can interact with biological material, in fact in my research I demonstrated that the exposure to this physical agent is able to induce a premature maturation and differentiation of cerebellar granule neurons.

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Kouzoukas, Dimitrios Elias. „The nitric oxide signaling pathway inhibits intracellular calcium release to prevent neurodevelopmental alcohol toxicity“. Diss., University of Iowa, 2010. https://ir.uiowa.edu/etd/838.

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In the context of fetal alcohol spectrum disorders, we investigated how the nitric oxide (NO) signaling pathway influences intracellular calcium (Ca2+) to mediate alcohol resistance, using a primary cell culture model of cerebellar granule neurons (CGN). Alcohol during fetal brain development triggers abnormally high apoptotic cell death in vulnerable neuronal populations, culminating in serious behavioral and cognitive deficits that persist into adulthood. Prior studies demonstrated that the NO signaling pathway [neuronal nitric oxide synthase → NO → soluble guanylyl cyclase → cyclic guanosine monophosphate → protein kinase G (PKG)] mitigates alcohol toxicity, consequently diminishing neuronal loss both in vivo and in vitro. Endoplasmic reticulum (ER) Ca2+ release, a key apoptotic mechanism, requires the inositol 1,4,5-trisphosphate receptor (IP3R), a known PKG substrate. Our studies focused on this crucial intersection point where the NO signaling cascade can influence Ca2+-mediated apoptotic mechanisms, and exposed a downstream mechanism where NO can moderate alcohol neurotoxicity. We hypothesized that as alcohol disturbs neuronal Ca2+ homeostasis to trigger cell death, the NO signaling pathway counters it by limiting Ca2+ release from the ER. We examined first the role of the phospholipase C (PLC) pathway [PLC → inositol 1,4,5-trisphosphate → IP3R → Ca2+] in developmental neurotoxicity through our in vitro CGN model, extending previous in vivo studies. We found that alcohol terminates developing neurons by eliciting abnormal Ca2+ release from the ER rather than from an extracellular source, via a PLC - IP3R-dependent signaling mechanism. Inhibiting either calcineurin or Ca2+ / calmodulin-dependent protein kinase ii (CaMKii), which participate in parallel Ca2+-activated apoptotic cascades, shielded CGN cultures from alcohol. Blocking the mitochondrial Ca2+ uniporter or the mitochondrial permeability transition pore also provided neuroprotection. That the activated pathways must interact to generate cell death likely explains why inhibiting one of multiple parallel signaling cascades limits alcohol toxicity. We next demonstrated that activating the NO pathway downstream at PKG eliminated both alcohol-related neuronal death and the accompanying rapid rise in intracellular Ca2+, an effect that markedly resembled IP3R inhibition. Experiments that temporally manipulated the addition of PKG activators in relation to alcohol exposure linked PKG's obstruction of alcohol-induced Ca2+ elevations to alcohol resistance. In contrast, brain-derived neurotrophic factor (BDNF), which does not rely on PKG to provide neuroprotection, failed to block alcohol-induced Ca2+ elevations while preventing alcohol toxicity. This indicates that although PKG blocks alcohol-induced Ca2+ elevations, averting these Ca2+ elevations is not necessary for neuroprotection. BDNF may confer alcohol resistance through an as yet unidentified process downstream from the disruption of intracellular Ca2+. In summary, we established that 1) alcohol induces toxic Ca2+ elevations originating from the ER through a PLC - IP3R-dependent pathway, and that 2) PKG-mediated alcohol resistance is linked to preventing the intracellular Ca2+ surges. These findings support the hypothesis that the NO signaling pathway shields developing neurons from alcohol by limiting Ca2+ release from the ER.

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Delestre-Delacour, Charlène. „Contribution à l'étude du rôle de la Chromogranine A dans la sécrétion neuroendocrine : identification de ses partenaires moléculaires impliqués dans la biogenèse des granules de sécrétion“. Rouen, 2014. http://www.theses.fr/2014ROUES007.

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Les cellules neuroendocrines expriment plusieurs granines impliquées dans la formation des granules de sécrétion (GS) et dans la sécrétion hormonale. Dans les cellules non-endocrines COS7, nous avons montré que l’expression de la chromogranine A (CgA) induit la formation de structures vésiculaires présentant les caractéristiques morphologiques et dynamiques des GS. Le but de ce travail a été d’identifier les mécanismes d’action de la CgA dans la sécrétion hormonale. Nous avons montré que le trafic des organites néoformés est sensible au Ca2+ et que leurs déplacements suggèrent une interaction avec le cytosquelette. L’analyse de leur protéome nous a permis d’identifier la myosine 1b comme partenaire indirect de la CgA. Dans les cellules COS7 exprimant la CgA et les cellules neuroendocrines PC12, nous avons montré que l’inhibition de l’expression de la myosine 1b provoque une diminution du nombre de granules CgA. Nous avons également montré que l’actine est recrutée à la membrane de l’appareil de Golgi, afin d’initier le bourgeonnement des granules CgA. De plus, nous avons montré in vitro que la CgA interagit avec l’acide phosphatidique et que l’inhibition de sa synthèse diminue le nombre de granules formés. De plus, une analyse du lipidome des membranes de granules CgA et de l’appareil de Golgi a révélé un enrichissement des membranes granulaires en PA. Ces données indiquent que la biogenèse des granules impliqués dans la sécrétion hormonale CgA-dépendante est contrôlée par l’interaction de la CgA avec la membrane de l’appareil de Golgi pour former des microdomaines enrichis en PA favorisant la courbure membranaire et le recrutement de la myosine 1b et de l’actine
Neuroendocrine cells coexpress several granins involved in the biogenesis of secretory granules (SG) and in the hormonal secretion. In the non endocrine COS7 cells (i. E. Devoid of granins and regulated secretory pathway), our team demonstrated that chromogranin A (CgA) expression induces the formation of vesicules with dynamical and structural characteristics of SG. The goal of this work was to elucidate the mechanism of action of CgA in this process. We showed that the trafficking of CgA-induced organelles is Ca2+-sensitive. Moreover, these organelles exhibit displacements suggesting their interaction with the cytoskeleton. Proteomic analysis of CgA-granules revealed that myosin 1b could be an indirect partner of CgA. In COS7 cells expressing CgA and neuroendocrine PC12 cells, silencing of myosin 1b provoked a significant decrease of the number of CgA granules. We also demonstrated that F-actin is coupled to the TGN membrane through Myo1b to induce the budding of CgA granules. Then, we showed that CgA binds in vitro phosphatidic acid (PA). We observed that inhibition of PA synthesis leads to a significant decrease of CgA granules. Moreover, the comparative analysis of the lipidomes of purified CgA-containing granules and Golgi membranes from COS7-CgA cells revealed an enrichment of PA in granular membrane. Altogether, these data indicate that the budding of CgA granules and the CgA-dependent hormone secretion are regulated by CgA interaction with TGN membrane to form PA-enriched microdomains mediating the membrane curvature and the recruitment of myosin 1b and actin

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Bou-Rouphaël, Johnny. „A new role for Barhl1 in a cerebellar germinative zone as inhibitor of T-cell factors transcriptional activity“. Electronic Thesis or Diss., Sorbonne université, 2023. http://www.theses.fr/2023SORUS009.

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Le cervelet humain contient plus de 50 % des neurones cérébraux. Les neurones granulaires cérébelleux représentent la population neuronale majeure. Les progéniteurs des neurones granulaires (GNP), définis par l’expression de Atoh1, émergent à partir de la lèvre rhombique supérieure (URL), une zone germinative située dans le territoire cérébelleux. Au cours du développement, les GNP prolifèrent, migrent et se différencient. Chacun de ces processus est régulé par un certain nombre de facteurs de transcription et de voies de signalisation. Les « T-Cell Factors » (Tcf/Lef) » sont des effecteurs transcriptionnels agissant en aval de la signalisation Wnt/β-caténine. Bien que les Tcf soient transcriptionnellement actifs dans la URL, leur(s) fonction(s) et leur(s) régulateur(s) développementaux n'ont été étudié. Le facteur de transcription « BarH-like 1 » (Barhl1) est exprimé dans les GNPs engagés, situés dans des zones dépourvues d'une activité transcriptionnelle Tcf. Par conséquent, les objectifs de cette thèse étaient d'étudier les fonctions de Tcf et Barhl1 en tant que régulateurs du développement des GNPs chez le Xénope. Les données présentées dans cette thèse englobent une analyse approfondie des marqueurs majeurs impliqués dans le développement des GNPs chez les amphibiens, et une étude des fonctions de Barhl1 et Tcf dans ce processus développemental. Nos expériences de gain et de perte de fonction, ainsi que l'analyse transcriptomique en absence de Barhl1 dans le rhombomère 1 valident un rôle clé de Tcf en tant qu'activateur transcriptionnel de atoh1 et en tant qu'inducteur du territoire cérébelleux, et un rôle pour Barhl1 en tant qu'inhibiteur développemental de l’activité Tcf, permettant aux GNPs de sortir de l'URL. Nous avons identifié des gènes cibles clés inhibés par Barhl1, et impliqués dans le maintien d’une zone germinative
The human cerebellum hosts more than 50% of all brain neurons. Cerebellar granule neurons are the smallest and most abundant neurons. atonal homologue 1 (Atoh1)-expressing granule neuron progenitors (GNPs) emerge from the upper rhombic lip (URL), a germinative zone located in the cerebellar primordium and displaying features of a niche of neural stem cells. GNPs proliferate, migrate, and differentiate to settle into the internal granule layer. These processes are tightly regulated by a number of transcription factors and signaling pathways. T-Cell Factor/Lymphoid Enhancer-binding Factor (Tcf/Lef) are transcriptional effectors acting downstream of Wnt/β-catenin signaling. Although Tcf is transcriptionally active in the URL, neither its function(s) nor its developmental regulator(s) have been addressed in this area. The transcription factor BarH-like 1 (Barhl1) is expressed in committed GNPs located in areas devoid of Tcf transcriptional activity. The aims of this thesis were to investigate the functions of Tcf and of Barhl1 as regulators of GNPs development using amphibian as experimental model. The data presented in this work encompass a thorough analysis of the spatial and temporal expressions of key markers involved in GNP development in amphibian, and an investigation of Barhl1 and Tcf functions in this developmental process. Our gain and loss of function experiments, together with the transcriptomic analysis of Barhl1 depletion in the rhombomere 1 validate a key role for Tcf as a transcriptional activator of atoh1 and as an inducer of the URL territory, and for Barhl1 as a developmental inhibitor of Tcf activity allowing GNPs to exit the URL. We identified key genes inhibited by Barhl1 and involved in the maintenance of URL germinative zone

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Le, Marec Nathalie. „Influence de l'irradiation précoce du cervelet aux rayons X sur l'apprentissage et la mémorisation chez le rat“. Rouen, 1995. http://www.theses.fr/1995ROUES030.

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L'étude présentée porte sur le rôle d'une des deux afférences au cortex cérébelleux (voie fibres moussues-cellules en grains-fibres parallèles) dans l'acquisition et la rétention de différents apprentissages. La lésion de cette voie est obtenue par des irradiations aux rayons X du cervelet pendant les deux premières semaines de vie post-natale. Les animaux étudiés ont subi des lésions partielles ou totales des cellules en grains. Certains de ces animaux lésés ont, en plus, subi au 15ème jour, une lésion totale de la 2ème afférence au cortex cérébelleux (voie fibres grimpantes) par administration I. P. De 3-AP. L'étude se divise en deux parties principales: apprentissage du comportement d'équilibration chez de jeunes rats les animaux sont ensuite soumis, à l'âge adulte, à un conditionnement d'évitement et à un apprentissage spatial. Dans les deux cas, l'apprentissage initial a été suivi, 7 jours plus tard, par un test de rappel. Les performances des animaux expérimentaux, ainsi que les stratégies qu'ils adoptent, sont comparées, dans les deux parties, à celles des animaux témoins. Les différents résultats montrent que l'intégrité de la voie fibres moussues-cellules en grains-fibres parallèles facilite l'acquisition mais n'intervient pas dans la rétention des apprentissages. De plus, l'absence, ou le manque d'inhibition comportementale chez les animaux lésés, perturbe la mise en place de stratégies adaptées

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Dissertationen zum Thema „Granular neuron“

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