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1
Zanini, Marco. "Ciliogenesis Control Mechanisms in Cerebellar Neuron Progenitors." Thesis, Université Paris-Saclay (ComUE), 2019. http://www.theses.fr/2019SACLS475/document.
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Pendant le développement du cervelet, les progéniteurs des neurones granulaires (PNG) nécessitent la présence du cil primaire pour proliférer en réponse à Sonic Hedgehog (SHH). En effet, la prolifération dérégulée des PNGs peut conduire à la formation d'une tumeur pédiatrique maligne appelée SHH-médulloblastome (MB), de ce fait comprendre comment le cil primaire est régulé dans les PNGs est crucial.Nous montrons que le facteur de transcription Atoh1 contrôle la présence du cil primaire dans les PNGs in vitro et in vivo. En particulier, la suppression du cil primaire par l’inactivation génétique de gènes impliqués dans la ciliogenèse (par exemple, Kif3a ou Ift88) empêche Atoh1 de maintenir les PNGs en prolifération, ce qui indique qu’Atoh1 favorise l’expansion des PNGs en maintenant la présence du cil primaire. D’un point de vue moléculaire, Atoh1 contrôle la formation du cil primaire en régulant le bon positionnement peri-centrosomal des satellites centriolaires (SC), complexes protéiques essentiels pour la ciliogenèse. L'inactivation de Atoh1 dans les PNGs perturbe en effet la distribution subcellulaire des SCs, altérant ainsi inévitablement la ciliogenèse. Cette nouvelle fonction de Atoh1 est gouvernée par la régulation transcriptionnelle directe d'un composant clé des SCs, Cep131. L’expression ectopique de Cep131 dans les PNGs restore les effets liés à l'inactivation d'Atoh1, rétablissant la localisation correcte du SC et comme conséquence la présence d’un cil primaire.De plus, nous avons montré que cette voie Atoh1-SC-cil primaire-SHH contrôlant la prolifération des PNGs est également conservée dans le contexte du SHH-MB, où Atoh1 est surexprimée et essentielle pour sa formation et sa maintenance.Ces données révèlent un mécanisme par lequel la ciliogenèse est régulée dans des progéniteurs de neurones, offrant de nouvelles informations sur la neurogenèse dans le cervelet et sur la pathogenèse du SHH-MBCerebellar granule neuron progenitors (GNPs) require the primary cilium to proliferate in response to Sonic Hedgehog (SHH) during cerebellar development. As aberrant proliferation of GNPs may lead to SHH-type medulloblastoma (SHH-MB), a pediatric brain tumor, understanding which mechanisms control ciliogenesis in GNPs represents a major interest in the field. Here, we show that the proneural bHLH transcription factor Atoh1 controls the presence of primary cilia in GNPs both in vitro and in vivo, thus maintaining GNPs responsive to the mitogenic effects of SHH. Indeed, loss of primary cilia induced via knockdown of specific ciliary components (e.g. Kif3a and Ift88) abolishes the ability of Atoh1 to keep GNPs in proliferation in vivo. Mechanistically, Atoh1 controls ciliogenesis by regulating the proper peri-centrosomal clustering of centriolar satellites (CS), large multiprotein complexes working as essential machineries for ciliogenesis. Knockdown of Atoh1 in GNPs perturbs CS subcellular distribution, leading to impairment of ciliogenesis. Luciferase reporter assays and chromatin immunoprecipitation experiments indicate that Atoh1 can directly regulate the expression of Cep131, a key CS core component. Importantly, ectopic expression of Cep131 in GNPs depleted of Atoh1, is sufficient to restore proper CS localization and consequent primary cilia formation, indicating that the Atoh1-Cep131-CS axis is responsible for ciliogenesis in GNPs.In addition, we further demonstrated that these functions of Atoh1 are conserved in the context of SHH-MB, where Atoh1 is typically overexpressed and acts as a lineage-dependent transcription factor.These data reveal a mechanism whereby ciliogenesis is regulated in neuron progenitors providing novel insights into cerebellar neurogenesis and pathogenesis of SHH-MB
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Houlton, R. E. "Influence of adaptation on single neuron and population coding in mouse primary visual cortex." Thesis, University College London (University of London), 2014. http://discovery.ucl.ac.uk/1417573/.
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In the visual system, prolonged exposure to a high contrast stimulus leads to a decrease in neuronal responsiveness, referred to as contrast adaptation. Contrast adaptation has been extensively studied in carnivores and primates, but has so far received little attention in mice. This thesis explores contrast adaptation and its mechanisms in mouse primary visual cortex (V1). Using extracellular tetrode recordings in mouse V1, I found contrast adaptation to be orientation unspecific. While this finding differs from reports in carnivores and primates, it is consistent with the notion that responsiveness of individual neurons is influenced by the activity history of the local network. Adaptation was also found to be cell-type specific, as putative parvalbumin (PV) expressing interneurons underwent less adaptation than other cell types. There is debate whether adaptation arises within the cortex or is inherited from the earlier stages in the visual pathway (e.g. visual thalamus or retina). In order to assess the relative contributions of cortical/subcortical mechanisms towards adaptation in mouse V1, I used optogenetic methods to suppress cortical activity (via activation of Channelrhodopsin-2 in PV interneurons) during an adapting stimulus. Suppressing cortical activity, and hence any activity-dependent cortical mechanisms, largely counteracted the effects of adaptation on neuronal responsiveness, consistent with a substantial cortical component of adaptation. Interestingly, whilst adaptation reduced both contrast and response gain, only the latter effect was influenced by cortical suppression. This suggests that the mechanisms mediating adaptation-induced alterations in contrast and response gain are different, and possibly occur at different loci within the visual pathway. The consequences of adaptation on V1 population responses were explored with two-photon calcium imaging. Adaptation to dynamic stimuli of multiple orientations caused a divisive scaling of responses, consistent with a reduction in response gain. Adaptation also decorrelated neuronal activity, leading to sparser and more distributed stimulus representations across the population. Whole-cell recordings further revealed that these effects were associated with decreased membrane depolarisation, and an increase in membrane potential variability.
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Lewis, Sara Ann. "Functions of Drosophila Pak (p21-activated kinase) in Morphogenesis: A Mechanistic Model based on Cellular, Molecular, and Genetic Studies." Diss., The University of Arizona, 2015. http://hdl.handle.net/10150/594389.
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Intellectual disability (ID) is a common phenotype of brain-development disorders and is heterogeneous in etiology with numerous genetic causes. PAK3 is one gene with multiple mutations causing ID. Affected individuals have microcephaly, and other brain-structure defects have been reported. Additionally, PAK3 is in a genetic network with eighteen other genes whose mutations cause ID, suggesting the molecular mechanisms by which PAK3 regulates of cognitive function may be shared by other genetic ID disorders. Studies in rodent models have shown that the orthologs of PAK3 are important for regulating dendrite spine morphology and postnatal brain size. In Drosophila melanogaster, the morphological processes of oogenesis, dorsal closure during embryogenesis, and salivary gland-lumen formation require Pak, the Drosophila ortholog of PAK3. Additionally, Pak is important for development of the subsynaptic reticulum of the neuromuscular junction, sensory axon pathfinding and terminal arborization in the Drosophila central nervous system (CNS). However, the role of Pak in mushroom body (MB) structure and intrinsic neurite arbor morphogenesis, as well as details of the underlying cellular and molecular mechanisms are unknown. To address this gap, I used Drosophila models of PAK3 gene mutations, Pak, and a combination of immunostaining, primary cell culture, and genetic interaction studies to elucidate these mechanisms. I performed a detailed characterization of the previously reported adult Pak phenotypes of decreased survival as well as leg and wing morphology. I found that decreased survival is a low-penetrance phenotype that is enhanced by chromosomes from the same mutagenesis. Defects of the adult wing include folding and misalignment between the layers, blisters, and missing or partial cross veins. The Pak-mutant legs are short and often misdirected in the pupal case with morphological defects in the shape of the leg segments themselves. The mushroom bodies are important insect learning and memory brain structures whose lobes are composed of axon bundles with individual axons bifurcating to form the α and β lobes. Mutations in Pak cause defects in the length, thickness, and direction of the MB α and β lobes. These defects increase in severity during metamorphosis, when neurogenesis and differentiation of these structures occur, suggesting that Pak stabilizes the branches of the α/β mushroom body neurons. Pak-mutant cultured neurons have reduced neurite arbor size with defects in neurite caliber. Initial outgrowth was normal, followed by a decrease in neurite branch number, again supporting the role of Pak in neurite-branch stability. There are defects in the cytoskeleton in growth cones at six hours post-plating as well as in neurons after three days in vitro. The Pak-mutant phenotype severity depends on the phosphorylation status of myosin regulatory light chain, supporting the mechanistic hypothesis that Pak regulates neurite-branch stability by inhibiting myosin light chain kinase. The neuronal phenotype of decreased branch stability suggests a mechanism of excessive retraction as the cellular pathogenesis underlying PAK3 mutation-associated brain disorders. I used western blotting to characterize the protein products of four nonsense mutations in Drosophila Pak to interpret genotype-phenotype relationships. Each allele has molecularly unique consequences: Pak¹¹, stop-codon read through and truncated protein; Pak¹⁶, no read through, but truncated protein; Pak⁶, read through with no truncated protein; Pak ¹⁴, neither readthrough nor truncated protein. Truncated proteins produced by Pak¹¹ and Pak¹⁶ alleles retained partial function for survival, wing blistering, leg morphology, and neurite length. Conversely, truncated protein increased the severity of the mushroom body defects. Truncated proteins have no effect on neuron branch number, wing folding, or vein defects. Together, these results demonstrate a role of Pak in regulating epithelial morphology, brain structure, and neurite arbor size and complexity. These closely resemble features of the human disorder, providing evidence that this is a good genetic model for this cause of ID.
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DI, BIASE ERIKA. "GM1 OLIGOSACCHARIDE ACCOUNTS FOR GM1 ROLE IN ENHANCING NEURONAL DEVELOPMENT ACTING ON TRKA-MAPK PATHWAY." Doctoral thesis, Università degli Studi di Milano, 2019. http://hdl.handle.net/2434/692335.
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Il ganglioside GM1 è un glicosfingolipide mono-sialilato presente nello strato esterno della membrana plasmatica cellulare ed è particolarmente abbondante nei neuroni. Numerosi studi in vitro e in vivo evidenziano il ruolo del GM1 non solo come componente strutturale ma anche come regolatore di diversi processi cellulari. Infatti, l'arricchimento di GM1 nei microdomini di membrana promuove il differenziamento e la protezione neuronale. Inoltre il contenuto di GM1 è essenziale per la sopravvivenza e il mantenimento dei neuroni. Nonostante vi siano numerose evidenze sugli effetti neuronotrofici mediati dal GM1, la conoscenza del meccanismo d'azione sottostante è scarsa. Recentemente, la catena oligosaccaridica del GM1 (oligoGM1) è stata identificata come responsabile delle proprietà neuritogeniche del ganglioside GM1 nelle cellule di neuroblastoma. Gli effetti mediati dall’oligoGM1 dipendono dal suo legame con il recettore specifico dell’ NGF, il TrkA, determinando così l'attivazione della via TrkA-MAPK. In questo contesto, il mio lavoro di dottorato mirava a confermare il ruolo dell’oligoGM1, come componente bioattiva dell’intero ganglioside GM1, capace di stimolare i processi di differenziaziamento e maturazione dei neuroni granulari cerebellari di topo. Come prima cosa, abbiamo eseguito analisi morfologiche in time -course sui neuroni primari coltivati in presenza o in assenza dei gangliosidi GM1 o GD1a (il quale rappresenta il diretto precursore catabolico del GM1), somministrati esogenamente. Abbiamo osservato che entrambi i gangliosidi aumentavano l’aggregazione e l'arborizzazione dei neuroni. Dopo successiva somministrazione dei rispettivi oligosaccaridi, abbiamo osservato che solo l’oligoGM1 favoriva la migrazione dei neuroni, mentre l’oligoGD1a non induceva nessun effetto discriminante rispetto alle cellule controllo. Questo risultato suggerisce l'importanza della specifica struttura saccaridica del GM1 nella mediazione degli effetti neuronotrofici del ganglioside. Quindi abbiamo caratterizzato biochimicamente l'effetto mediato dall’oligoGM1 nei neuroni e abbiamo osservato un più elevato tasso di fosforilazione delle proteine FAK e Src, le quali rappresentano i regolatori intracellulari chiave della motilità neuronale. Inoltre, in presenza dell’ oligoGM1 i neuroni granulari cerebellari mostravano un aumento del livello di marcatori neuronali specifici (ad es. β3-Tubulina, Tau, Neuroglicano C, Sinapsina), suggerendo uno stadio di maturazione più avanzato rispetto ai controlli. Inoltre, abbiamo scoperto che l'oligoGM1 accelera l'espressione del pattern di gangliosidi tipico dei neuroni maturi che è caratterizzato da alti livelli di gangliosidi complessi (cioè GM1, GD1a, GD1b e GT1b) e basso livello del ganglioside più semplice GM3. Per studiare il meccanismo d'azione dell'oligoGM1, abbiamo usato il suo derivato marcato con il trizio e abbiamo scoperto che l'oligoGM1 interagisce con la superficie cellulare senza entrare nelle cellule. Questa scoperta suggerisce la presenza di un bersaglio biologico sulla membrana plasmatica neuronale. È interessante notare che abbiamo riscontrato una precoce attivazione della via di segnalazione del TrkA associata alle MAP chinasi in seguito alla somministrazione dell’oligoGM1 nelle culture neuronali. Questo risultato suggerisce che questo evento rappresenti un punto di partenza degli effetti dell’ oligoGM1 nei neuroni. I nostri dati rivelano che gli effetti del ganglioside GM1 sul differenziamento e la maturazione neuronale sono mediati dalla sua porzione di oligosaccaride. Infatti, l’oligoGM1 interagisce con la superficie cellulare, innescando così l'attivazione di processi biochimici intracellulari che sono responsabili della migrazione neuronale, dell'emissione dei dendriti e della crescita degli assoni. Nel complesso, i nostri risultati sottolineano l'importanza dell’ oligoGM1 come un nuovo e promettente fattore neurotrofico.The GM1 ganglioside is a mono-sialylated glycosphingolipid present in the outer layer of the cell plasma membrane and abundant in neurons. Numerous in vitro and in vivo studies highlight the role of GM1 not only as a structural component but also as a functional regulator. Indeed, GM1 enrichment in membrane microdomains promotes neuronal differentiation and protection, and the GM1 content is essential for neuronal survival and maintenance. Despite many lines of evidence on the GM1-mediated neuronotrophic effects, our knowledge on the underlying mechanism of action is scant. Recently, the oligosaccharide chain of GM1 (oligoGM1) has been identified as responsible for the neuritogenic properties of the GM1 ganglioside in neuroblastoma cells. The oligoGM1-mediated effects depend on its binding to the NGF specific receptor TrkA, thus resulting in the TrkA-MAPK pathway activation. In this context, my PhD work aimed to confirm the role of the oligoGM1, as the bioactive portion of the entire GM1 ganglioside, capable of enhancing the differentiation and maturation processes of mouse cerebellar granule neurons. First, we performed time course morphological analyses on mouse primary neurons plated in the presence or absence of exogenously administered gangliosides GM1 or GD1a (direct GM1 catabolic precursor). We found that both gangliosides increased neuron clustering and arborization, however only oligoGM1 and not oligoGD1a induced the same effects in prompting neuron migration. This result suggests the importance of the specific GM1 saccharide structure in mediating neuronotrophic effects. Then we characterized biochemically the oligoGM1-mediated effect in mouse primary neurons, and we observed a higher phosphorylation rate of FAK and Src proteins which are the intracellular key regulators of neuronal motility. Moreover, in the presence of oligoGM1 cerebellar granule neurons showed increased level of specific neuronal markers (e.g., β3-Tubulin, Tau, Neuroglycan C, Synapsin), suggesting an advanced stage of maturation compared to controls. In addition, we found that the oligoGM1 accelerates the expression of the typical ganglioside pattern of mature neurons which is characterized by high levels of complex gangliosides (i.e., GM1, GD1a, GD1b, and GT1b) and low level of the simplest one, the GM3 ganglioside. To study the mechanism of action of the oligoGM1, we used its tritium labeled derivative and we found that the oligoGM1 interacts with the cell surface without entering the cells. This finding suggests the presence of a biological target at the neuronal plasma membrane. Interestingly, we observed the TrkA-MAP kinase pathway activation as an early event underlying oligoGM1 effects in neurons. Our data reveal that the effects of GM1 ganglioside on neuronal differentiation and maturation are mediated by its oligosaccharide portion. Indeed, oligoGM1 interacts with the cell surface, thus triggering the activation of intracellular biochemical pathways that are responsible for neuronal migration, dendrites emission and axon growth. Overall, our results point out the importance of oligoGM1 as a new promising neurotrophic player.
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Vieira, Diogo Porfirio de Castro. "Análises de estabilidade e de sensibilidade de modelos biologicamente plausíveis do córtex visual primário." Universidade de São Paulo, 2008. http://www.teses.usp.br/teses/disponiveis/59/59135/tde-18032009-163830/.
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A neurociência computacional é uma vasta área que tem como objeto de estudo o entendimento ou a emulação da dinâmica cerebral em diversos níveis. Neste trabalho atenta-se ao estudo da dinâmica de neurônios, os quais, no consenso atual, acredita-se serem as unidades fundamentais do processamento cerebral. A importância do estudo sobre o comportamento de neurônios se encontra na diversidade de propriedades que eles podem apresentar. O estudo se torna mais rico quando há interações de sistemas internos ao neurônio em diferentes escalas de tempo, criando propriedades como adaptação, latência e comportamento em rajada, o que pode acarretar em diferentes papéis que os neurônios podem ter na rede. Nesta dissertação é feita uma análise sob o ponto de vista de sistemas dinâmicos e de análise de sensibilidade de seis modelos ao estilo de Hodgkin-Huxley e compartimentais de neurônios encontrados no córtex visual primário de mamíferos. Esses modelos correspondem a seis classes eletrofisiológicas de neurônios corticais e o estudo feito nesta dissertação oferece uma contribuição ao entendimento dos princípios de sistemas dinâmicos subjacentes a essa classificação.Computational neuroscience is a vast scientific area which has as subject of study the unsderstanding or emulation of brain dynamics at different levels. This work studies the dynamics of neurons, which are believed, according to present consensus, to be the fundamental processing units of the brain. The importance of studying neuronal behavior comes from the diversity of properties they may have. This study becomes richer when there are interactions between distintic neuronal internal systems, in different time scales, creating properties like adaptation, latency and bursting, resulting in different roles that neurons may have in the network. This dissertation contains a study of six reduced compartmental conductance-based models of neurons found in the primary visual cortex of mammals under the dynamical systems and sensitivity analysis viewpoints. These models correspond to six eletrophysiological classes of cortical neurons and this dissertation offers a contribution to the understanding of the dynamical-systems principles underlying such classification.
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Fellows, Matthew R. "Spatiotemporal tuning for position and velocity in primate primary motor cortex neurons /." View online version; access limited to Brown University users, 2005. http://wwwlib.umi.com/dissertations/fullcit/3174598.
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Gaffuri, Anne-Lise. "Drosophila melanogaster, as a model system to study the cell biology of neuronal GPCRs." Thesis, Paris 5, 2012. http://www.theses.fr/2012PA05T063.
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Le récepteur cannabinoique de type 1 (CB1R) est l’un des récepteurs couplés aux protéines G les plus abondants du cerveau mammifère. CB1R a longtemps été décrit comme un récepteur présynaptique régulant de manière rétrograde la transmission synaptique. Cependant, depuis les vingt dernières années, de nouveaux rôles ont été découverts et il est maintenant clairement admis que l’action des endocannabinoides (eCBs) ne se limite pas à la régulationde la neurotransmission au niveau de synapses adultes déjà établies. En effet, les eCBs et le CB1R sont des acteurs majeurs de l’ensemble des phases du développement cérébral. Cependant, les mécanismes moléculaires impliqués n’ont toujours pas été identifiés. Les mécanismes cellulaires auxquels nous nous intéressons ne dépendant pas de l’environnement cellulaire, nous proposons donc de combiner la puissance génétique du modèle drosophile à l’accessibilité et la haute résolution offerte par la culture primaire de neurones. De plus, le récepteur CB1 ne possédant pas d’orthologue parmi les invertébrés, ce système offre la possibilité d’étudier la biologie du récepteur en s’affranchissant de la machinerie endocannabinoide. Cependant, actuellement, aucun protocole de culture primaire de neurones de drosophile ne permet d’obtenir des cellules hautement différenciées et polarisées à basse densité. Ainsi, nous avons tout d’abord développé, optimisé et validé un nouveau protocole permettant de d’obtenir des neurones fonctionnels, hautement différenciés et polarisés en culture de basse densité. Dans un second temps, nous avons démontré que l’activation durécepteur CB1, exprimé ectopiquement dans les neurones de drosophile, entrainait son internalisation, de manière identique à ce qui avait déjà été observé chez les mammifères. Puis, nous avons étudié l’effet de l’expression et de l’activation ectopique de CB1R sur le développement neuronal chez la drosophile. Ainsi, nous avons démontré que l’activation du récepteur module directement la dendritogénèse. Afin de compléter la caractérisation de notremodèle, nous avons démontré que l’activation transitoire du récepteur dans les corps pédonculés (le centre de la mémoire olfactive chez la drosophile) altérait spécifiquement la formation d’une forme consolidée de mémoire après un conditionnement aversif. En conclusion, la validation du modèle drosophile dans l’étude de la biologie cellulaire durécepteur CB1 ouvre de nouvelles perspectives quant à la détermination des mécanismes moléculaires régissant l’action du récepteur sur le fonctionnement neuronalThe type-1 cannabinoid receptor (CB1R), the neuronal receptor for the major psychoactive substance of marijuana, is one, of the most abundant G-protein coupled receptors in the mammalian central nervous system. CB1R is traditionally described as a presynaptic receptor that retrogradely regulates synaptic transmission. In addition to this now relatively wellcharacterized function, in the last two decades it has become widely recognized that endocannabinoid (eCB) actions in the brain are not limited to the regulation of neurotransmission at established adult synapses. Indeed, eCB and CB1R are now recognized to be involved in brain development at the synaptic, neuronal and network levels. However, precise mechanisms underlying these processes remain poorly described. Since cellular mechanisms that mediate CB1R-activition dependent neuronal remodeling and subneuronal targeting have been demonstrated to be cell-autonomous, we aimed to combine the power of Drosophila genetics with the experimental accessibility and single-cell resolution of lowdensity primary neuronal cultures, a tool currently lacking in Drosophila. Moreover, becauseDrosophila does not have a CB1R ortholog, CB1R cell biology may be observed independently from eCB machinery. Thus, we first developed and validated an in vitro culture protocol that yields mature and fully differentiated Drosophila neurons. Secondly, we showed that activation-dependent endocytosis of ectopically expressed CB1R is conserved in Drosophila neurons. Next, we investigated whether ectopic expression and activation of CB1R in Drosophila modulate neuronal development. As observed in mammals, we observed that activation of CB1R impairs dendritogenesis in a cell-autonomous manner. For further characterization of our model, we showed that, as with mammals, transient ectopic CB1R expression and activation in mushroom body neurons (the center of olfactory memory in Drosophila) modulate the formation of a consolidated form of aversive memory. In conclusion, the validation of this new animal model opens new perspectives to better characterize mechanisms underlying modulation of neuronal functions induced by CB1Ractivity
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Sprague, Jared Michael. "TRPV1 Sensitization in Primary Sensory Neurons." Thesis, Harvard University, 2014. http://dissertations.umi.com/gsas.harvard:11441.
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Pain is a major personal and community burden throughout the world with currently limited treatment options for persistent pain due to unacceptable side effects, dependence or frank inefficacy. It is necessary to understand the anatomical and molecular pathways leading to pain to better cope with the current challenge of treating it.
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McCue, Michael Patrick. "Acoustic responses from primary vestibular neurons." Thesis, Massachusetts Institute of Technology, 1993. http://hdl.handle.net/1721.1/17330.
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Thesis (Ph. D.)--Massachusetts Institute of Technology, Whitaker College of Health Sciences and Technology, 1993.Includes bibliographical references (leaves 93-99).
by Michael Patrick McCue.
Ph.D.
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Ruffo, Mark. "The role of the corticothalamic projection in the primate motor thalamus /." Thesis, Connect to this title online; UW restricted, 2007. http://hdl.handle.net/1773/10626.
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Gladwin, Karen M. "Carbon nanotube biocompatibility with primary sensory neurons." Thesis, University of Brighton, 2010. https://research.brighton.ac.uk/en/studentTheses/7de21b7a-9c7c-4367-8e1c-ddbd347fd0c9.
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The repair of peripheral nerve lesions presents a common clinical challenge, with those injured suffering from an array of debilitating symptoms and sensory or motor handicaps. The current method of repairing peripheral nerve lesions involves the use of nerve autografts or artificial nerve repair conduits to bridge the gap between the two ends of the damaged nerve. However, results from the use of these techniques rarely produce full functional recovery. Several studies have shown that carbon nanotubes (CNTs) can be used as a successful substrate for the growth and guidance of neurons. These data suggest CNTs could be used as a neural tissue scaffold that may be incorporated into the lumen of existing nerve repair conduits to enhance axonal guidance at the nanoscale. Despite the substantial interest in the use of CNTs as a biomaterial in neurobiology, very little is understood about the interactions of CNT’s with neurons. The aim of this research project is to 1) provide an assessment of CNT biocompatibility with cells of the peripheral nervous system and 2) assess the ability of a CNT substrate to support neurite outgrowth.
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Genfors, Björn. "siRNA knockdown of Tau kinases in primary neurons." Thesis, KTH, Skolan för bioteknologi (BIO), 2012. http://urn.kb.se/resolve?urn=urn:nbn:se:kth:diva-149472.
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PICCI, CRISTINA. "Exploitation of new pharmacological targets for neuropathic pain reliefe." Doctoral thesis, Università degli Studi di Cagliari, 2015. http://hdl.handle.net/11584/266610.
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Neuropathic pain is a complex chronic condition which affects the somatosensory system, poorly managed with the conventional treatments despite the immense advances in pain treatment strategies. Damage of peripheral nervous system, due to injury or disease, leads to abnormal responses to painful and not-painful stimuli; conventional analgesics can only alleviate pain in acute situation, and finding an effective treatment which can relief chronic neuropathic pain remains still challenging.
Mammalian STOML3, a MEC-2 homologue, is a member of a large family of stomatin proteins characterized by a common stomatin domain, expressed by DRG sensory neurons involved in regulation of mechanosensation, which is required for normal mechanoreceptor function. Previous data revealed that in STOML3 null mice 30-40% of Aδ and Aβ fibers lacked all mechanosensitivity; in addition, tactile behaviors are impaired and symptoms of neuropathic pain in CCI mice are also largely attenuated (Wetzel et al, 2007).
Here I investigated the mechanisms by which STOML3 acts as an important contributor in the neuropathic pain symptoms and I demonstrate that small molecule modulation that both reversibly silence mechanoreceptors in vivo and attenuate touch perception in mice can reverse established neuropathic pain symptoms, making STOML3 a promising novel peripheral target for the treatment of sensory disorders.
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Karchewski, Laurie Ann. "Neurotrophins and neurotrophin receptors in adult primary sensory neurons." Thesis, National Library of Canada = Bibliothèque nationale du Canada, 2000. http://www.collectionscanada.ca/obj/s4/f2/dsk1/tape2/PQDD_0034/NQ63884.pdf.
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Anand, Uma. "Target derived influences on primary afferent neurons in rats." Thesis, King's College London (University of London), 1993. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.283305.
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Yao, Dongyuan. "Properties of neurons in primate face motor cortex in relation to orofacial movements and influence of face primary somatosensory cortex." Thesis, National Library of Canada = Bibliothèque nationale du Canada, 2000. http://www.collectionscanada.ca/obj/s4/f2/dsk1/tape2/PQDD_0022/NQ49871.pdf.
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Bains, Mona. "Estrogen-mediated neuroprotection of primary mesencephalic dopamine neurons : a dissertation /." San Antonio : UTHSC, 2007. http://proquest.umi.com/pqdweb?did=1320942841&sid=1&Fmt=2&clientId=70986&RQT=309&VName=PQD.
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Kiasalary, Reineh Zahra. "Anatomical and functional studies on TRPV1- expressing primary sensory neurons." Thesis, Queen Mary, University of London, 2005. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.420426.
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Fan, Guoping. "Developmental regulation of catecholaminergic phenotypic expression in primary sensory neurons." Case Western Reserve University School of Graduate Studies / OhioLINK, 1995. http://rave.ohiolink.edu/etdc/view?acc_num=case1062509030.
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Barrantes, Georgina Elida. "Nicotinic acetylcholine receptor subtypes in primary cultures of hippocampal neurons." Thesis, University of Bath, 1994. https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.386845.
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Fotheringhame, David K. "Temporal coding in primary visual cortex." Thesis, University of Oxford, 1997. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.339357.
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Ming, Yu. "Regulation of neurotrophic signaling molecules in motor neurons, primary sensory neurons and target tissues in senescence /." Stockholm, 2003. http://diss.kib.ki.se/2003/91-7349-591-3.
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Pejović, Vojislav. "Glutamate induced potentiation of calcium influx in primary hippocampal culture neurons." [S.l.] : [s.n.], 2001. http://ArchiMeD.uni-mainz.de/pub/2001/0027/diss.pdf.
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Enes, Joana. "Electrical activity suppresses intrinsic growth competence in adult primary sensory neurons." Diss., lmu, 2009. http://nbn-resolving.de/urn:nbn:de:bvb:19-100706.
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劉智輝 and Chi-fai Lau. "Investigation of neuroprotective effects of testosterone in primary cultured hippocampal neurons." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2012. http://hub.hku.hk/bib/B48334042.
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Synaptic dysfunction is a critical neuropathological feature prior to the formation of extracellular senile plaques and intracellular fibrillary tangles (NFTs) in Alzheimer’s disease (AD). The synapse loss and neurites impairment lead to synaptic dysfunction that can be induced by oligomeric Aβ. The administration of oligomeric Aβ reduced the pre-synaptic vesicle proteins and altered the cytoskeletal proteins. The synaptic vesicles (SVs) playing a crucial role to transport and recycle the SV proteins and neurotransmitters (NTs) in synaptic terminals. However, the uptake and release capabilities of SVs were also disrupted by oligomeric Aβ. The disruption of SVs recycling and neurites impairment attenuate neurotransmission that exacerbates the pathogenesis of AD. Therefore, any agents can maintain the SVs recycling and protect the neurites development that could be a therapeutic target for AD.
Testosterone is a male sex steroid hormone, which is a potent therapeutic drug for neurodegenerative diseases. It has been found the neuroprotective effects for neuronal death, but the implication on synaptoprotection is still not clear. This study investigated the neuroprotective effects of testosterone from oligomeric Aβ-induced synaptic dysfunction in primary cultured hippocampal neurons. My study demonstrated that testosterone prevented Aβ-induced reduction of pre-synaptic proteins and shortening neurites. Also, testosterone could protect SVs recycling by increasing SVs unloading capability via estrogenic independent pathway. The findings reinforce the neuroprotective effects of testosterone. They are probably facilitating future development for using the concept of male sex hormone as therapy and the intervention of therapeutic drugs for AD patients.published_or_final_version
Anatomy
Master
Master of Medical Sciences
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Abou-Sherif, Sherif Saad Mohamed. "Morphological effects of radiofrequency (pulsed and continuous) on primary afferent neurons." Thesis, King's College London (University of London), 2003. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.416619.
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Smrt, Richard D., Sara A. Lewis, Robert Kraft, and Linda L. Restifo. "Primary culture of Drosophila larval neurons with morphological analysis using NeuronMetrics." University of Oklahoma, 2015. http://hdl.handle.net/10150/604939.
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Coggan, Jay Steven. "Electrophysiological and muscarinic properties of celiac ganglion neurons in primary culture." Diss., The University of Arizona, 1992. http://hdl.handle.net/10150/186062.
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This dissertation comprises studies of the responsiveness to cholinergic agonists and the electrical membrane properties of neurons of the prevertebral, sympathetic, celiac ganglion of the guinea pig in primary culture. More specifically, the major content of this work is the investigation of the mechanisms of slow cholinergic or muscarinic excitation in these cells. The primary mechanisms of muscarinic responses in these cells resulted from the inhibition of two potassium currents: the M-current and a muscarine-sensitive leak-current. During intracellular current-clamp recording, cells were assessed for their passive and active membrane properties including: resting potential, time constant, input resistance, rheobase, spike amplitude, afterhyperpolarization amplitude and duration, and degree of accommodation. These cells responded to acetylcholine with both fast nicotinic and slow muscarinic depolarizations. The results indicated that celiac neurons in primary culture retain certain electrophysiological properties similar to those in intact ganglia, and produce varied responses to cholinergic stimulation. Responses to muscarine were studied in the dissociated neurons using the whole-cell voltage-clamp technique. Muscarine, administered to cells for 1.5 seconds, evoked inward shifts in holding current which were concentration-dependent. The amplitude of the inward current transients decreased with hyperpolarization toward the equilibrium potential for potassium, where the null or reversal potential was reached. Evidence for the presence of the M-potassium current was obtained in eighty percent of the neurons. Further investigation, however, revealed that these cells exhibit two ubiquitous and independent mechanisms of muscarinic excitation. These two mechanisms were the inhibition of two potassium currents: the M-current and a muscarine-sensitive leakage current. These currents could be expressed together in the same neuron or separately. The cation potassium channel blockers, cesium and barium, had dissimilar effects on these currents. While barium effectively blocked both types of potassium channels equally, cesium preferentially blocked M-current. Thus, cesium was able to differentiate between the two currents.
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Wang, H. Fredrik. "Neuronal tracers for fine caliber spinal primary afferents and their response to peripheral nerve injury /." Stockholm, 1998. http://diss.kib.ki.se/1998/91-628-3199-2/.
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DiLorenzo, Daniel John. "Neural correlates of motor performance in primary motor cortex." Thesis, Massachusetts Institute of Technology, 1999. http://hdl.handle.net/1721.1/9089.
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Thesis (Ph.D.)--Massachusetts Institute of Technology, Dept. of Mechanical Engineering, 1999.Includes bibliographical references (leaves 101-103).
Prior experiments have characterized the behavior of cells in the primary motor cortex that correlate with movement of the upper limb. The patterns of behavior of cells before, during, and after the application of an external forcefield to the hand of a primate performing a motor reaching task have been described. In these forcefields, forces that are proportional in magnitude and perpendicular in direction to the velocity of the hand are generated, resulting in disturbances in the motor trajectory. This research explored the motor disturbances and their neural correlates during an interference task in which a sequence of forcefields of opposite polarity were applied. The goals of the present research were to characterize the motor performance and neural correlates in a task that requires the sequential recall and utilization of previously learned motor memories for performing opposing tasks. Recent research has demonstrated that opposing tasks performed in close temporal proximity interfere with motor learning. This research aims to explore degradation in motor performance occurring when a series of previously learned motor tasks are performed in sequence, as evidence that interference occurs between temporally spaced motor memories. In addition, identification of neural correlates of this interference phenomenon are sough:. specifically performance of the recently described memory cell. Furthermore. in responding to forcefield-induced perturbations, motor performance was found to be substantially degraded during an early "transient" phase. with resumption of relatively improved levels of performance during subsequent steady-state phases. The neural behavior during these transient and steady-state phases was analyzed to glean some insight into the neural correlates of feedback control. In this task, single-cell activity from primary motor cortex was recorded while a primate performed a motor reaching task through a 7-stage session. This 7-stage task involves the application of 3 forcefields of alternating polarity, with the first and third being identical and the second or interference forcefield of opposite polarity. with four null field stages interposed between forcefields. Motor performance was markedly degraded in the interference forcefield. particularly during a transient phase immediately following the onset of the interference forcefield. Within each of the forcefields. the most marked degradation in motor performance was found to occur during a transient phase following the onset of the forcefield. Neural behavior was analyzed during time periods corresponding to the transient and steady-state phases of motor performance in each stage. Discovery of a subtle neural response in the transient phase led to the definition of a new metric, termed sharpness of tuning. which was used in the characterization of neural behavior in the current experimental paradigm. Distinct differences in patterns of neural firing rate and sharpness of tuning between the transient and steady-state phases were identified. and their implications on the neural correlates of motor control are discussed.
Daniel John DiLorenzo.
Ph.D.
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Souopgui, Jacob. "Identification and functional characterization of novel genes involved in primary neurogenesis in Xenopus laevis." Doctoral thesis, [S.l.] : [s.n.], 2002. http://deposit.ddb.de/cgi-bin/dokserv?idn=96525710X.
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Stumpf, Erika. "Neurons in cat primary auditory cortex sensitive to correlates of auditory motion in three-dimensional space." Thesis, University of British Columbia, 1990. http://hdl.handle.net/2429/29640.
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The primary auditory cortex (area AI) plays an important role in the localization of static sound sources. However, little is known concerning how it processes information about sound source motion. This study was undertaken to investigate the responses of single neurons in the primary auditory cortex of the cat to correlates of auditory motion in space. Diotic and dichotic changes in sound intensity presented through earphones simulated auditory motion in four directions: toward and away from the receiver along the midline, into the ipsilateral hemifield and into the contralateral hemifield. Different rates of intensity change simulated sound source velocity. Results indicate that AI neurons can be highly selective to intensity correlates of auditory motion. Three major classes of neurons were encountered: neurons sensitive to motion toward or away from the receiver, neurons sensitive to ipsilateral- or contralateral-directed motion, and monaural-like neurons. The different classes of direction-selective neurons were spatially segregated from each other and appeared to occur in clusters or columns in the cortex. In addition to their selectivity for different directions of simulated sound source motion, AI neurons also responded selectively to the rate and excursion of intensity changes, a correlate of sound source velocity. The major determinants of direction and velocity selectivity were interactions between the following response properties of AI neurons: binaural interaction type, ear dominance, on/off responses, and monotonicity of rate/intensity function. These findings suggest that neural processing of auditory motion may involve neural mechanisms distinct from those involved in static sound localization, and indicate that some neurons in the primary auditory cortex may be part of a specialized motion-detecting mechanism in the auditory system.Arts, Faculty of
Psychology, Department of
Graduate
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Bongenhielm, Ulf. "Structure and function of trigeminal primary sensory neurons after peripheral nerve injury /." Stockholm, 1999. http://diss.kib.ki.se/1999/91-628-3954-3/.
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Vastani, N. "Mechanisms of thermal sensitivity in rodent primary afferent neurons innervating the skin." Thesis, University College London (University of London), 2009. http://discovery.ucl.ac.uk/15289/.
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The role of temperature sensations elicited from the skin, include object identification, thermoregulation and the conscious perception of pain. Humans can differentiate at least three distinct cold sensations: innocuous cooling, cold pain and pain evoked by freezing. However, patients with painful neuropathies often suffer from cold allodynia, where normally non-painful cool stimuli begin to induce pain or cold hyperalgesia, a heightened sensitivity to a painful cold stimulus. It is therefore vital to understand the mechanisms by which cold is signalled under normal conditions and to investigate which changes occur under pathological conditions. The thesis will describe sets of electrophysiological recordings carried out from rodent primary afferent neurons using the in vitro skin nerve preparation in an attempt to reveal mechanisms underlying thermal sensitivity. The discovery of thermally sensitive transient receptor potential (TRP) ion channels has given insights into the molecular mechanisms of thermal transduction. These include the heat sensitive TRPV1 ion channel and cold sensitive TRPM8 and TRPA1 ion channels. However, the role of the TRPA1 receptor in cold transduction remains controversial. Cold sensitivity of primary afferents in adult rat was studied. Selective TRP channel agonists capsaicin, menthol, and mustard oil were then applied onto the receptive field of primary afferents to determine the expression pattern of thermosensitive TRP channels. The majority of cold sensitive A and C fibre nociceptors as well as thermoreceptors were sensitive to menthol, indicating that TRPM8 is the transducer of cold on these afferents. The poor correlation of TRPA1 expression and cold sensitivity in nociceptive A and C fibres indicates that TRPA1 is unlikely to play a significant role is detecting noxious cold. TRPV2 is another heat activated ion channel. The sensory phenotype of TRPV2 knock-out mice was studied and compared against TRPV2 wild-type mice in both hairy and glabrous skin. Mice lacking TRPV2 had normal heat sensitive nociceptors and afferents retained mechanical sensitivity. The involvement of potassium (K+) channels in mediating and/or modulating thermosensation has been suggested. Based on these previous findings, the effects of the broad spectrum potassium channel blockers 4-aminopyridine (4- AP) and Tetraethylammonium (TEA) were studied on primary afferents neurons. Application of 4-AP or TEA directly on the receptive fields induced a novel cold sensitivity in a proportion of low threshold mechanoreceptors and increased the cold responses in a proportion of cold sensitive A and C fibre nociceptors. Interestingly 4-AP or TEA had no effect on the cold responses of innocuous cold thermoreceptors. Drug induced cold sensitivity was investigated using the chemotherapeutic agent oxaliplatin, which induces a sensory neuropathy in patients. Following infusion of the drug, patients experience abnormal skin sensations (paresthesias), which are triggered or aggravated by exposures to cold. The receptive properties of afferents were investigated before and after oxaliplatin application to provide an insight into the mechanism by which this abnormal cold sensitivity develops. This study shows for the first time, that oxaliplatin applied directly on the receptive fields induces a novel cold sensitivity in half of previously cold insensitive Aβ mechanoreceptors. Just over a third of Aδ nociceptors also displayed a novel or increased sensitivity to cold after oxaliplatin application. In contrast, receptive properties of C fibres remained unchanged. Overall, the results of the thesis provide evidence that TRPM8 is involved in the transduction of cold stimuli and that potassium and sodium conductances are involved in modulating the final response to a cold stimulus.
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de, Sousa Valente Joao Manuel. "Role of the cannabinoid system in nociceptive processing in primary sensory neurons." Thesis, Imperial College London, 2014. http://hdl.handle.net/10044/1/45542.
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The endogenous ligand N-arachydonoylethanolamine (anandamide) is an important modulator of nociceptive processing in primary sensory neurons (PSN), because it activates both the excitatory transient receptor potential vanilloid type 1 ion channel (TRPV1) and the inhibitory cannabinoid type-1 (CB1) receptor, which are co-expressed in PSN and plays a pivotal role in the development and maintenance of pain associated with peripheral pathologies. However, the mechanisms involved in the anandamide-mediated modulation of nociceptive processing in PSN are not well understood. Here, we studied some important aspects of anandamide-mediated signaling in PSN. We found that multiple anandamide-synthesising pathways are present in PSN. The only Ca2+-sensitive anandamide-synthesising enzyme, Nacylphosphatidylethanolamine phospholipase D (NAPE-PLD), exhibits a high degree of co-expression with TRPV1, the CB1 receptor and the main anandamide-hydrolysing enzyme, fatty acid amid hydrolase. Spinal nerve injury, but not inflammation significantly alters this expression pattern. Although, the excitatory effect of anandamide is mediated by TRPV1 in PSN, not all TRPV1- expressing cells respond to anandamide. Blocking or deleting the CB1 receptor significantly reduces anandamide responsiveness of TRPV1, and PSN either express TRPV1 and the CB1 receptor in segregation or in close association. Cultured spinal microglia, in addition to PSN, also synthesise anandamide and that synthesis may depend on the activation state of spinal microglia and involve the activity of phosphatidylinositol-3,4,5-trisphosphate 5-phosphatase 1 (Inpp5). 3 Our findings support the view that anandamide-mediated signalling may occur through autocrine mechanisms in PSN, and indicate that nerve injury may induce deregulation of that signalling which may contribute to the development of neuropathic pain. However, paracrine mechanisms, for example through anandamide synthesis in spinal microglia may also contribute to anandamide-mediated signalling, which is shaped, among others, by a complex crosstalk between the CB1 receptor and TRPV1. Finally, our findings suggest that NAPE-PLD and Inpp5 might be targets for future analgesics.
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Martin-Biran, Magali. "Etude par spectroscopie de RMN du métabolisme des neurones et des astrocytes en culture primaire." Bordeaux 2, 1994. http://www.theses.fr/1994BOR28314.
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Dans la perspective de mieux comprendre les phénomènes de compartimentation cellulaire au sein du système nerveux central, nous avons choisi de définir les caractéristiques métaboliques des neurones et des astrocytes en culture primaire homogène. Le devenir métabolique du [1-13C]glucose dans les neurones et les astrocytes cérébelleux, de même que dans les astrocytes corticaux, a été caractérisé par spectroscopie de RMN. Les astrocytes, contrairement aux neurones, synthétisent la glutamine. La maturation des voies de biosynthèse de cet acide aminé est retardée dans les astrocytes cérébelleux par rapport aux astrocytes corticaux. La quantification des flux du catabolisme du glucose exogène a été réalisée. Ces résultats ont montré l'utilisation quasi-exclusive du glucose comme source de carbone par les neurones, alors que les astrocytes utilisent des sources plus diversifiées (glucose, acides aminés exogènes, sources endogènes de carbone). De même, l'activité de la voie de la pyruvate carboxylase est de faible importance dans les neurones, ce qui implique la nécessité d'un apport de carbone extérieur pour ces cellules. Cette étude nous a permis de mettre en évidence des composés synthétisés et libérés par les astrocytes dans le milieu extracellulaire, l'alanine et le citrate, susceptibles de servir de navettes de carbone et/ou d'azote, autres que la glutamine, entre les neurones et les astrocytes. Les données acquises par RMN du 31P ont révélé des charges énergétiques très similaires dans les neurones et les astrocytes cérébelleux, de même que dans le cervelet entier. Des différences concernant les composés liés au métabolisme des membranes ont pu être observées. Une étude du développement du cervelet de rat a été réalisée par RMN du 31P et du 1H, démontrant l'existence d'un contenu élevé en acétate dans le cervelet à la naissance. Celui-ci décroît lors des 1ers jours postnataux, alors que la concentration en NAA augmenteIn order to investigate the cellular compartmentation of the central nervous system, we first defined the metabolic properties of neurons and astrocytes in homogenous primary culture. The metabolic fate of [1-13C]glucose in cerebellar neurons and astrocytes, as well as in cortical astrocytes, was characterized by NMR spectroscopy. The astrocytes, contrary to neurons, synthesized glutamine. The maturation of the glutamine synthesis pathway was delayed in cerebellar astrocytes, as compared to cortical astrocytes. The fluxes involved in exogenous glucose utilization were quantified. The results demonstrated that if neurons used exclusively glucose as carbon source to fuel the Krebs cycle, the carbon sources for astrocytes were diversified (glucose, exogenous amino acids, endogenous carbon sources). In the same way, the pyruvate carboxylase activity was of minor importance in neurons, that implied the need for these cells of exogenous carbon substrates. We evidenced that alanine and citrate were also synthesized by astrocytes and exported to their extracellular medium. These metabolites may play a role as carbon and/or nitrogen shuttles betwen neurons and astrocytes. 31P NMR data showed similar energy charges in cerebellar neurons, astrocytes and in the cerebellum. Differences in the content of metabolites linked to membrane metabolism were observed. The postnatal development of the cerebellum was studied using 31P and 1H NMR spectroscopy. A large content of acetate was evidenced at birth, that decreased during the first postnatal days whereas the NAA content increased
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Dylda, Evelyn. "Neuronal circuits of experience-dependent plasticity in the primary visual cortex." Thesis, University of Edinburgh, 2018. http://hdl.handle.net/1842/31234.
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Our ability to learn relies on the potential of neuronal networks to change through experience. The primary visual cortex (V1) has become a popular system for studying how experience shapes cortical neuronal networks. Experience-dependent plasticity in V1 has been extensively studied in young animals, revealing that experiences in early postnatal life substantially shape neuronal activity in the developing cortex. In contrast, less is known about how experiences modify the representation of visual stimuli in the adult brain. In addition, adult experience-dependent plasticity remains largely unexplored in neurodevelopmental disorders. To address this issue, we established a two-photon calcium imaging set-up, suitable for chronic imaging of neuronal activity in awake-behaving mice. We implemented protocols for the reliable expression of genetically encoded calcium indicators (GCaMP6), for the implantation of a chronic cranial window and for the analysis of chronic calcium imaging data. This approach enables us to monitor the activity of hundreds of neurons across days, and up to 4-5 weeks. We used this technique to determine whether the daily exposure to high-contrast gratings would induce experience-dependent changes in V1 neuronal activity. We monitored the activity of putative excitatory neurons and of three non-overlapping populations of inhibitory interneurons in layer 2/3 of adult mice freely running on a cylindrical treadmill. We compared the results obtained from mice that were exposed daily to either a high-contrast grating or to a grey screen and characterized their neuronal response properties. Our results did not reveal significant differences in neuronal properties between these two groups, suggesting a lack of stimulus-specific plasticity in our experimental conditions. However, we did observe and characterize, in both groups, a wide range of activity changes in individual cells over time. We finally applied the same method to investigate impairments in experience-dependent plasticity in a mouse model of intellectual disability (ID), caused by synaptic GTPase-activating protein (SynGAP) haploinsufficiency. SynGAP haploinsufficiency is a common de novo genetic cause of non-syndromic ID and is considered a Type1 risk for autism spectrum disorders. While the impact of Syngap gene mutations has been thoroughly studied at the molecular and cellular levels, neuronal network deficits in vivo remain largely unexplored. In this study, we compared in vivo neuronal activity before and after monocular deprivation in adult mutant mice and littermate controls. These results revealed differences in baseline network activity between both experimental groups. These impairments in cortical neuronal network activity may underlie sensory and cognitive deficits in patients with Syngap gene mutations.
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Tomba, Caterina. "Primary brain cells in in vitro controlled microenvironments : single cell behaviors for collective functions." Thesis, Grenoble, 2014. http://www.theses.fr/2014GRENY039/document.
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Du fait de sa complexité, le fonctionnement du cerveau est exploré par des méthodes très diverses, telles que la neurophysiologie et les neurosciences cognitives, et à des échelles variées, allant de l'observation de l'organe dans son ensemble jusqu'aux molécules impliquées dans les processus biologiques. Ici, nous proposons une étude à l'échelle cellulaire qui s'intéresse à deux briques élémentaires du cerveau : les neurones et les cellules gliales. L'approche choisie est la biophysique, de part les outils utilisés et les questions abordées sous l'angle de la physique. L'originalité de ce travail est d'utiliser des cellules primaires du cerveau dans un souci de proximité avec l'in vivo, au sein de systèmes in vitro dont la structure chimique et physique est contrôlé à l'échelle micrométrique. Utilisant les outils de la microélectronique pour un contrôle robuste des paramètres physico-chimiques de l'environnement cellulaire, ce travail s'intéresse à deux aspects de la biologie du cerveau : la polarisation neuronale, et la sensibilité des cellules gliales aux propriétés mécaniques de leur environnement. A noter que ces deux questions sont étroitement imbriquées lors de la réparation d'une lésion. La première est cruciale pour la directionalité de la transmission de signaux électriques et chimiques et se traduit par une rupture de symétrie dans la morphologie du neurone. La seconde intervient dans les mécanismes de recolonisation des lésions, dont les propriétés mécaniques sont altérées., Les études quantitatives menées au cours de cette thèse portent essentiellement sur la phénoménologie de la croissance de ces deux types de cellules et leur réponse à des contraintes géométriques ou mécaniques. L'objectif in fine est d'élucider quelques mécanismes moléculaires associés aux modifications de la structure cellulaire et donc du cytosquelette. Un des résultats significatifs de ce travail est le contrôle de la polarisation neuronale par le simple contrôle de la morphologie cellulaire. Ce résultat ouvre la possibilité de développer des architectures neuronales contrôlées in vitro à l'échelle de la cellule individuelleThe complex structure of the brain is explored by various methods, such as neurophysiology and cognitive neuroscience. This exploration occurs at different scales, from the observation of this organ as a whole entity to molecules involved in biological processes. Here, we propose a study at the cellular scale that focuses on two building elements of brain: neurons and glial cells. Our approach reachs biophysics field for two main reasons: tools that are used and the physical approach to the issues. The originality of our work is to keep close to the in vivo by using primary brain cells in in vitro systems, where chemical and physical environments are controled at micrometric scale. Microelectronic tools are employed to provide a reliable control of the physical and chemical cellular environment. This work focuses on two aspects of brain cell biology: neuronal polarization and glial cell sensitivity to mechanical properties of their environment. As an example, these two issues are involved in injured brains. The first is crucial for the directionality of the transmission of electrical and chemical signals and is associated to a break of symmetry in neuron morphology. The second occurs in recolonization mechanisms of lesions, whose mechanical properties are impaired. During this thesis, quantitative studies are performed on these two cell types, focusing on their growth and their response to geometrical and mechanical constraints. The final aim is to elucidate some molecular mechanisms underlying changes of the cellular structure, and therefore of the cytoskeleton. A significant outcome of this work is the control of the neuronal polarization by a simple control of cell morphology. This result opens the possibility to develop controlled neural architectures in vitro with a single cell precision
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Pruski, Michal. "ARL13B and IFT172 truncated primary cilia and misplaced cells." Thesis, University of Aberdeen, 2017. http://digitool.abdn.ac.uk:80/webclient/DeliveryManager?pid=231675.
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Primary cilia are cellular organelles that protrude into the extracellular space, acting as antennas. They detect a wide range of chemical cues, including SHH and PDGF, as well as fluid flow, and they modulate downstream signalling systems, such as WNT and ERK. Due to this cue-sensing ability and the close association of the primary cilium with the centrosome the organelle is able to influence both cell cycle progression and cell migration. This work investigated the effect of mutations on two genes associated with primary cilia: Arl13b and Ift172. The effects of the HNN genotype of Arl13b and the WIM genotype of Ift172 on cell migration were assessed uniquely within the context of direct current electric fields. Both cell lines showed a decreased migratory response when compared to WT cells, despite no clear involvement of cilia in sensing the direction of the electric field. This corroborated with previous data of in vivo Arl13b cellular migration. Through the use of in utero electroporation the migratory deficits of IFT172 knock down were then confirmed in vivo in the developing mouse neocortex. Further in vitro investigation revealed a slower proliferation rate of HNN and WIM cells, though this was not confirmed in vivo after IFT172 knock down using a standard BrDU protocol. Nevertheless, further in vitro investigations revealed a wide variety of cell cycle and intracellular changes within both cell lines. The commonalities included lower numbers of cells in the S-phase and lower MAPK3 phosphorylation compared to WT, and differences such as GSK3β phosphorylation on Ser9. This work showed for the first time that ciliopathies affect galvanotaxis, and revealed fundamental commonalities in cell migration and proliferation between various ciliary mutations, as well as differences in specific signalling pathways. This will hopefully aid in developing future therapeutic interventions for ciliary diseases.
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Amaral, Ana Isabel Porém. "Metabolic flux analysis of neural cell metabolism in primary cultures." Doctoral thesis, Universidade Nova de Lisboa. Instituto de Tecnologia Química e Biológica, 2011. http://hdl.handle.net/10362/6849.
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Dissertation presented to obtain the Ph.D degree in Biochemistry, NeuroscienceBrain energy metabolism results from a complex group of pathways and trafficking mechanisms between all cellular components in the brain, and importantly provides the energy for sustaining most brain functions. In recent decades, 13C nuclear magnetic resonance (NMR) spectroscopy and metabolic modelling tools allowed quantifying the main cerebral metabolic fluxes in vitro and in vivo. These investigations contributed significantly to elucidate neuro-glial metabolic interactions, cerebral metabolic compartmentation and the individual contribution of neurons and astrocytes to brain energetics. However, many issues in this field remain unclear and/or under debate.
To the financial support provided by Fundação para a Ciência a Tecnologia (SFRH/BD/29666/2006; PTDC/BIO/69407/2006) and to the Clinigene – NoE (LSHBCT2006- 010933). I further acknowledge the Norwegian Research Council for a fellowship that allowed me to perform part of my PhD work at NTNU, Norway.
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Schock, Elizabeth N. B. S. "The Role of Primary Cilia in Neural Crest Cell Development." University of Cincinnati / OhioLINK, 2017. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1504800027927076.
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Moore, Daniel John. "Identification and characterisation of conserved ciliary genes expressed in Drosophila sensory neurons." Thesis, University of Edinburgh, 2014. http://hdl.handle.net/1842/17918.
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Drosophila provide an excellent model organism in which to study cilia as there are only two ciliated cell types; the sensory neurons and sperm cells. The chordotonal neuron is one such ciliated cell and is required for hearing, proprioception and gravitaxis. Mechanical manipulation of the cilium that extends from the neuronal dendrite is required for signal transduction. Chordotonal neuronal differentiation is regulated by a transcription factor cascade. Atonal begins the cascade, which is then continued by RFX and Fd3F for ciliary genes (Cachero et al 2011, Newton et al 2012). Genes expressed in developing chordotonal neurons are downstream of these transcription factors and their characterisation can further elucidate how neuronal differentiation is regulated. Ciliary genes are highly enriched in developing chordotonal cells; uncharacterised genes enriched in these cells can therefore be considered candidate ciliary genes (Cachero et al 2011). A behavioural assay was conducted to identify further genes that could have a role in ciliary formation and function. Candidate genes were identified by combining enrichment data with previous genomic, proteomic and transcriptomic studies of cilia. A climbing assay of RNAi mediated knock down of these genes identified a number of candidates for future work. One gene found to be highly enriched in developing chordotonal neurons is CG11253. CG11253EY10866 P element insertion mutant flies show a mild uncoordinated phenotype in a climbing assay consistent with reduced chordotonal organ function. Male flies are also infertile due to a lack of motile sperm. CG11253 is expressed in motile ciliated cells and is conserved in organisms with motile cilia. CG11253 expression is also regulated by RFX and Fd3F, suggesting that it is involved in cilium motility. This was confirmed by electron microscopy, which showed disruption of axonemal dynein arm localisation in chordotonal cilia and sperm flagella. A CG11253::mVenus fusion protein was found to localise mainly to the cytoplasm and to a lesser extent the cilia of chordotonal neurons. Patients with symptoms consistent with Primary Ciliary Dyskinesia (PCD), a condition caused by cilium immotility, have subsequently been found to have point mutations in ZMYND10, the human homologue of CG11253. The identification of PCD patients with ZMYND10 mutations showed that investigating cilium motility in Drosophila chordotonal neurons could identify novel PCD genes. It was thought that investigating previously uncharacterised targets of Fd3F could identify novel genes involved in cilium motility and thus candidate PCD genes. CG31320 is a gene regulated by RFX and Fd3F and conserved in organisms with motile cilia. RNAi mediated knock down of CG31320 resulted in both a mild uncoordinated phenotype and male infertility due to a lack of motile sperm. Electron microscopy showed a complete loss of axonemal dynein arms in chordotonal neuron cilia. An mVenus fusion protein of CG6971, an inner dynein arm component, was also mislocalised from the cilia in CG3132027 deletion mutant larvae. This shows that CG31320 is required for the appropriate localisation of the axonemal dynein arms and thus cilium motility. This further showed that uncharacterised genes enriched in chordotonal neurons and regulated by Fd3F could be novel ciliary genes required for cilium motility. Our collaborators and Horani et al (2012) showed that the human homologue of CG31320 (HEATR2) is mutated in patients with PCD, further confirming that this method can be used to identify PCD genes. I have identified two factors required for cilium motility. Disruption of the axonemal dynein arms in both cases results in reduced coordination, and lack of fertility due to sperm immotility. Mutations in the human homologues of these genes have been found to result in PCD. This indicates that further PCD genes could be identified from genes enriched in Drosophila chordotonal neurons that are regulated by Fd3F.
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Dingwall, Riki. "Characterization of two ASD-associated genes in primary hippocampal neurons : SEMA5A and PTEN." Thesis, University of British Columbia, 2017. http://hdl.handle.net/2429/62435.
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Lu, Xin 1950. "Responses and functions of macrophages in injury and regeneration of primary sensory neurons." Thesis, McGill University, 1994. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=41694.
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Peripheral nerve injury (conditioning lesions) can cause unknown changes in the nerve cell body that enhance axonal regeneration (Richardson & Issa, 1986; Richardson & Verge, 1987). This thesis further investigated the signals that cause changes in nerve cell bodies which are favourable to axonal regeneration. When inflammatory reaction was induced in the lumbar dorsal root ganglion by injection of Corynebacterium-parvum, axons in the crushed dorsal root were stimulated to regenerate just as by sciatic nerve transection. The numbers of macrophages in lumbar dorsal root ganglion increased 4 days after sciatic nerve transection and this increase lasted at least for a month. mRNAs for the regeneration-associated molecules GAP-43 and C-jun are increased after injection of Corynebacterium-parvum into lumbar dorsal root ganglion as after sciatic nerve transection.These studies indicate that the signals from inflammatory cells can contribute to axonal regeneration and that macrophages are in position to influence cell bodies when their axons are regenerating.
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Coiro, Pierluca [Verfasser]. "Plasticity-related gene 5 induces spine formation in immature primary neurons / Pierluca Coiro." Berlin : Freie Universität Berlin, 2011. http://d-nb.info/1025355571/34.
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Gibb, Stuart Lee. "Mechanism of survival subversion in primary neurotrophin-dependent neurons by the cytokine CNTF." Thesis, University of Cambridge, 2003. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.619932.
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Lawler, Polly Anne. "Neurotrophic factor regulation of gene expression in primary sensory neurons of the mouse." Thesis, Cardiff University, 2007. http://orca.cf.ac.uk/56171/.
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In this study, the expression of several sensory neuron specific/predominant genes, and the effects of neurotrophic factors upon them were studied in embryonic, postnatal and adult mouse sensory neurons. In the embryonic mouse, NGF/TrkA signalling was shown to be essential for the expression of mRNAs encoding substance P and the sodium channels Navl.8 and Navl.9 in DRG and trigeminal ganglia. Differential regulation of the two isoforms of calcitonin gene related peptide (CGRP) mRNA was apparent in the DRG with a requirement of NGF/TrkA signalling for expression of a, but not p CGRP. This was not reflected in the trigeminal ganglia. Postnatally, experiments revealed that NGF/TrkA signalling within the DRG and trigeminal ganglia is 1) essential for expression of SP, ocCGRP, pCGRP, Navl.8, Navl.9 mRNAs, 2) possibly required for expression of the neuropeptide galanin and the capsaicin receptor vanilloid receptor 1 (VR1) mRNAs, 3) not required for pituitary adenylate cyclase-activating peptide (PACAP) mRNA. Conversely, within the nodose ganglia, expression of Navl .8 and Navl .9 mRNAs did not require NGF/TrkA signalling. No regulation of all aforementioned genes by neurotrophin-3 (NT-3) was observed in trigeminal, nodose or dorsal root ganglia. In the adult mouse, DRG cultures were utilised to study gene regulation by the neurotrophic factors NGF, artemin and macrophage stimulating protein (MSP). Expression of SP, aCGRP, pCGRP, Navl.8, Navl.9 and VR1 mRNAs all showed a decrease following 96 hours in culture that was inhibited by presence of MSP (50ng/ml), NGF (lOng/ml) or artemin (lOng/ml). PACAP, galanin, damage induced neuronal endopeptidase (DINE) and activating transcription factor 3 (ATF3) mRNAs increased over time, but neurotrophic factors could impede such increases. No axotomy or neurotrophic factor-induced effects were observed for P2X3, Navl.6 or Navl.7 mRNAs. Interestingly the additional presence of leukaemia inhibitory factor (LIF) opposed NGF, MSP and artemin-induced effects on PCGRP, SP, VR1 and galanin mRNAs, whilst enhancing effects on PACAP and DINE transcripts.
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Wang, Liping. "Regulation of GABA(A) receptor function by hypoxia in rat primary cortical neurons." University of Toledo Health Science Campus / OhioLINK, 2009. http://rave.ohiolink.edu/etdc/view?acc_num=mco1251386977.
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Wang, Liping. "Regulation of GABA [subscript] A receptors by hypoxia in rat primary cortical neurons." Toledo, Ohio : University of Toledo, 2009. http://rave.ohiolink.edu/etdc/view?acc%5Fnum=mco1251386977.
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Dissertation (Ph.D.)--University of Toledo, 2009."Submitted in partial fulfillment of the requirements for the degree of Doctor of Philosophy in Biomedical Sciences." Title from title page of PDF document. Table of contents (p. iv) gives incorrect starting page numbers for "Bibliography" and "Abstract". "Bibliography" starts on p. 120 (not p. 119); "Abstract" starts on p. 150. Bibliography: p. 64-70, 97-100, 120-149.
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Briggs, Farran. "Local circuitry and function of deep layer neurons in monkey primary visual cortex /." Diss., Connect to a 24 p. preview or request complete full text in PDF format. Access restricted to UC campuses, 2003. http://wwwlib.umi.com/cr/ucsd/fullcit?p3077804.
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