Thèses : « Human neurogenesis »

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Andersson, Annika. "Studies on neurogenesis in the adult human brain." Thesis, Södertörn University College, School of Life Sciences, 2010. http://urn.kb.se/resolve?urn=urn:nbn:se:sh:diva-3646.

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Many studies on neurogenesis in adult dentate gyrus (DG) have been performed on rodents and other mammalian species, but only a few on adult human DG. This study is focusing on neurogenesis in adult human DG. To characterize the birth of cells in DG, the expression of the cell proliferation marker Ki67 was examined using immunohistochemistry. Ki67-positive labelling was indeed observed in the granular cell layer and the molecular layer of dentate gyrus and in the hilus of hippocampus, as well as in the subgranular zone (SGZ). The Ki67 positive nuclei could be divided into three groups, based on their morphology and position, suggesting that one of the groups represents neuronal precursors. Fewer Ki67 positive cells were seen in aged subjects and in subjects with an alcohol abuse. When comparing the Ki67 positive cells and the amount of blood vessels as determined by anti factor VIII, no systematic pattern could be discerned. To identify possible stem/progenitor cells in DG a co-labelling with nestin and glial fibrillary acid protein was carried out. Co-labelling was found in the SGZ, but most of the filaments were positive for just one of the two antibodies. Antibodies to detect immature/mature neurons were also used to investigate adult human neurogenesis in DG. The immature marker βIII-tubulin showed a weak expression. The other two immature markers (PSA-NCAM and DCX) used did not work, probably since they were not cross-reacting against human tissue. In summary, this study shows that new cells are continuously formed in the adult human hippocampus, but at a slower pace compared to the rat, and that some of these new cells may represent neuronal precursors.

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Yu, Chieh. "Heparan sulfate proteoglycans in human models of Neurogenesis." Thesis, Queensland University of Technology, 2020. https://eprints.qut.edu.au/203960/1/Chieh_Yu_Thesis.pdf.

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This thesis examined cell surface glycoproteins the heparan sulfate proteoglycans, as regulators of the human nervous system and identified a number of potentially novel stem cell targets for use in treating neurological disorders. Due to the poor outcome of current stem cell transplantation therapies for brain injury and neurodegeneration, this project aimed to understand the fundamentals of human neurogenesis with implications in improving stem cell therapy, understanding brain development, and the factors mediating neurodegeneration.

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Komuro, Yutaro. "Altered adult neurogenesis in a mouse model of human tauopathy." Case Western Reserve University School of Graduate Studies / OhioLINK, 2015. http://rave.ohiolink.edu/etdc/view?acc_num=case1434743393.

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Ahmad, Ruhel [Verfasser], and Albrecht [Akademischer Betreuer] Müller. "Neurogenesis from parthenogenetic human embryonic stem cells / Ruhel Ahmad. Betreuer: Albrecht Müller." Würzburg : Universitätsbibliothek der Universität Würzburg, 2013. http://d-nb.info/1031379878/34.

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Wei, Yulei. "Genetic Knowledge-based Artificial Control over Neurogenesis in Human Cells Using Synthetic Transcription Factor Mimics." Kyoto University, 2018. http://hdl.handle.net/2433/232265.

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Garnett, Shaun. "Generating a proteomic profile of neurogenesis, through the use of human foetal neural stem cells." Doctoral thesis, Faculty of Science, 2019. http://hdl.handle.net/11427/31143.

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Introduction Neurogenesis, the development of new neurons, starts soon after the formation of the neural tube and is largely completed by birth. Development of the brain after birth is mainly reliant on the formation of new connections between surviving neurons. However, adult neurogenesis does continue in the subgranular zone of the hippocampus from quiescent adult neural stem cells. Traditionally neural stem cells were cultured as neurospheres, a heterogeneous agglomeration of neural cells at various stages of differentiation. This heterogeneity prevented accurate quantitative analysis. In 2008 Sun et al produced the first non-immortalised human foetal neural stem (NS) cell line from nine week old human foetal cortex. These cells are cultured as monolayers, have a radial glia like appearance, self renew and form all three neural cell types, neurons, astrocytes and oligodendrocytes upon differentiation. More recently human foetal neuroepithelial like (NES) stem cells have been produced from five week old human foetal hind-brain, they resemble neuroepithelial cells, with characteristic rosettes, upon differentiation they appear to form a pure population of neurons. These homogeneous monolayer cultures enable quantitative proteomic analysis, to increase our understanding of early brain development Methods Three NES and two NS cell lines were available for analysis. They proliferate by stimulation from FGF and EGF, removal of these growth factors results in spontaneous differentiation. Proliferating NES and NS cells were compared using SILAC labelling. In addition, each cell line was differentiated for 12 days, 6 timepoints were taken and compared using label free quantitation. Results 4677 proteins were quantitated with 473 differentially expressed, revealing fundamental differences between NES and NS cells. NES cells are less differentiated, expressing SOX2 and LIN28, have active cell cycle processes, DNA elongation, histone modification and miRNA mediated gene silencing. Whereas NS cells are more developmentally defined, express multiple membrane proteins, have activated focal adhesion, thereby increasing their binding and interaction with their environment. NS metabolism is more oxidative, utilises lipid metabolism, the pentose phosphate pathway and produces creatine phosphate. Upon differentiation the cell cycle processes are downregulated and neurogenic and gliogenic processes increased. Conclusion This work represent a detailed in vitro characterisation of non immortalised human foetal neural stem cells, it describes the regulatory, metabolic and structural changes occurring within neural stem cells in early brain development. The information herein points towards de-differentiation potentially through LIN28-let7, as a means to produce more neurogenic neural stem cells in vitro thus aiding regenerative therapies, as well as provides a wealth of information for better understanding neurological developmental disorders.

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Bramwell, Thomas William. "Investigations into the use of human embryonal carcinoma stem cells as a model to study dopaminergic neurogenesis." Thesis, Durham University, 2009. http://etheses.dur.ac.uk/2071/.

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Parkinson's disease in reality arises as a result of a complex series of events, however it is strongly linked to the loss of a specific cellular population of midbrain dopaminergic neurons making it a candidate for stem cell based research. Stem cells can be cultured in vitro and via asymmetric cell division possess the capacity for both self renewal and the production of differentiated derivatives. The use of specific molecules and culture conditions can be applied to promote the differentiation of them towards particular cellular fates, in turn facilitating the possibility of producing enriched populations of cells displaying characteristics of a certain phenotype of interest. There has been much research focussed on the in vitro generation of dopaminergic neurons from various stem cell types. In this work the Tera2.cl.SP12 embryonal carcinoma stem cell line was the primary vehicle investigated for its ability to produce cells that were reflective of a dopaminergic phenotype. Retinoic acid was found to be able to up regulate the expression of a range of dopaminergic markers in the Tera2.cl.SP12 cell line over time. However it was clear that lowered oxygen culture, a method known to promote the production of neurons reflective of a dopaminergic phenotype in mesencephalic cultures, had no effect on the dopaminergic differentiation capacity of the embryonal carcinoma stem cells. The glycoprotein Wnt1 when applied to Tera2.cl.SP12 cultures in concert with retinoic acid was shown to increase the number and percentage of cells positive for the neuronal marker Beta III tubulin approximately 1.5 fold. This was accompanied by a concomitant rise in the mRNA expression of this marker, thus suggesting that the use of Wnt1 may be a means to produce cultures derived from embryonal carcinoma cells that are more neuronal, based on marker expression data. Other established methods to achieve dopaminergic differentiation such as suspension culture, stromal cell co-culture and the application of Sonic hedgehog and Fibroblast growth factor 8 are also able to induce a degree of neuronal and dopaminergic marker expression in Tera2.cl.SPI2 cultures. Overall these results suggest that the Tera2.cl.SP12 cell line might be one vehicle for the study of dopaminergic neurogenesis in vitro, in particular when Wnt1 and retinoic acid are used as a means to favourably enrich the population of cells displaying neuronal characteristics.

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Oikari, Lotta Emilia. "Regulation of human neural stem cell fate determination by proteoglycans." Thesis, Queensland University of Technology, 2017. https://eprints.qut.edu.au/103844/8/Lotta_Emilia_Oikari_Thesis.pdf.

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This thesis investigated how human neural stem cells are regulated, focusing specifically on heparan sulfate proteoglycans, the key proteins of the extracellular space. The findings of this study identified central roles for proteoglycans in mediating neural stem cell events, including self-renewal and differentiation. This research has improved our understanding of human stem cell and human neurogenesis biology and provided novel approaches for the development of improved neural stem cell applications, including using these cells for brain damage therapy.

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GUARNIERI, GIULIA. "Human cholinergic neurons from nucleus basalis of Meynert: a new promising tool to study pathogenetic mechanisms affecting neurogenesis." Doctoral thesis, Università di Siena, 2019. http://hdl.handle.net/11365/1072770.

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The degeneration of basal forebrain cholinergic neurons within the nucleus basalis of Meynert (NBM) is responsible for the cognitive decline in neurodegenerative disorders, including Alzheimer’s disease (AD) and Parkinson’s disease (PD). Indeed, the major therapeutic strategies have been directed toward the cholinergic system. However, no effective therapies exist to contrast NBM cholinergic neuron loss and investigations in the field are strongly restricted by the lack of human models. Thus, the work of this thesis firstly contributed to establish and characterise a novel primary culture of cholinergic neurons from the human foetal NBM (hfNBM). An extensive phenotypic and functional characterization confirmed the cholinergic identity of hfNBM cells, including positivity for specific markers (ChAT, VAChT and AChE) and acetylcholine release as well as the presence of functional cholinergic receptors. Treatment with Nerve Growth Factor (NGF), the main neurotrophin for NBM neurons, activated the specific NGF/TrkA signalling pathway and promoted differentiation of hfNBM cells. Moreover, when intravenously injected in a NBM-lesioned rat model, hfNBM cells led to a significant improvement in cognitive and memory functions, confirming the functional value of these cells. Given the key role of neuroinflammation in the onset and progression of neurodegenerative diseases, another objective of this work was to investigate the effects of the main pro-inflammatory cytokine, tumor necrosis factor α (TNF-α), on cholinergic neuron development and plasticity. TNF-α exposure reduced immature neuronal markers (nestin, β-tubulin III) and increased the mature marker MAP2 along with neurite elongation. Interestingly, TNF-α treatment significantly reduced the number of neurons expressing primary cilium, a non-motile sensory antenna required for neurogenesis. Furthermore, a significant reduction of TrkA along with an increase of p75NTR, the high- and low-affinity NGF receptors, essential for survival or apoptotic signals, respectively, were observed upon TNF-α stimulation. Lastly, based on the emerging evidences demonstrating inflammation-driven epigenetic modifications, a significant increase of DNMT1, one of the key enzymes regulating DNA methylation, was detected after TNF-α stimulation. Interestingly, the genome-wide methylome analysis of hfNBM cells revealed an alteration of methylation pattern after the inflammatory insult. In particular, TNF-α exposure for 48 hours led to promoter hypermethylation of genes involved in neuronal development, such as chordin like-1 (CHRDL1) and mesoderm specific transcript (MEST). Accordingly, the mRNA levels of both genes were significantly reduced by TNF-α treatment. Overall, these results suggest that TNF-α-mediated inflammation may affect hfNBM cell development and maturation most likely interfering with the DNA methylation status. In conclusion, our findings indicate that hfNBM cells may represent a proven powerful in vitro model for studying disorders of the human nervous system, such as those affecting the differentiation and maintenance of cholinergic NBM neurons.

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Pigeon, Julien. "The role of NEUROG2 T149 phosphorylation site in the developing human neocortex." Electronic Thesis or Diss., Sorbonne université, 2024. http://www.theses.fr/2024SORUS092.

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Le développement des fonctions cognitives supérieures observée au cours de l'évolution des mammifères, repose sur la capacité des progéniteurs corticaux à augmenter leur production neuronale et ainsi étendre la surface du neocortex. Chez les mammifères dit gyrencéphaliques, où la période de production neuronale est allongée, la régulation du type de division, proliférative ou neurogénique, des progéniteurs corticaux est d'autant plus importante pour garantir l'accumulation de neurones. Dans le télencéphale dorsal, à l'origine du néocortex, c'est l'articulation de la voie de signalisation Notch et du gène proneural Neurogenin2 (NEUROG2) qui contrôle le choix de division. L'expression de NEUROG2 à elle seule étant suffisante pour induire la production de neurones dans le néocortex, sa régulation au niveau génique a déjà fait l'objet d'études approfondies chez la souris. Cependant, de nouveaux travaux démontrent qu'au niveau protéique, les modifications post-traductionnelles peuvent aussi influencer profondément l'activité et la stabilité des protéines. Ainsi, la modulation du site de phosphorylation T149 de NEUROG2 dans le néocortex murin perturbe les proportions de progéniteurs corticaux et les différents sous types de neurones des couches profondes et superficielles qu'ils produisent. Toutefois, il n'est pas connu comment ces régulations pourraient moduler l'activité de NEUROG2 sous des niveaux endogènes et comment cela pourrait affecter le développement du néocortex humain.Nous avons donc supposé que la régulation de l'activité de NEUROG2 via la modulation du site de phosphorylation T149 pourrait réguler la différenciation des progéniteurs corticaux en neurones dans le développement cortical humain.Afin de tester cette hypothèse, nous avons utilisé des organoïdes corticaux issus de la différenciation de cellules iPS génétiquement remodifiées. Nous avons commencé par étudier le rôle de NEUROG2 dans la différenciation neuronale des progéniteurs en induisant la perte d'expression de NEUROG2 grâce aux ciseaux moléculaires CRISPR/Cas9. Nous avons observé une diminution des proportions de neurones à des stades intermédiaire et avancé du développement des organoïdes corticaux. A cela s'ajoute une ventralisation des progéniteurs corticaux via la diminution de l'expression de gènes leur conférant une idendité dorsale et une augmentation de ceux leur conférant une identité ventrale. Ainsi, grâce à la validation du rôle crucial de NEUROG2 dans la neurogénèse corticale chez l'humain, nous avons étudié comment la perte du site de phosphorylation T149 de NEUROG2 via son remplacement par une Alanine, T149A affecte la production neuronale dans le néocortex humain.Pour cela, nous avons combiné de l'imagerie sur cellules vivantes et fixées dont nous avons quantifiés les proportions avec des algorithmes d'apprentissage profond combinées à des techniques de reprogrammtion cellulaire ainsi que du séquencage ARN et de la ChIP pour étudier les propriétés de notre NEUROG2 T149A mutant sur la neurogeneses corticale. Nous avons observé que la mutation T149A homozygote ne change ni l'expression de NEUROG2 dans les cellules de la glie radiaire ni dans les progéniteurs intermédiaires, ni sa capacité à se lier à l'ADN et à activer l'expression de ses gènes cibles. Cependant, nous avons observé que les cellules de la glie radiaire effectuent plus de divisions neurogéniques, produisant donc plus de neurones, aux stades intermédiaire et avancé du développement des organoïdes corticaux. On note d'autre part que ce phénotype s'accompagne d'une augmentation de l'expression des gènes responsables de l'organisation structurale et fonctionnelle du cil des cellules de la glie radiaire. Or, ces gènes sont moins exprimés dans les mutants NEUROG2 KO suggérant un lien fort entre ce cil, NEUROG2, son profil de phosphorylation, et la régulation de la neurogénèse corticale chez l'humain ce qui pourrait donc constituer un potentiel mécanisme moléculaire Neocortical expansion throughout evolution has been responsible for higher-order cognitive abilities and relies on the increased proliferative capacities of cortical progenitors to increase neuronal production. Therefore, in gyrencephalic species such as humans and primates, where the neurogenic period is protracted, the regulation of the balance between progenitor maintenance and differentiation is of key importance for the right neuronal production. The control of this balance in the dorsal telencephalon, which gives rise to the neocortex, is mediated by feedback regulation between Notch signaling and the proneural transcription factor Neurogenin2 (NEUROG2). As the expression of NEUROG2 alone is sufficient to induce neurogenesis in the neocortex, its regulation at the gene level has been extensively studied in mice. However, recent findings highlight that regulation at the protein level through post-translational modifications can profoundly influence protein activity and stability. Indeed, the modulation of the conserved NEUROG2 T149 phosphorylation site in the developing mouse neocortex results in an altered pool of progenitors and number of neurons in the deep and upper layers. Nevertheless, it is not known how such post-translation modification regulates NEUROG2 activity in the development of the human neocortex under endogenous levels and its contribution to the development of the neocortex.We hypothesize that modulation of the activity of the transcription factor NEUROG2 through this T149 phosphorylation site may regulate the pace of the temporal advance of human cortical progenitors down the differentiation landscape.To test this hypothesis in humans, we used 3D cortical organoids derived from CRISPR/Cas9 engineered iPSCs lines to study cortical neurogenesis. Before diving into the role of post translational modifications regulating NEUROG2 activity we started by confirming, for the first time in humans that Neurogenin2 is indeed the gateway gene of neuronal differentiation. In differentiated iPSCs NEUROG2 KO clones, we observed reduced proportions of neurons after 70 and 140 days in vitro at both the mid and late stages of cortical organoid development. This phenotype is accompanied by a ventralization of these dorsal forebrain organoids with a downregulation of the genes encoding for the dorsal forebrain identity and an upregulation of the genes encoding for the ventral forebrain identity. Knowing that Neurogenin2 is required for cortical neurogenesis, we next studied how the loss of NEUROG2 phosphorylation site T149 by its replacement with an Alanine (T149A) at endogenous levels alters neuronal production. To this end we combined live imaging of radial glial clones, immunohistochemistry for key cell fate markers, machine-learning based cell type quantification, transcriptional activation and stem cell reprogramming assays, RNA sequencing and chromatin immunoprecipitation to analyze cortical neurogenesis. We found, on the one hand, the TA/TA mutant does not change the pattern of NEUROG2 expression in both radial glial cells and intermediate progenitors, nor its ability to bind and activate target genes or reprogram human stem cells to neurons. However, the TA/TA mutant radial glia switch their division mode from proliferative to neurogenic and generate more neurons at both the mid and late stages of cortical development in organoids. Mechanistically, we found that this phenotype is accompanied by an upregulation of the genes encoding the organization and the movements of the primary cilium of radial glial cells, which are downregulated in the NEUROG2 KO clones. These results suggest a strong link between the primary cilium, Neurogenin2, and its phosphorylation profile with the regulation of neurogenesis in human cortical organoids

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Oladimeji, Paul Babajide. "Disc 1 and neurogenesis in schizophrenia and other major psychiatric disorders : a post-mortem study of the human hippocampus." Thesis, Cranfield University, 2013. http://dspace.lib.cranfield.ac.uk/handle/1826/8620.

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Psychiatric illnesses are disorders that affect millions worldwide. Evidence from quantitative and molecular genetics analysis suggests a strong genetic component to these disorders. There is also evidence that embryonic neurodevelopment is a key period in the progression schizophrenia. The aim of the present study was to use post-mortem human hippocampus from subjects of a variety of psychiatric phenotypes to investigate neurodevelopmentally- relevant gene expression in this region of the adult human brain. Particular interest is paid to schizophrenia risk gene DISC1; it has been shown to exhibit linkage and association to schizophrenia and is highly involved in embryonic and post natal neurodevelopmental processes. The results reported in this study indicate that DISC1 binding partners, and genes used to mark neurogenesis, can be found aberrantly expressed in schizophrenia and bipolar disorder, relative to controls. The results also suggest that DISC1 genotype may predict expression patterns of DISC1 binding partners and neurogenesis markers, irrespective of diagnosis. This may provide clues to the timing and nature of abnormal brain development in this illness and aid in development of treatment strategies.

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Borsini, Alessandra. "A human in vitro model to investigate the effects of inflammation on adult hippocampal neurogenesis in the context of depression." Thesis, King's College London (University of London), 2017. https://kclpure.kcl.ac.uk/portal/en/theses/a-human-in-vitro-model-to-investigate-the-effects-of-inflammation-on-adult-hippocampal-neurogenesis-in-the-context-of-depression(0eb27c3a-a0b2-4f85-b2e7-164adea3add4).html.

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Interferon (IFN)-α treatment for hepatitis C virus (HCV) is a well-recognized clinical model for inflammation-induced depression, but the mechanisms underlying these effects are not clear. Previous data reported an alteration in peripheral levels of inflammatory and neuroplasticity markers in depressed versus non-depressed patients. There is indeed evidence for blood factors, including IFN-α, to penetrate the blood brain barrier and modulate different signalling in the brain. Using a human hippocampal progenitor cells (HPCs) model firstly I examined the damaging effects of IFN-α on neurogenesis and apoptosis; secondly I investigated the effect of serum from depressed and non-depressed patients with HCV on neurogenesis and apoptosis across disease progression at baseline (before receiving IFN-α, treatment week (TW) 0) and after four weeks (TW4) of IFN-α treatment. In the in vitro study with IFN-α I show that the cytokine decreased neurogenesis and increased apoptosis. Moreover, IFN-α increased the expression of IFN-stimulated gene 15 (ISG15), ubiquitin-specific peptidase 18 (USP18), and levels of interleukin-6 (IL-6), via activation of STAT1. Like IFN-α itself, combination treatment with ISG15, USP18 and IL-6 was able to reduce neurogenesis and to enhance apoptosis, via further downstream activation of STAT1. Using transcriptomic analyses, I also showed that IFN-α regulated pathways involved in oxidative stress and immune response. In the in vitro study with serum samples from IFN-α-treated HCV patients I show that a high percentage of apoptotic cells observed upon treatment of HPCs with TW0 serum, and a low percentage of neurogenic cells observed upon treatment with TW4 serum was predictive of later depression. Furthermore, a low increase in the percentage of neurogenic cells between TW0 and TW4 was also predictive of IFN-α-induced depression, proposing this model as the best predictive one. In conclusion, both studies provide further insights on the association between inflammation-dependent regulation of neurogenesis and later development of neuropsychiatric conditions.

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Rolland, Maude. "Physiopathologie de l'infection par le cytomégalovirus sur les progéniteurs neuraux humains." Thesis, Toulouse 3, 2016. http://www.theses.fr/2016TOU30314/document.

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L'infection congénitale par le cytomégalovirus humain (HCMV) est la première cause de séquelles acquises du système nerveux central (CNS). Elle est responsable de surdités neurosensorielles, de paralysies cérébrales ou d'anomalies neuro-développementales graves (0,1% des naissances) telles que des microcéphalies ou des anomalies de gyration. Pour étudier les effets de l'infection par le HCMV sur le développement cérébral, nous utilisons des cellules souches neurales (NSC) humaines dérivées de cellules souches embryonnaires (ES), ainsi que des coupes histologiques de cerveaux fœtaux infectés. Notre travail a porté sur l'analyse des conséquences de l'infection sur un facteur de transcription essentiel lors du développement cérébral, le Peroxisome Proliferator-Activated Receptor gamma (PPARg). Nous avons démontré que l'infection par le HCMV diminuait la neuronogénèse, en association avec une augmentation des niveaux d'expression et d'activité de PPARg. En accord avec ces résultats, nous avons montré que le niveau d'expression de l'acide 9-hydroxyoctadecadienoique (9-HODE), un agoniste connu de PPARg était augmenté dans les NSC infectées. En outre, l'ajout de 9-HODE dans les NSC reproduit l'effet de l'infection sur PPARg conduisant à une augmentation du nombre de cellules positives pour l'antigène viral IE parmi les NSC infectées. De plus, nous avons démontré que : (1) l'activation pharmacologique ou l'expression ectopique de PPARg suffisent pour perturber la neuronogénèse de NSC non infectées ; (2) le traitement de NSC non infectées par le 9-HODE diminue la différenciation des NSC ; (3) le traitement de NSC infectées par du T0070907, un inhibiteur de PPARg restaure un taux normal de différenciation. Le rôle crucial de PPARg dans les pathologies fœtales liées à l'infection a été souligné par la mise en évidence de sa translocation nucléaire au sein des zones germinatives de cerveaux fœtaux infectés congénitalement par le HCMV (N=20), mais pas dans les cas contrôles. Nous avons également identifié un des gènes cibles de PPARg dans le cerveau infecté: LIS1, le gène de la lissencéphalie classique, dont l'expression est également augmentée dans les NSC infectées, de façon dépendante de l'activité de PPARg. Nous avons mis en évidence que l'expression de LIS1 était augmentée de façon massive dans les cerveaux fœtaux infectés congénitalement par le HCMV (N=6) par rapport aux cas contrôles (N=3). Ceci pourrait jouer un rôle central dans la physiopathologie, car il est connu que toute perturbation de l'expression de LIS1 conduit à des anomalies importantes de la migration neurale et au développement d'un phénotype dit "lissencephaly-like". L'ensemble de nos données révèle le rôle clé de PPARg dans la neuronogénèse et la pathophysiologie de l'infection congénitale par le HCMV. Elles ouvrent la voie à une meilleure compréhension des mécanismes régissant les phénotypes pathologiques, notamment concernant le rôle de LIS1 dans les anomalies de la migration neurale Congenital infection by human cytomegalovirus (HCMV) is a leading cause of permanent sequelae of the central nervous system, including sensorineural deafness, cerebral palsies or devastating neurodevelopmental abnormalities (0.1 % of all births). To gain insight on the impact of HCMV on neuronal development, we used both neural stem cells from human embryonic stem cells (NSC) and brain sections from infected fetuses. We investigated the outcome of infection on Peroxisome Proliferator-Activated Receptor gamma (PPARg, a transcription factor critical in the developing brain. We observed that HCMV infection dramatically impaired the rate of neuronogenesis and strongly increased PPARg levels and activity. Consistent with these findings, levels of 9-hydroxyoctadecadienoic acid (9-HODE), a known PPARg agonist, were significantly increased in infected NSCs. Likewise, exposure of uninfected NSCs to 9-HODE recapitulated the effect of infection on PPARg activity. It also increased the rate of cells expressing the IE antigen in HCMV-infected NSCs. Further, we demonstrated that (1) pharmacological activation of ectopically expressed PPARg was sufficient to induce impaired neuronogenesis of uninfected NSCs, (2) treatment of uninfected NSCs with 9-HODE impaired NSC differentiation and (3) treatment of HCMV infected NSCs with the PPARg inhibitor T0070907 restored a normal rate of differentiation. The role of PPARg in the disease phenotype was strongly supported by the immunodetection of nuclear PPARg in brain germinative zones of congenitally infected fetuses (N=20), but not in control samples. We also identified LIS1 as one of the target genes for PPAR??in the infected brain. Levels of LIS1, the gene of classical lissencephaly, were strongly increased in infected NSC, presumably resulting from increased PPAR? activity. The relevance of this finding was further supported by our demonstration of a massive increase in the immunodetection in LIS1 fetal brains congenitally infected with HCMV (N = 6), relative to control cases (N = 3). Indeed, it is well known that overexpression of LIS1 is responsible for significant abnormalities of neural migration and development of a lissencephaly-like phenotype. Altogether, our findings reveal a key role for PPARg in neurogenesis and in the pathophysiology of HCMV congenital infection. They also pave the way to the identification of PPARg gene targets in the infected brain

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Wimmer, Ryszard. "Migration of neural stem cells during human neocortical development." Electronic Thesis or Diss., Université Paris sciences et lettres, 2024. http://www.theses.fr/2024UPSLS016.

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Chez les espèces gyrencéphaliques, et en particulier chez l'homme, la forte augmentation de la taille du néocortex est largement soutenue par une niche neurogénique élargie, la zone sous-ventriculaire externe (oSVZ). Cela est dû en grande partie à l'amplification d'une population de cellules souches neurales, les cellules gliales radiales basales (bRG, également appelées oRG). Les cellules bRG colonisent la zone sous-ventriculaire externe grâce à un mouvement dépendant de l'acto-myosine appelé translocation somale mitotique (MST). Le mécanisme moléculaire exact de la MST, la question de savoir si le cytosquelette des microtubules contrôle également d'autres étapes de la translocation des cellules bRG et la contribution de ces mouvements à la dissémination des cellules bRG dans le néocortex humain en développement sont toutefois inconnus. Ici, en utilisant l'imagerie en direct du tissu fœtal humain de la semaine 14-21 et des organoïdes cérébraux, nous identifions un mode de translocation en deux étapes pour les cellules bRG. En plus de la TMS, les cellules bRG subissent un mouvement dépendant des microtubules pendant l'interphase, que nous appelons translocation somale interphasique (TSI). L'IST est plus lente que la TMS et contrôlée par le complexe LINC qui recrute le moteur moléculaire dynéine et son activateur LIS1 vers l'enveloppe nucléaire pour le transport. Par conséquent, le TSI est affecté dans les organoïdes dérivés de patients LIS1. Nous montrons en outre que la TMS se produit pendant la prométaphase et qu'il s'agit donc d'un événement de translocation du fuseau mitotique. Le TSI et le TMS sont tous deux bidirectionnels, avec un mouvement basal net de 0,57 mm par mois de gestation du fœtus humain.Nous montrons que 85% de ce mouvement dépend de l'IST, qui est à la fois plus polarisé et plus processif que le MST.Enfin, nous démontrons que l'IST et le MST sont conservés dans les cellules de glioblastome liées à bRG et qu'ils interviennent par les mêmes voies moléculaires. Dans l'ensemble, notre travail identifie comment les cellules bRG colonisent le cortex fœtal humain et comment ces mécanismes peuvent être liés à des conditions pathologiques In gyrencephalic species, and in particular in humans, the strong size increase of the neocortex is largely supported by an expanded neurogenic niche, the outer subventricular zone (oSVZ). This is largely due to the amplification of a neural stem cell population, the basal radial glial cells (bRGs, also known as oRGs). bRG cells colonize the oSVZ through an acto-myosin dependent movement called mitotic somal translocation (MST). The exact molecular mechanism of MST, whether the microtubule cytoskeleton also controls other steps of bRG cell translocation, and the contribution of these movements to bRG cell dissemination into the human developing neocortex are however unknown. Here, using live imaging of gestational week 14-21 human fetal tissue and cerebral organoids, we identify a two-step mode of translocation for bRG cells. On top MST, bRG cells undergo a microtubule-dependent movement during interphase, that we call interphasic somal translocation (IST). IST is slower than MST and controlled by the LINC complex that recruits the dynein molecular motor and its activator LIS1 to the nuclear envelope for transport. Consequently, IST is affected in LIS1 patient derived organoids. We furthermore show that MST occurs during prometaphase and is therefore a mitotic spindle translocation event. MST is controlled by the mitotic cell rounding molecular pathway, that increases the cell cortex stiffness to drive translocation. Both IST and MST are bidirectional with a net basal movement of 0,57 mm per month of human fetal gestation. We show that 85% of this movement is dependent on IST, that is both more polarized and more processive than MST. Finally, we demonstrate that IST and MST are conserved in bRG-related glioblastoma cells and occur through the same molecular pathways. Overall, our work identifies how bRG cells colonize the human fetal cortex, and how these mechanisms can be linked to pathological conditions

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Abuawad, Mohammad. "Pathological changes in Alexander disease : a comparative study in human and mice with GFAP mutations." Thesis, Sorbonne Paris Cité, 2017. http://www.theses.fr/2017USPCC296.

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La maladie d'Alexander est une maladie neurodégénérative due à des mutations hétérozygotes du gène GFAP codant le principal filament intermédiaire des astrocytes matures. Nous avons étudié l'effet des mutations GFAP dans l'hippocampe d'un patient avec AxD infantile et de deux souris knockin, l'une portant une mutation dans le rod domain (p.R85C) et l'autre dans le tail domain (p.T409I). Chez le patient, nous décrivons pour la première fois: (i) des changements morphologiques sévères des cellules GFAP+ dans la zone subgranulaire du gyrus denté, qui ont perdu la plupart de leurs processus radiaux; (ii) une réactivité microgliale; (iii) et un déficit de la neurogénèse hippocampique postnatale. Nous avons trouvé des anomalies similaires dans les deux souris knockin, plus sévères chez les homozygotes. La comparaison de ces modèles a montré que ces anomalies prédominent chez les souris GFAPT409I, tandis que l’accumulation de GFAP est supérieure chez les souris GFAPR85C. La comparaison des deux modèles de souris a montré que les conséquences pathologiques dépendent la localisation de la mutation dans la GFAP. Ces résultats suggèrent qu'en plus du gain évident de fonction, d'autres dysfonctions astrocytaires dans peuvent être dues à une perte de fonction. De plus, nous avons traité les souris mutantes avec de la ceftriaxone, connu pour son effet neuroprotecteur, mais nous n'avons observé aucun effet significatif. Enfin, la mégalencéphalie étant fréquente chez les patients AxD, nous avons mesuré la quantité d'eau cérébrale chez les souris mutantes GFAP. Nous avons trouvé une augmentation significative de la teneur en eau chez les souris GFAPR85C/R85C âgées d'un an. Nous avons observé une localisation anormale de l'AQP4 dans les astrocytes des asouris mutées, pouvant participer au déséquilibre hydrique cérébral Alexander disease is a neurodegenerative disorder caused by heterozygous mutations of GFAP gene coding the major intermediate filament of mature astrocytes. We studied the effect of GFAP mutation in the hippocampus of infantile onset AxD patient and two novel knockin mouse models, one bearing a mutation located in the rod domain (p.R85C), and the other bearing a mutation located in the tail domain (p.T409I) of mouse Gfap. In the AxD patient, we describe for the first time: (i) obvious morphological changes of GFAP+ cells in the subgranular zone of the dentate gyrus, which have lost most of their radial processes; (ii) microglial reactivity; (iii) and deficit in postnatal hippocampal neurogenesis. We found similar abnormalities in the two knockin mouse lines, more obvious in homozygous mice. A comparison of these mouse models showed that pathological findings predominated in the GFAPT409I mice, whereas GFAP accumulated in larger amounts in the GFAPR85C mice. The comparison of the two mouse models showed that their pathological consequences depend on the location of the mutated residues in GFAP. These findings suggest that in addition to the evident gain of GFAP function, other astrocyte dysfunctions in this disease may be due to a loss of function of GFAP. In addition, we treated the mice mutants with ceftriaxone, which has been reported to have a neuroprotective effect, but we observe no significant effect. Finally, AxD patients have often megalencephaly, therefore we measured the brain water content in AxD mouse models. We found a significant increase in brain water content in the one year old GFAPR85C/R85C mice vs controls. We observed mislocalization of AQP4 in mutant mice astrocytes that can participated to water imbalance in brain

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Carlsson, Josefine. "The affects of exercise and brain plasticity, discussed in relation to Functional oriented Music Therapy; a theoretical study." Thesis, University of Skövde, School of Humanities and Informatics, 2007. http://urn.kb.se/resolve?urn=urn:nbn:se:his:diva-68.

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AbstractThis essay examines which role functional oriented music therapy, which is supposed to help sensorimotor development, can have in schools and in health care. To find this out, research about what kinds of effects exercise can have on academic achievements and in recovery from brain injuries has been brought up. The research concerning academic achievements was conducted with school children; some children without difficulties, some with sensory integration problems, and some with motor skill difficulties. In addition to this, research about the brain structure superior colliculus, which lies behind sensory integration, is also brought up.The results showed that children who were given more exercise had significantly better scores in academic skills than the children with normal academic education. Thus, it might be reasonable to practise functional oriented music therapy in schools, both as helping general development, but also for children with different types of difficulties.The research concerning exercise and injuries has made clear that the adult brain can change via neurogenesis, plasticity and cortical reorganization. These three aspects are important when practicing a skill or when recovering from an injury. Exercise has been shown to affect these three aspects positively and can therefore also aid the recovery from injuries.Thus, there seems to be many theoretical aspects supporting the FMT- method. However, the question is if the results of one treatment form can generalize over such a wide range of injuries and defects that the FMT –adepts usually have. It is therefore also discussed if further experiments on the FMT-method could help make it a more effective tool for rehabilitation.

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Cao, William Sam. "Characterization and application of human pluripotent stem cell-derived neurons to evaluate the risk of developmental neurotoxicity with antiepileptic drugs in vitro." Scholarly Commons, 2015. https://scholarlycommons.pacific.edu/uop_etds/131.

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The risks of damage to the developing nervous system of many chemicals are not known because these studies often require costly and time-consuming multi-generational animal experiments. Pluripotent stem cell-based systems can facilitate developmental neurotoxicity studies because disturbances in nervous system development can be modeled in vitro. In this study, neurons derived from embryonal carcinoma (EC) and induced pluripotent stem (iPS) cells, were first characterized to establish their suitability for developmental neurotoxicity studies. The EC stem cell line, TERA2.cl.SP-12, was differentiated into neurons that expressed voltage-gated sodium and potassium channels as well as ionotropic GABA and glutamate receptors. These cells could also fire action potentials when stimulated electronically. However spontaneous action potentials were not observed. In contrast, pre-differentiated neurons derived from iPS cells fired evoked and spontaneous action potentials. Furthermore, iPS cell-derived neurons also expressed a wide array of functional voltage- and ligand-gated ion channels. Antiepileptic drugs (AEDs) are associated with developmental neurotoxicity. These agents can cause congenital malformations, cognitive deficits and behavioral impairment in children as a result of in utero exposure. The impact of four major AEDs, namely phenobarbital, valproic acid, carbamazepine and lamotrigine, on cell viability, cell cycle and differentiation of TERA2.cl.SP-12 into neurons was studied. All AEDs tested reduced differentiating stem cell viability. Valproic acid and carbamazepine increased apoptosis and reduced cell proliferation. A brief exposure to phenobarbital, valproic acid and lamotrigine at the start of differentiation impaired the subsequent generation of neurons. Additionally, the effect of transient exposure to phenobarbital and carbamazepine on neuronal maturation of iPS-derived neurons was investigated. Exposure to both AEDs resulted in diminished membrane potentials and reduced the proportion of cells that were able to fire action potentials spontaneously in culture. The data from these studies suggest that impairments in proliferation, differentiation and maturation of neurons derived from human stem cells may be sensitive indicators of neurodevelopmental disruption by these drugs that can result from in utero exposure. Furthermore, these findings suggest that the use of human pluripotent stem cells and neurons derived from them can reduce the time, cost and the number of animals used in toxicological research.

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Wölfle, Martina. "Comparative analyses of the neurogenic capacity of human neuroprogenitor populations derived from neural and mesodermal tissue." [S.l. : s.n.], 2008. http://nbn-resolving.de/urn:nbn:de:bsz:289-vts-63715.

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Rainer, Quentin. "Effets comportementaux et neurogéniques des antidépresseurs dans un nouveau modèle d'anxiété/dépression chez la Souris adulte." Phd thesis, Université Paris Sud - Paris XI, 2011. http://tel.archives-ouvertes.fr/tel-00672775.

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Les pathologies dépressives se caractérisent par des symptômes hétérogènes impliquant de nombreuses régions cérébrales. L'une d'entre elles, l'hippocampe, est le siège d'un processus physiologique, appelé neurogenèse, qui, chez l'adulte, serait impliqué dans l'étiologie de la dépression et la réponse au traitement antidépresseur.L'objectif de ce travail a été d'étudier le rôle des 4 étapes du processus de neurogenèse hippocampique dans l'action des antidépresseurs dans un modèle physiopathologique de la dépression, chez la Souris adulte.

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Bayer, Ronny. "Veränderungen der adulten Neurogenese im Hippocampus von Drogenabhängigen." Doctoral thesis, Universitätsbibliothek Leipzig, 2015. http://nbn-resolving.de/urn:nbn:de:bsz:15-qucosa-163780.

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Die Neubildung von Neuronen persistiert lebenslang in der Subgranularzellschicht des Hippocampus und der Subventrikularzone des Großhirns und wird als adulte Neuroge-nese bezeichnet. Es wird vermutet, dass diese beim erwachsenen Menschen einen rele-vanten Einfluss auf degenerative Veränderungen, verschiedene neurologische Krank-heitsbilder und auf die (Dys-)Funktion des Gedächtnisses hat. Im Tiermodell wurde eine Verringerung der Neurogenese nach chronischer Morphingabe nachgewiesen. Vorarbeiten zeigten einen Zusammenhang zwischen chronischem Heroinmissbrauch und reaktiver Astrogliose, Mikrogliose und einer vermehrten Expression des polysialylated neural cell adhesion molecule im humanen Hippocampus. Daraus leitet sich die Hypothese ab, dass chronischer Heroinmissbrauch, als Modell für eine Abhängigkeitserkrankung, einen Einfluss auf die adulte humane Neurogenese hat. Es wurden in Formalin fixierte Gewebeproben aus dem Hippocampus von Verstorbenen mit einer letalen Heroinintoxikation und mit bekanntem Heroinmissbrauch (n = 20) un-tersucht und mit einer nach Alter und Geschlecht angepassten Kontrollgruppe (n = 28) verglichen. Hierbei wurden spezifische Neurogenesemarker mittels immunhistochemi-scher Methoden angewendet und ausgewertet. Es bestand eine generell sehr geringe zelluläre Proliferationsrate und eine signifikante Reduktion Musashi-1 positiver neuro-naler Vorläuferzellen bei gleichzeitig unveränderter Anzahl Nestin positiver reifender und Calretinin positiver migrierender postmitotischer Neurone. Zudem wurde ein ver-ändertes Calretinin-Expressionsmuster als Hinweis auf eventuelle funktionelle neuronale Defizite bei Drogenabhängigen festgestellt. Der potentielle Einfluss von chronischem Heroinmissbrauch auf die adulte humane Neurogenese wird erstmals gezeigt. Die Ergebnisse weisen auf eine negative Beeinflus-sung im Stadium neuronaler Vorläuferzellen und der Zellfunktion migrierender Neurone in der Fallgruppe im Vergleich zu einer gesunden Kontrollgruppe hin. Diese Hemmung der Neurogenese könnte eine Erklärungsmöglichkeit für kognitive Defizite und Funktionsstörungen des Gedächtnisses infolge chronischen Drogenkonsums bieten und zugleich eine Bedeutung bei der Entstehung von Abhängigkeitserkrankungen haben. Insofern könnte sich hier ein Ansatzpunkt für zukünftige Therapiestrategien derartiger Erkrankungen oder ihrer Folgen bieten.

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Scordel, Chloé. "Identification des déterminants viraux et mécanismes moléculaires impliqués dans l’interférence du virus de la maladie de Borna avec la neurogenèse humaine." Thesis, Paris 11, 2014. http://www.theses.fr/2014PA114849.

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Le virus de la maladie de Borna (BDV) est un virus persistant dans le système nerveux central responsable de troubles du comportement chez l’animal et possiblement chez l’homme. En utilisant des cellules progénitrices neurales humaines, des travaux antérieurs à mon arrivée au laboratoire ont montré que BDV altère la neurogenèse humaine. Les objectifs de ma thèse étaient d’identifier les déterminants viraux responsables de cette altération et de caractériser les mécanismes moléculaires impliqués. Nous avons montré que la phosphoprotéine (P) et la nucléoprotéine (N), mais pas la protéine X, induisent une inhibition spécifique de la neurogenèse humaine, la genèse des astrocytes n’étant pas altérée. Ensuite, focalisant notre étude sur P, nous avons montré qu’elle affectait particulièrement la genèse des neurones GABAergiques. La caractérisation moléculaire a ensuite révélé une diminution de l’expression de gènes impliqués dans la spécification (ApoE et Noggin) et dans la maturation (SCG10/Stathmin2 et TH) neuronale. En conclusion, nos résultats démontrent, pour la première fois, qu’une protéine virale perturbe la neurogenèse GABAergique humaine, un processus connu pour être dérégulé dans certaines maladies psychiatriques. Ils améliorent ainsi notre compréhension de la pathogenèse de ce virus persistant et de son rôle possible dans les maladies psychiatriques chez l’homme Borna disease virus (BDV) is a persistent neurotropic virus causing neurobehavioral disorders in animals and possibly humans. Using human neural progenitor cells, it had been shown, before my arrival in the laboratory, that BDV induces an alteration in human neurogenesis. Here, we aimed at identifying the viral determinants involved in BDV-induced impairment of neurogenesis and at characterizing the underlying molecular mechanisms. We demonstrated that the phosphoprotein (P) and the nucleoprotein (N), but not the X protein, reduce neurogenesis. Focusing on the role of P, we evidenced an impairment of GABAergic neurogenesis. Then, seeking for the molecular mechanisms responsible for P-induced inhibition of neurogenesis, we showed that it induces a decrease in the expression of cellular factors involved in either neuronal specification (ApoE, Noggin) or maturation (SCG10/Stathmin, TH). Thus, in this study, we demonstrated for the first time that a viral protein is capable of inhibiting GABAergic neurogenesis, a process that is dysregulated in some psychiatric diseases. Our results improve our understanding of the pathogenesis of this persistent neurotropic virus and of its possible role in psychiatric disorders

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Royo, Julie. "Performances cognitives et neurogenèse au cours du vieillissement chez un primate non-humain." Thesis, Paris, Muséum national d'histoire naturelle, 2020. http://www.theses.fr/2020MNHN0001.

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La neurogenèse correspond à la capacité du cerveau à former de nouveaux neurones. Ce mécanisme permet d’induire des changements structurels et fonctionnels dans le cerveau pouvant atténuer le déclin cognitif observé avec l’âge. Cette neuroplasticité persiste à l’âge adulte mais diminue au cours de la vie. Au cours de ce travail, nous avons caractérisé l’évolution des fonctions cognitives et de la neurogenèse avec l’âge chez le Microcèbe (Microcebus murinus) qui présente des changements morphologiques, comportementaux et physiologiques similaires à ceux observés chez l’Homme au cours du vieillissement. Nous avons pu montrer qu’une partie des animaux âgés présentaient une diminution de leurs capacités cognitives tandis que d’autres ont conservé des performances à un niveau équivalent à celui des individus jeunes. Ce maintien des fonctions cognitives avec l’âge pourrait être dû en partie au processus de neurogenèse. En effet, au niveau de la zone sous-ventriculaire, la balance neurone/glie serait en faveur de la neurogenèse dans la partie dorsale tandis que l’oligodendrogenèse serait favorisée dans la corne. La stimulation de la neurogenèse pourrait permettre de remplacer les neurones lésés avec l’âge ou détruits par un traumatisme. Parmi les stratégies possibles pour stimuler ce mécanisme, l’alimentation et l’activité physique apparaissent être des interventions pertinentes. Au cours de ce travail de thèse, nous nous sommes intéressés, en particulier, à l’impact d’une supplémentation en acides gras polyinsaturés n-3 ainsi qu’à la combinaison de la restriction calorique et de l’activité physique à l’âge adulte. Ces interventions ont induit une amélioration des fonctions cognitives associée à une hausse du nombre de nouveaux neurones. Ces différentes approches constituent donc une stratégie non médicamenteuse prometteuse afin de lutter contre le déclin des fonctions cognitives au cours du vieillissement en participant à la plasticité cérébrale Neurogenesis is the ability of the adult brain to build new neurons. This process induces structural and functional changes in the brain that can reduce cognitive decline during aging. This neuroplasticity exists throughout life but it gradually decreases with aging. In this study, we characterized the evolution of cognitive functions and neurogenesis during aging in the grey mouse lemur (Microcebus murinus) that shares morphological, behavioural and physiological changes with aged humans. We observed that some aged animals presented a specific deficit in learning and memory whereas others had cognitive performances equivalent or better than young animals. It might be due to the neurogenesis process that would preserve cognitive functions during aging. Indeed, in the subventricular zone, the balance between neurons and glial cells would be in favour of neurogenesis in the dorsal part while oligodendrogenesis would be favoured in the horn. Stimulation of neurogenesis could help replace neurons lost due to injury or aging. Among the possible strategies to stimulate neurogenesis, food and physical activity seem pertinent. During this thesis project, we studied, in particular, the impact of n-3 polyunsaturated fatty acid supplementation and the combination of caloric restriction and physical activity in adulthood. These interventions induced an improvement of cognitive functions associated with an increase in the number of new neurons. These different approaches constitute a promising strategy without drugs against cognitive decline during aging by participating in brain plasticity

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Badsha, Farhath. "A comparative study of neocortical development between humans and great apes." Doctoral thesis, Saechsische Landesbibliothek- Staats- und Universitaetsbibliothek Dresden, 2017. http://nbn-resolving.de/urn:nbn:de:bsz:14-qucosa-224196.

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The neocortex is the most recently evolved part of the mammalian brain which is involved in a repertoire of higher order brain functions, including those that separate humans from other animals. Humans have evolved an expanded neocortex over the course of evolution through a massive increase in neuron number (compared to our close relatives-‐‑ the chimpanzees) in spite of sharing similar gestation time frames. So what do humans do differently compared to chimpanzees within the same time frame during their development? This dissertation addresses this question by comparing the developmental progression of neurogenesis between humans and chimpanzees using cerebral organoids as the model system. The usage of cerebral organoids, has enabled us to compare the development of both the human neocortex, and the chimpanzee neocortex from the very initiation of the neural phase of embryogenesis until very long periods of time. The results obtained so far suggest that the genetic programs underlying the development of the chimpanzee neocortex and the human neocortex are not very different, but rather the difference lies in the timing of the developmental progression. These results show that the chimpanzee neocortex spends lesser time in its proliferation phase, and allots lesser time to the generation of its neurons than the human neocortex. In more scientific terms, the neurogenic phase of the neocortex is shorter in chimpanzees than it is in humans. This conclusion is supported by (1) an earlier onset of gliogenesis in chimpanzees compared to humans which is indicative of a declining neurogenic phase, (2) an earlier increase in the chimpanzee neurogenic progenitors during development, compared to humans, (3) a higher number of stem cell– like progenitors in human cortices compared to chimpanzees, (4) a decline in neurogenic areas within the chimpanzee cerebral organoids over time compared to human cerebral organoids.

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Gouazé, Alexandra. "Implication de la plasticité cérébrale hypothalamique dans la régulation de l'homéostasie énergétique chez la souris : effet d'un régime gras." Phd thesis, Université de Bourgogne, 2012. http://tel.archives-ouvertes.fr/tel-00841824.

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L'hypothalamus joue un rôle crucial dans le contrôle de l'homéostasie énergétique. Chez l'adulte, cette zone est plastique afin de s'adapter rapidement aux pressions environnementales. Ces remodelages hypothalamiques sont perturbés lors de pathologies métaboliques comme l'obésité. Nous nous sommes demandé si un régime gras provoquant des pathologies de surcharges à long terme, provoquait des modifications rapides du réseau hypothalamique chez l'individu adulte. Pour répondre à cette question, nous avons mis en place un modèle de souris présentant une réponse homéostatique rapide à un régime gras, et nous avons évalué deux types de plasticités hypothalamiques: la plasticité synaptique et la neurogenèse. Nos résultats montrent une stimulation des neurones anorexigènes dès les 3 premiers jours sous régime. Ce phénomène implique la polysialisation de la protéine d'adhésion NCAM. Nous avons également démontré que le remaniement de ces connexions synaptiques s'accompagne d'une augmentation de la prolifération cellulaire. Le blocage de cette prolifération avec l'anti-mitotique araC empêche la réponse homéostatique et accélère de manière drastique l'apparition de l'obésité. Ceci suggère que les nouvelles cellules produites sont essentielles pour le maintien de l'équilibre énergétique. Ces nouvelles cellules se différencient majoritairement en neurones quelque soit le régime, mais le régime gras va diriger la maturation des nouveaux neurones vers un phénotype anorexigène. Nos expériences montrent que suite à un déséquilibre énergétique, l'hypothalamus subit une succession de modifications plastiques conduisant à un rapide rétablissement de l'homéostasie énergétique

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Barkas, Lisa Jane. "The role of adult neurogenesis on learning and memory in humans and animals with temporal lobe epilepsy." Thesis, Open University, 2013. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.664607.

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Mesial temporal lobe epilepsy (MTLE) is the most common drug resistant form of epilepsy, and is associated with progressive memory impairment. Currently there is no pharmacological means to restore memory function in these patients, making it a significant unmet therapeutic need. This research thesis shows severe impairment in spatial memory acquisition and long term retention on a virtual Morris Water Maze (MWM) task in patients who had trans-slyvian selective amagdalohippocampectomies as treatment for MTLE. This pattern of impairment was also found in patients with MTLE and with MRI positive hippocampal sclerosis. Memory impairment in MTLE has been associated with depleted levels of stem cell derived new neurons, a process called neurogenesis which occurs almost exclusively in the dentate gyrus of the hippocampus; a brain area frequently associated with memory. Rats with kainate induced epilepsy also show learning and memory deficits on a MOlTis Water Maze We have shown that neurogenesis is depleted in chronic animal models of epilepsy, supporting the theory that there is a temporary increase in neurogenesis post insult but then a chronic depletion in the levels of neurogenesis. We are also one of a very small number of studies able to show abnonnal neurite sprouting in new neurons born in the chronically epileptic hippocampus. Uniquely we have been able to restore spatial learning ability and reverse the reduction in neurogenesis seen in chronically epileptic animals by administration of chronic dose of fluoxetine, although this did not alleviate the accelerated forgetting impairment. This opens a possible therapeutic avenue for h·eating spatial memory impairment in patients with MTLE.

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Ho, Joses Wei-hao. "Functional investigation of microRNA pathways in human speech and language disorders." Thesis, University of Oxford, 2014. http://ora.ox.ac.uk/objects/uuid:0e350300-03b0-4d0b-ba8f-6548d66494bc.

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Wahlund, Thomas. "Emotional resilience in humans as an effect of hippocampal pattern separation." Thesis, Högskolan i Skövde, Institutionen för biovetenskap, 2021. http://urn.kb.se/resolve?urn=urn:nbn:se:his:diva-19925.

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Pattern separation is the means by which the brain discriminates similar experiences. It enables retrieval of individuated memories without confusing them with other memories. It is the reason one remembers where one parked the car today and does not mix it up with where one parked it previously. Adult neurogenesis refers to the ongoing production of neurons in the mature brain. One of the likely roles of adult neurogenesis in the hippocampus is facilitating pattern separation. Induced reduction of adult neurogenesis in non-human animals is associated with depression- and anxiety-like behaviors. One possible explanation is that reduced neurogenesis leads to reduced pattern separation, further leading to overgeneralization of threat situations. Instead of perceiving threats where it should, the animal risks perceiving threats everywhere. Emotional resilience is the ability to recover from adversity with a minimum of lingering negative effects such as depression or anxiety. This thesis investigates whether pattern separation in the human hippocampus supports emotional resilience. I performed a systematic review of studies that used the Mnemonic Similarity Task – a memory task commonly used to measure human pattern separation – to investigate the relationship between pattern separation and anxiety. The results are inconclusive but suggest a possible interaction effect whereby pattern separation and high-arousal states like stress predict anxiety. Together with the evidence from the non-human animal studies, this suggests that reduced pattern separation as caused by reduced neurogenesis could make one vulnerable to developing anxiety disorders.

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Secolin, Rodrigo. "Aplicação de modelos estatísticos e desenvolvimento de algoritmos para estudo genético de doenças neuro-psiquiátricas." [s.n.], 2011. http://repositorio.unicamp.br/jspui/handle/REPOSIP/309732.

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Orientador: Iscia Teresinha Lopes Cendes Tese (doutorado) - Universidade Estadual de Campinas, Faculdade de Ciências Médicas Made available in DSpace on 2018-08-17T11:06:08Z (GMT). No. of bitstreams: 1 Secolin_Rodrigo_D.pdf: 5866562 bytes, checksum: 5079bfd5d88341ce619480ba6e19fb16 (MD5) Previous issue date: 2011 Resumo: Fatores genéticos têm sido descritos para diversas doenças do sistema nervoso central. Uma etapa importante na identificação de genes responsáveis por estas doenças são os estudos de mapeamento genético. Além disso, devido às novas tecnologias de aquisição de dados de genótipos dos indivíduos, é necessário o estudo e desenvolvimento de programas de processamento de grande quantidade de dados para as análises estatísticas. Os objetivos deste trabalho foram: 1) criar uma interface entre os equipamentos de aquisição de dados de genótipos e os programas estatísticos, por meio de programas de processamento de dados; 2) aplicar e avaliar os modelos estatísticos em amostras de famílias segregando três doenças neuro-psiquiátricas: epilepsia do lobo temporal mesial (ELTM), polimicrogiria perisylviana bilateral congênita (PPBC) e transtorno afetivo bipolar (TAB). A interface foi desenvolvida a partir de um algoritmo lógico, o qual adiciona a matriz dos dados dos genótipos provenientes dos equipamentos em uma matriz representativa dos dados das famílias. Este algoritmo, denominado JINGLEFIX, foi programado em linguagem de computador PERL e ambiente R e utilizado posteriormente nos estudos de mapeamento genético da ELTM, PPBC e TAB. Análise de segregação foi realizada em 148 famílias nucleares com ELTM, com um total de 698 indivíduos, visto que esta síndrome não possui padrão de herança conhecido. Uma família, segregando PPBC com um total de 15 indivíduos e um padrão conhecido de herança ligada ao X dominante, foi submetida à análise paramétrica de ligação por meio do pacote de programas LINKAGE, utilizando 18 marcadores microssátelites na região candidata Xq27-Xq28. Análise não paramétrica de ligação realizada em uma amostra de 74 famílias segregando TAB, totalizando 411 indivíduos, por meio do teste de transmissão de desequilíbrio de ligação (TDT), utilizando 21 single nucleotide polymosphisms (SNPs) para 21 regiões candidatas. A análise de segregação revelou a presença de um gene de maior efeito com um padrão autossômico dominante, além da presença de genes de menor efeito influenciando no fenótipo da ELTM. O posterior mapeamento genômico da ELTM, utilizando os parâmetros definidos na análise de segregação, revelou ligação genética na região 18p11. A análise paramétrica de ligação genética levou ao mapeamento da região Xq27 para a família com PPBC, diferente da região candidata previamente descrita. Esta diferença pode ser explicada pelo tipo de amostra familiar utilizada pelos dois estudos. Em relação ao TAB, a análise não paramétrica identificou a região candidata 3p22. Posterior estudo de refinamento da região 3p21-3p22 utilizando 94 SNPs adicionais e estudo de expressão gênica identificou o gene ITGA9 como possível gene de susceptibilidade para o TAB. Comparando o poder estatístico entre as análises, foi observado maior poder estatístico na análise paramétrica utilizando uma ou poucas famílias, com um número grande de indivíduos por família; enquanto que o poder estatístico foi maior nas análises não paramétricas utilizando múltiplas famílias de tamanhos moderados e estruturas variadas. Conclui-se que o algoritmo de processamento de dados e a adequada aplicação dos modelos estatísticos são fundamentais para sucesso do mapeamento genético das regiões e dos genes responsáveis pelas doenças neuro-psiquiátricas estudadas Abstract: Genetic factors have been described for several central nervous system diseases. A main step for disease gene identification is genetic mapping study. In addition, due new genotype acquire technology, the development of genotype processing data software is required. The objectives of this work were: 1) to generate interface between genotype equipment and statistical software by processing data algorithm; 2) to apply and evaluate statistical models in family sample segregating three neurological diseases: mesial temporal lobe epilepsy (MTLE), bilateral perysilvian polymicrogyria (BPP) and bipolar affective disorder (BPAD). Data interface was developed from a logic algorithm, which adds a genotype matrix data from equipment to a family data matrix. This algorithm, called JINGLEFIX, was implemented in PERL computer language and R environment. In addition, this software was used in genetic mapping study for MTLE, BPP and BPAD. Segregation analysis was performed in 148 nuclear MTLE pedigrees, with a total of 698 individuals, since this syndrome has not known inheritance pattern. One BPP pedigree with known X-linked dominant pattern of inheritance, with a total of 15 individuals, was submitted to parametric linkage analysis by LINKAGE package, using 18 microsatellite markers on candidate region Xq27-Xq28. Non-parametric linkage analysis was performed from 74 BPAD families, with a total of 411 individuals, by transmission disequilibrium test (TDT) and using 21 single nucleotide polymorphisms (SNPs) for 21 candidate regions. Segregation analysis revealed a major effect gene with an autosomal dominant pattern of inheritance and minor gene effect, which could influence MTLE phenotype. Further whole genome analysis mapped the putative MTLE major gene on 18p11. Parametric linkage analysis mapped Xq27 locus for BPP, a different region compared to the Xq28 previous described. This difference could be explained to sample type used by the two studies. Non-parametric linkage for BPAD identified the candidate region on 3p22. Further studies using 94 additional SNPs on 3p21-3p22 and gene expression analysis identified ITGA9 as susceptibility gene for BPAD. A comparison of statistical power between statistical analyses showed a high statistical power for parametric linkage analysis from one or a few large families; whereas a high statistical power was observed for non-parametric linkage analysis using several moderate size families. The conclusion of this study is that data processing algorithm and adequate statistical model applying are fundamental tools for successful of genetic mapping of complex diseases Doutorado Neurociencias Doutor em Ciências

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Etievant, Adeline. "Stimulation du cortex préfrontal : Mécanismes neurobiologiques de son effet antidépresseur." Phd thesis, Université Claude Bernard - Lyon I, 2012. http://tel.archives-ouvertes.fr/tel-00865594.

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La stimulation cérébrale profonde (DBS) du gyrus cingulaire subgénual est actuellement en coursd'évaluation comme nouvelle cible thérapeutique chez les patients souffrant de dépression majeure.Afin de caractériser les mécanismes sous-jacents l'action de la DBS, et plus particulièrement, lapossible implication du système glial, les effets de la stimulation du cortex préfrontal infralimbique surplusieurs marqueurs précliniques de la réponse antidépressive ont été évalués chez le rat. Ce travailde thèse, en utilisant des approches électrophysiologiques, immunohistochimiques etcomportementales, montre que la DBS aigue (130 Hz, 150 μA) induit des comportements pseudoantidépresseurs(évalués dans le test de nage forcée) qui sont associés à une augmentation del'activité des neurones 5-HT du raphé dorsal et de la neurogenèse du gyrus denté. De plus, la DBSaigue est capable de renverser les effets du stress sur la métaplasticité synaptique hippocampique.Par ailleurs, la DBS à plus faible intensité (20 μA, 130 Hz) induit des effets pro-cognitifs, i.e. unefacilitation de la plasticité synaptique au sein de l'hippocampe dorsal et une amélioration desperformances mnésiques des rats dans le test de reconnaissance d'objet. De façon importante, ceseffets neurobiologiques sont prévenus par une lésion pharmacologique gliale avec la gliotoxine Lalpha-aminoadipic acid. Ensemble, nos données in vitro et in vivo soulignent pour la première fois lerôle crucial des astrocytes dans les mécanismes d'action de la DBS. Cette étude propose donc quel'intégrité du système glial au niveau le site de stimulation est un pré-requis majeur afin d'optimiserl'efficacité de la DBS

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Nogueira, Adriano Barreto. "Mapeamento de potencial nicho neurogênico no lobo temporal humano." Universidade de São Paulo, 2014. http://www.teses.usp.br/teses/disponiveis/5/5138/tde-13082014-152043/.

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No final do século 19, o neurônio foi descrito como a unidade funcional básica do sistema nervoso e sua formação era considerada inexistente na fase adulta, explicando a ausência de recuperação significativa em doenças neurológicas. Evidências de geração de neurônios em mamíferos adultos surgiram na década de 1960 e foram confirmadas três décadas depois. Atualmente, predomina a visão de que mamíferos adultos possuem dois nichos neurogênicos independentes: a zona subventricular (ZSV) e a zona subgranular (ZSG) do giro denteado. No entanto, a existência de nichos neurogênicos em humanos adultos é controversa. Nossa hipótese foi de que o mapeamento de nichos neurogênicos no lobo temporal humano poderia esclarecer aspectos sobre a neurogênese adulta. A detecção destes nichos foi buscada em 28 lobos temporais através de imuno-histoquímica para nestina, o marcador mais comum de células-tronco neurais, que são aquelas capazes de se autorrenovar e de gerar novas células neurais. A neurogênese foi pesquisada no hipocampo pelo uso de DCX (do inglês \"doublecortin\"), o principal marcador de neuroblastos e neurônios imaturos. Nestina foi observada em uma camada contínua formada pela ZSV, zona subpial do lobo temporal medial e ZSG, terminando no subículo. A partir do subículo, uma intensa expressão de DCX ocorreu através da principal via eferente do hipocampo até a fímbria. A visão panorâmica das marcações por nestina e DCX mostrava em conjunto uma linha que circundava as estruturas límbicas do lobo temporal. Por isto, foi denominada linha externa de células do sistema límbico (LECEL). Uma possível explicação para os resultados é que a LECEL seja um nicho neurogênico no qual a ZSV, a zona subpial do lobo temporal medial e a ZSG formam uma unidade contendo células-tronco neurais que se diferenciam em neurônios no subículo. Curiosamente, a área identificada previamente como sendo a corrente migratória rostral humana (formada por células neurais imaturas migrando a partir da ZSV do corno frontal) pode ser na verdade o fórnix, que contém axônios originados no subículo. A implicação mais intrigante dos resultados é que se as características da LECEL seguirem além do lobo temporal, então o encéfalo humano pode conter um anel neurogênico límbico, em que a neurogênese ocorreria principalmente no subículo e seria modulada pelas estruturas relacionadas à fissura coroideia. Este estudo sugere que a neurogênese ocorre de maneira orquestrada em uma área ampla do lobo temporal humano At the end of the 19th century, the neuron was described as the basic functional unit of the nervous system. The formation of neurons was thought to be absent in adulthood, thus explaining the lack of significant recovery from neurological diseases. Evidence for the generation of neurons in adult mammals was reported in the 1960s and confirmed three decades later. Currently, the prevailing view is that adult mammals harbour two neurogenic niches: the subgranular zone (SGZ) of the dentate gyrus and the subventricular zone (SVZ). Nonetheless, the existence of these niches in adult humans is controversial. We hypothesised that mapping neurogenic niches in the human temporal lobe could clarify this issue. The presence of neurogenic niches was examined in 28 temporal lobes via immunostaining for nestin, the most common marker for neural stem cells, which are cells with the capacities of self-renewal and the generation of neural cells. The presence of neurogenesis was examined in the hippocampus with doublecortin (DCX), a prominent marker for neuroblasts and immature neurons. Nestin was observed in a continuous layer that was formed by the SVZ, the subpial zone of the medial temporal lobe and the SGZ, terminating in the subiculum. In the subiculum, remarkable DCX expression was observed through the principal efferent pathway of the hippocampus to the fimbria. A panoramic view of nestin and DCX staining collectively displayed a line that surrounded the limbic structures of the temporal lobe. Hence, we termed it the external line of cells of the limbic system (EXCEL). A possible explanation for the results is that the EXCEL is a neurogenic niche, in which the SVZ, the subpial zone of the medial temporal lobe and the SGZ form a unit containing neural stem cells that differentiate into neurons in the subiculum. Curiously, the area previously identified as the human rostral migratory stream (formed by immature neural cells that migrate from the SVZ of the frontal horn) may in truth be the fornix, which contains axons that originate in the subiculum. Perhaps most intriguingly, if the EXCEL acts as a neurogenic niche beyond the boundaries of the temporal lobe, the human brain may contain a limbic neurogenic ring, in which neurogenesis would occur in the subiculum through the modulation of choroid fissure-related structures. This study suggests that neurogenesis may occur in an orchestrated manner in a broad area of the human temporal lobe

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Attias, Lior Rivka, and Lior Rivka Attias. "A genetic understanding of language development through cognitive and neurogenetic studies: an exploration of the FOXP2 gene, songbird development, human language, and autism." Thesis, The University of Arizona, 2017. http://hdl.handle.net/10150/626743.

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It is well known that FOXP2 has a connection to human language. In a familial case study of humans in one family with a mutated FOXP2, it was found that all members showed Developmental Verbal Dyspraxia, a cognitive language deficit. In knock out experiments in mice, it was found that FOXP2 is critical for Purkinje cell development in the brain as well as lung development. In FOXP2 knock out experiments in songbirds, it was found that songbirds could no longer learn new songs or cognitively understand song, which is used as a type of language in these animals. In knock in experiments with rats, it was found that rats with humanized FOXP2 show increased ability to switch between two central types of learning, a critical aspect of habit formation. It is thought that this habit formation is the basis of human language learning and development. Through a deep analysis of studies such as these, as well as of the genetic structure of FOXP2, it is hypothesized that the FOXP2 gene plays a critical role in allowing for appropriate connectivity on neurons in the brain, which could explain its role in language understanding and development, as well as its role in Autism in humans.

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Xia, Lin. "Analyse de profils d'expression génique dans des modèles murins d'anxiété/dépression." Phd thesis, Université Paris Sud - Paris XI, 2012. http://tel.archives-ouvertes.fr/tel-00923149.

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Dans le cadre de la modélisation des pathologies anxio-dépressives, notre équipe a créé par des approches génétiques et pharmacologiques deux modèles de souris, les souris privées des récepteurs 5-HT1A et 5-HT1B de la sérotonine (5-HT1A/1B-/-) et les souris CORT ayant reçu une exposition chronique de corticostérone exogène (modèle CORT). Ces modèles présentent respectivement un phénotype hyper anxieux et anxio-dépressif. A l'aide de la technique des puces à ADN, nous avons tenté de caractériser le phénotype moléculaire des troubles comportementaux observés dans les différentes régions cérébrales cortico-limbiques de ces modèles et de rechercher les effets des antidépresseurs sur le transcriptome. Nos études ont montré que les états anxio-dépressifs induisent des changements transcriptomiques spécifiques des différentes régions cérébrales du circuit cortico-limbique. Les traitements antidépresseurs ont non seulement inversé ces changements moléculaires, mais également induit des transcriptions génomiques régionales spécifiques.

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Cavallin, Mara. "Physiopathologie moléculaire et cellulaire des anomalies du développement du cortex cérébral : le syndrome d'Aicardi WDR81 mutations cause extreme microcephaly and impair mitotic progression in human fibroblasts and Drosophila neural stem cells TLE1, a key player in neurogenesis, a new candidate gene for autosomal recessive postnatal microcephaly Mutations in TBR1 gene leads to cortical malformations and intellectual disability Aicardi syndrome: Exome, genome and RNA-sequencing of a large cohort of 19 patients failed to detect the genetic cause Recurrent RTTN mutation leading to severe microcephaly, polymicrogyria and growth restriction Recurrent KIF2A mutations are responsible for classic lissencephaly Recurrent KIF5C mutation leading to frontal pachygyria without microcephaly Rare ACTG1 variants in fetal microlissencephaly De novo TUBB2B mutation causes fetal akinesia deformation sequence with microlissencephaly: An unusual presentation of tubulinopathy A novel recurrent LIS1 splice site mutation in classic lissencephaly Further refinement of COL4A1 and COL4A2 related cortical malformations Prenatal and postnatal presentations of corpus callosum agenesis with polymicrogyria caused By EGP5 mutation Delineating FOXG1 syndrome from congenital microcephaly to hyperkinetic encephalopathy Delineating FOXG1 syndrome: From congenital microcephaly to hyperkinetic encephalopathy." Thesis, Sorbonne Paris Cité, 2019. https://wo.app.u-paris.fr/cgi-bin/WebObjects/TheseWeb.woa/wa/show?t=2213&f=18201.

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Les malformations du cortex cérébral (MDC) représentent une cause importante de handicap et d'épilepsie pharmaco-résistante. Le séquençage à haut débit a permis une amélioration considérable de l'identification des bases moléculaires des MDC non syndromiques. Toutefois, certaines formes, notamment les MDC complexes, demeurent inexpliquées. Mon projet de thèse a pour objectif de progresser dans la compréhension des MDC complexes en utilisant deux modèles : les microlissencéphalies (MLIS) et le syndrome d'Aicardi (AIC), une forme syndromique particulière associant des malformations de l'oeil et du cerveau uniquement rapporté chez les filles. L'étude par séquençage d'exome en trios de 16 familles MLIS m'a permis d'identifier et de caractériser un nouveau gène, WDR81, impliqué dans le cycle cellulaire. Par la même stratégie, j'ai pu identifier un variant homozygote pathogène dans TLE1, un partenaire majeur de FOXG1 dans la balance prolifération/différenciation de progéniteurs neuronaux, dans une famille consanguine de microcéphalie postnatale dont le phénotype est proche du syndrome FOXG1. En parallèle, mes travaux ont permis de préciser les spectres phénotypiques associés à RTTN, EPG5, COL4A1, COL4A2, TBR1, KIF5C, KIF2A et FOXG1. La deuxième partie de mon projet avait pour objet l'identification des bases moléculaires du syndrome d'Aicardi à partir d'une cohorte internationale de 19 patientes. Après avoir exclu un biais d'inactivation du chromosome X et la présence de microremaniements chromosomiques, j'ai réalisé un séquençage d'exome en trio. Aucun variant récurrent n'a été retrouvé dans les séquences codantes. Dans un second temps, j'ai testé une approche combinant les données du séquençage de génome et l'analyse du transcriptome (RNA-Seq) sur fibroblastes, me permettant d'identifier des transcrits dérégulés qui étaient impliqués dans le développement du cerveau et de l'oeil. J'ai comparé les résultats de cette analyse avec ceux de l'analyse du génome dans le but d'identifier des variants dans ces gènes candidats. En conclusion, mon travail de thèse a permis d'améliorer la connaissance des bases moléculaires des MDC complexes et d'ouvrir des perspectives de nouveaux mécanismes tels que ceux engageant les gènes WDR81 et EPG5, et le rôle des endosomes et de l'autophagie dans les MDC, et aussi TLE1 comme nouvelle cause de microcéphalies postnatales. Mes travaux ont également permis de générer une collection de données de séquençage haut débit (WES, WGS et RNA-Seq) qui seront mises en commun dans le cadre d'un consortium international afin de développer des nouvelles stratégies d'analyse en particulier pour les séquences non codantes. Cette approche permettra également d'ouvrir la voie vers la compréhension des mécanismes cellulaires impliqués dans la formation du cerveau et de l' œil Malformations of cortical development (MCD) are a major cause of intellectual disability and drug-resistant epilepsy. Next Generation Sequencing (NGS) has considerably improved the identification of the molecular basis of non-syndromic MCD. However, certain forms, including complex MCD, remain unexplained. My PhD project aimed to improve the understanding of complex MCD using two disorders: Microlissencephaly (MLIS) and Aicardi Syndrome (AIC), the latter associating brain and eye malformations and only reported in girls. Trio Whole Exome Sequencing (WES) performed in 16 MLIS families allowed me to identify and functionally characterize a new MLIS gene, WDR81, in which mutations lead to cell cycle alteration. Moreover, using the same strategy, I was able to identify a pathogenic homozygous variant in TLE1 in a patient from consanguineous family with a postnatal microcephaly, suggestive of a FOXG1-like presentation. Interestingly, TLE1 is a major partner of FOXG1, a gene involved in maintaining the balance between progenitor proliferation and differentiation. In parallel, my work allowed me to redefine the phenotypic spectrum associated with RTTN, EPG5, COL4A1 and COL4A2, TBR1, KIF5C, KIF2A and FOXG1. The second part of my PhD program was aimed at identifying the genetic basis of AIC in an international cohort of 19 patients. After excluding a skewed X chromosome inactivation and the presence of chromosomal rearrangements, I performed WES in trios. The analysis of the data from WES did not allow me to identify any recurrent variants. I therefore tested a new approach combining Whole Genome Sequencing (WGS) and RNA-Sequencing (RNA-Seq) on fibroblast cells. I identified a number of deregulated transcripts implicated in brain and eye development. I compared the results of this analysis with the WGS analysis in order to find variants in these candidate genes. In conclusion, these studies have improved the knowledge of the molecular basis of complex MCD, such as TLE1 in postnatal microcephaly, and revealed the pathogenic mechanisms such as WDR81 in cell cycle progression and EPG5 in endosomes and autophagy. My work has also generated a collection of NGS data (WES, WGS and RNA-Seq) that will be shared in an international consortium to develop new analytical strategies, in particular for the non-coding DNA regions. This novel strategy provides opportunities to improve understanding of the cellular mechanisms involved in brain and eye development

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Ahmad, Ruhel. "Neurogenesis from parthenogenetic human embryonic stem cells." Doctoral thesis, 2012. https://nbn-resolving.org/urn:nbn:de:bvb:20-opus-75935.

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Imprinted genes play important roles in brain development. As the neural developmental capabilities of human parthenogenetic embryonic stem cells (hpESCs) with only a maternal genome were not assessed in great detail, hence here the potential of hpESCs to differentiate into various neural subtypes was determined. In addition DNA methylation and expression of imprinted genes upon neural differentiation was also investigated. The results demonstrated that hpESC-derived neural stem cells (hpNSCs) showed expression of NSC markers Sox1, Nestin, Pax6, and Musashi1 (MS1), the silencing of pluripotency genes (Oct4, Nanog) and the absence of activation of neural crest (Snai2, FoxD3) and mesodermal (Acta1) markers. Moreover, confocal images of hpNSC cultures exhibited ubiquitous expression of NSC markers Nestin, Sox1, Sox2 and Vimentin. Differentiating hpNSCs for 28 days generated neural subtypes with neural cell type-specific morphology and expression of neuronal and glial markers, including Tuj1, NeuN, Map2, GFAP, O4, Tau, Synapsin1 and GABA. hpNSCs also responded to region-specific differentiation signals and differentiated into regional phenotypes such as midbrain dopaminergic- and motoneuron-type cells. hpESC-derived neurons showed typical neuronal Na+/K+ currents in voltage clamp mode, elicited multiple action potentials with a maximum frequency of 30 Hz. Cell depicted a typical neuron-like current pattern that responded to selective pharmacological blockers of sodium (tetrodotoxin) and potassium (tetraethylammonium) channels. Furthermore, in hpESCs and hpNSCs the majority of CpGs of the differentially methylated regions (DMRs) KvDMR1 were methylated whereas DMR1 (H19/Igf2 locus) showed partial or complete absence of CpG methylation, which is consistent with a parthenogenetic (PG) origin. Upon differentiation parent-of-origin-specific gene expression was maintained in hpESCs and hpNSCs as demonstrated by imprinted gene expression analyses. Together this shows that despite the lack of a paternal genome, hpNSCs are proficient in differentiating into glial- and neuron-type cells, which exhibit electrical activity similar to newly formed neurons. Moreover, maternal-specific gene expression and imprinting-specific DNA-methylation are largely maintained upon neural differentiation. hpESCs are a means to generate histocompatible and disease allele-free ESCs. Additionally, hpESCs are a unique model to study the influence of imprinting on neurogenesis Imprinted Gene spielen eine wichtige Rolle bei der Gehirnentwicklung. Da das neurale Entwicklungspotenzial von hpESCs bisher noch nicht ausführlich untersucht wurde, war das Ziel dieser Arbeit das Differenzierungspotenzial von hpESCs zu verschiedenen neuralen Subtypen zu untersuchen. Außerdem wurden die DNA-Methylierung und Expression imprinted Gene in hpESCs während der neuralen Differenzierung analysiert. Die Ergebnisse zeigten, dass von hpESCs abgeleitete neurale Stammzellen (hpNSCs) die NSC-Marker Sox1, Nestin, Pax6 und Musashi1 (MS1) exprimierten, Pluripotenzmarker-Gene (Oct4, Nanog) abschalteten und keine Aktivierung von Markern der Neuralleistenzellen (Snai2, FoxD3) sowie dem mesodermalen Marker Acta1 stattfand. Immunfärbungen zeigten weiterhin, dass aus hpESCs abgeleitete Stammzellen die NSC-Marker Nestin, Sox1, Sox2 und Vimentin auf Proteinebene exprimierten. Durch gerichtete neurale Differenzierung für 28 Tage konnten aus hpESCs neurale Subtypen abgeleitet werden, die eine neurale Zelltyp-spezifische Morphologie aufweisen und positiv für neuronale und gliale Marker wie Tuj1, NeuN, Map2, GFAP, O4, Tau, Synapsin1 und GABA sind. Um aus hpNSCs dopaminerge und Motoneuronen abzuleiten, wurden während der Differenzierung Morphogene und trophische Faktoren zugegeben. Elektrophysiologische Analysen konnten zeigen, dass die in vitro differenzierten Neuronen, die von hpESCs abgeleitet wurden, für Neurone typische Na+/K+ Ströme sowie Aktionspotentiale (30 Hz) vorweisen ausbilden und auf ausgewählte pharmakologische Natrium- (Tetrodotoxin) und Kalium- (Tetraethylammonium) Kanal-Blocker reagierten. Desweiteren war der Großteil der CpGs von differentiell methylierten Regionen (DMRs) KvDMR1 in hpESCs und hpNSCs methyliert, während DMR1 (H19/Igf2 Locus) eine partiell oder komplett abwesende CpG-Methylierung zeigte, was dem parthenogenetischen Ursprung entspricht. Während der Differenzierung wurde die elternabhängige (parent-of-origin) spezifische Genexpression in hpESCs und hpNSCs aufrechterhalten, wie mit Genexpressionsanalysen imprinted Gene gezeigt werden konnte. In der Summe zeigen die hier dargestellten Ergebnisse, dass hpESCs, die kein paternales Genom besitzen, keine Beeinträchtigung im neuralen Differenzierungspotential zeigten und zu Gliazellen und Neurone differenziert werden konnten. Elektrophysiologische Analysen zeigten ferner, dass von hpESCs abgeleitete Neurone funktionell sind. Zudem wird die Expression maternal-spezifischer Gene und die Imprinting-spezifische DNA-Methylierung während der Differenzierung größtenteils aufrechterhalten. In der Summe stellen hpESCs ein einzigartiges Modell dar, um den Einfluss des Imprintings auf die Neurogenese zu untersuchen

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Nelson, Aaron D. "Growth factors modulate human cortical neurogenesis in vitro." 2006. http://catalog.hathitrust.org/api/volumes/oclc/83779490.html.

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Heyworth, Nadine. "The role of adult neurogenesis and oligodendrogenesis in age-related cognitive decline in the non-human primate." Thesis, 2016. https://hdl.handle.net/2144/16729.

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Cognitive aging is a biological process characterized by physical changes in the brain and subsequent alterations in cognitive function. While neurodegenerative diseases result in extensive neuronal death and anatomical abnormalities, normal aging has subtle changes resulting in a range of cognitive abilities. Early studies of cognitive aging focused on changes in the neuronal population, but evidence has demonstrated that forebrain neurons are largely preserved with age. Furthermore, the proliferation of new neurons in the adult brain has generated great speculation regarding the role and contribution of new neurons to cognitive function. Conversely, both imaging and ultrastructural analyses have shown that age-related alterations in white matter and myelin are good predictors of cognitive impairment, suggesting that alterations in connectivity between brain regions may result in cognitive decline. In this dissertation, a rhesus monkey model of normal aging was used to assess the contribution of adult-neurogenesis and oligodendrogenesis to cognitive function. First, cell proliferation and adult neurogenesis were assessed in the subgranular zone of the hippocampal dentate gyrus. Aged animals demonstrated a decline in proliferating cells and neurogenesis but only limited correlations with behavioral impairment. Immature neurons were also identified in temporal lobe cortices, but results indicate these immature cortical neurons are most likely not adult-generated. Moreover, despite an age-related decline in numbers, they persist throughout the lifespan and many differentiate into Calretinin neurons. Further investigation of white matter alterations used immunohistochemistry and diffusion spectrum imaging to correlate oligodendrocyte numbers with white matter connectivity. In the corpus callosum and cingulum bundle, there were no correlations with age, but cognitive impairment was associated with increased oligodendrocyte number and decreased white matter connectivity. These correlations were only present in the anterior aspect of the cingulum bundle, not the posterior cingulum suggesting differential oligodendrocyte responses along the anterior-posterior axis of the brain. Together, these data demonstrate an age-related decline in adult neurogenesis may be only a small contributor to cognitive impairment. Additionally, a reserve pool of immature neurons continues to differentiate in the temporal cortex potentially contributing to local plasticity. Furthermore, cognitive impairment rather than aging has a stronger correlation with oligodendrocytes alterations and connectivity.

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Palitz, Lauren. "Neurogenesis in the subventricular zone and hippocampus following cell therapy in a non-human primate model of cortical damage." Thesis, 2016. https://hdl.handle.net/2144/19483.

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Approximately 795,000 Americans experience a new or recurrent stroke each year (American Heart Association 2016; Mozaffarian et al. 2016). However, the only experimental therapeutic to have gained FDA approval for treatment of stroke in humans is the thrombolytic agent tPA that can dissolve clots and restore blood flow, if given within a narrow therapeutic window of a few hours following stroke onset (AHA 2016, Li et al. 2016). Nevertheless, in many cases with or without tPA there is significant residual impairment, and there are currently no FDA approved therapeutic agents that facilitate functional recovery following stroke (Zhang L et al. 2012). Recent studies have suggested that neural plasticity and neurogenesis following stroke may play a role in recovery of function, and promising findings have been demonstrated with cell therapies for enhancing recovery after stroke (Kokaia and Darasalia, 2015; Kozorovitskiy et al, 2013; Zhao et al, 2012). Our recent study (Moore et al. 2013) showed significant recovery of function following a reproducible ischemic lesion limited to the hand representation of the motor cortex in non-human primates (NHPs) treated with the investigational cell drug product CNTO 0007, that contains human umbilical tissue-derived cells (hUTC). While the treatment group in this study demonstrated significantly better recovery of motor function, the mechanism of recovery remains unclear. Previous studies conducted with brain tissue from these monkeys have suggested that functional recovery may be related to cortical reorganization induced by the hUTC treatment. To explore the possibility that neurogenesis may have also played a role in the enhanced recovery, these same monkeys received an injection of the thymidine analog Bromodeoxyuridine (BrdU), which was visualized in the brain tissue to investigate cell proliferation in the subventricular zone and hippocampus. Results show that there is no significant difference in the number of BrdU positive cells in the hUTC treated vs. untreated monkeys, however there is a trend towards significant increase in BrdU labeling in the granule cell layer of the hippocampus of the hUTC treated animals. Clusters of proliferating cells were also found in the GCL of treated monkeys, but not in the untreated monkeys. These findings support the hypothesis that enhanced recovery of function may be related to a combination of reorganization of undamaged cortical motor regions and generation of new cells in the brain.

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Großert, Alessandra. "Elucidation of the molecular mechanism of action of psychoactive substances as novel antidepressants." Doctoral thesis, 2020. https://repositorium.ub.uni-osnabrueck.de/handle/urn:nbn:de:gbv:700-202003312713.

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According to the World Health Organization (WHO) depression is the leading cause of disability worldwide with more than 300 million patients affected. Current antidepressants have a delayed onset of action and moreover, only two-thirds of patients suffering from depressive disorder respond to antidepressant drug treatment. The N-methyl-D-aspartate (NMDA) receptor antagonist ketamine offers promising perspectives for the treatment of major depressive disorder. Although ketamine demonstrates rapid and long-lasting effects, even in treatment-resistant patients, to date, the underlying mode of action remains elusive. Thus, the aim of this thesis was to investigate the molecular mechanism of ketamine and its major metabolites at clinically relevant concentrations by establishing an in vitro model based on human induced pluripotent stem cells (iPSCs)-derived neural progenitor cells (NPCs). As the pathophysiology of depression correlates with decreased adult neurogenesis, I aimed to investigate the molecular effects of ketamine on neural progenitor cell proliferation using a human-based iPSC-model. The findings from this thesis substantially contribute to an enhanced understanding of the molecular mode of action of ketamine as a novel signaling pathway involved in ketamine-induced effects was identified. Ketamine induced proliferation of human iPSC-derived NPCs and bioinformatic analysis of RNA-Seq data revealed significant upregulation of insulin-like growth factor2 (IGF2) and p11, a member of the S100 EF-hand protein family, which are both implicated in the pathophysiology of depression, 24 hours after ketamine treatment. In line with this, ketamine dependent proliferation was significantly impaired after IGF2 knockdown. Moreover, ketamine was able to enhance cAMP signaling in NPCs and both, cell proliferation as well as IGF2 expression, were reduced after protein kinase A (PKA)-inhibition. Noteworthy, the Nestin-expressing NPCs do not express functional NMDA receptors, suggesting that the proproliferative effect of ketamine in NPCs is NMDA receptor-independent. Furthermore, 24 hours post administration of ketamine (15 mg/kg) in vivo confirmed phosphorylation of extracellular signal-regulated protein kinases 1 and 2 (ERK1/2) in the subgranular zone (SGZ) of the hippocampus in C57BL/6 mice. In conclusion, ketamine promotes proliferation of NPCs presumably by involving cAMP-IGF2 signaling.

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Chen, Wan-shih, and 陳宛詩. "Human umbilical cord blood-derived CD34+ cells attenuate inflammation but stimulate both angiogenesis and neurogenesis after traumatic brain injury in rats." Thesis, 2012. http://ndltd.ncl.edu.tw/handle/955k2r.

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碩士 嘉南藥理科技大學 藥物科技研究所 100 Umbilical cord blood contained <0.2% CD34+ cells have been shown to be beneficial in reducing neurological deficits in animals after fluid percussion injury（FPI）. This study aimed to generate cord blood-derived CD34+ cells（>95%）and to investigate the mechanisms underlying their beneficial effects in treating FPI in rats. Rats were divided into three groups:（1）sham operation; （2）FPI+CD34- cells（5×105 cord blood lymphocytes and monocytes that containing <0.2% CD34+ cells）; and （3） FPI+CD34+ cells（5×105 cord blood lymphocytes and monocytes that contained 95% CD34+ cells）. Behavioral dysfunction and brain infarction, inflammation, apoptosis, angiogenesis, and neurogenesis were evaluated 4 days post FPI. As compared to sham operation controls, CD34- -treated FPI rats had motor and cognitive dysfunctions and cerebral infarction, apoptosis, and inflammation. FPI-induced neurological dysfunction and cerebral infarction, apoptosis, and inflammation could be significantly attenuated by CD34+ cell therapy. In addition, CD34+ cells migrated to the injured brain regions and significantly promoted both angiogenesis and neurogenesis in the injured brain. The results indicate that therapy using umbilical cord blood-derived CD34+ cells may be beneficial in attenuating traumatic brain injury in rats.

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Stringer, Megan Elizabeth. "Effect of Epigallocatechin-3-gallate on a pattern separation task and hippocampal neurogenesis in a mouse model of Down syndrome." Thesis, 2015. http://hdl.handle.net/1805/10037.

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Indiana University-Purdue University Indianapolis (IUPUI) Down syndrome (DS) is caused by three copies of human chromosome 21 (Hsa21) and results in an array of phenotypes including intellectual disability. Ts65Dn mice, the most extensively studied DS model, have three copies of ~50% of the genes on Hsa21 and display many phenotypes associated with DS, including cognitive deficits. DYRK1A is found in three copies in humans with Trisomy 21 and in Ts65Dn mice, and is involved in a number of critical pathways including CNS development and osteoclastogenesis. Epigallocatechin-3-gallate (EGCG), the main polyphenol in green tea, inhibits Dyrk1a activity. We have shown that a three-week EGCG treatment (~10mg/kg/day) during adolescence normalizes skeletal abnormalities in Ts65Dn mice, yet the same dose did not rescue deficits in the Morris water maze spatial learning task (MWM) or novel object recognition (NOR). Others have reported that An EGCG dose of 2-3 mg per day (90mg/ml) improved hippocampal-dependent task deficits in Ts65Dn mice. The current study investigated deficits in a radial arm maze pattern separation task in Ts65Dn mice. Pattern separation requires differentiation between similar memories acquired during learning episodes; distinguishing between these similar memories is thought to depend on distinctive encoding in the hippocampus. Pattern separation has been linked to functional activity of newly generated granule cells in the dentate gyrus. Recent studies in Ts65Dn mice have reported significant reductions in adult hippocampal neurogenesis, and after EGCG treatment, enhanced hippocampal neurogenesis. Thus, it was hypothesized that Ts65Dn mice would be impaired in the pattern separation task, and that EGCG would alleviate the pattern separation deficits seen in trisomic mice, in association with increased adult hippocampal neurogenesis. At weaning, Ts65Dn mice and euploid littermates were randomly assigned to the water control, or EGCG [0.4 mg/mL], with both treatments yielding average daily intakes of ~50 mg/kg/day. Beginning on postnatal day 75, all mice were trained on a radial arm maze-delayed non-matching-to-place pattern separation task. Euploid mice performed significantly better over training than Ts65Dn mice, including better performance at each of the three separations. EGCG did not significantly alleviate the pattern separation deficits in Ts65Dn mice. After the behavioral testing commenced, animals were given ad libitum food access for five days, received a 100mg/kg injection of BrdU, and were perfused two hours later. Coronal sections through the dorsal hippocampus were processed for BrdU labeling, and cells were manually counted throughout the subgranular zone of the dentate gyrus. The euploid controls had significantly more BrdU labeled cells than Ts65Dn mice, however, EGCG does not appear to increase proliferation of the hippocampal neuroprogenitor cells. This is the first report of deficits in Ts65Dn mice on a pattern separation task. To the extent that pattern separation depends on the functional involvement of newly generated neurons in an adult dentate gyrus, this approach in Ts65Dn mice may help identify more targeted pharmacotherapies for cognitive deficits in individuals with DS.

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Miljus, Natasa. "Erythropoietin-mediated neuroprotection in insects." Doctoral thesis, 2016. http://hdl.handle.net/11858/00-1735-0000-0028-881F-A.

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Kerr, Fiona. "Creating and leading adaptive organisations: the nature and practice of emergent logic." Thesis, 2014. http://hdl.handle.net/2440/91144.

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This study examines how leaders enable their organisations to adapt and succeed in complex environments. Through the joint lenses of complexity theory and the cognition and social neuroscience of leadership it focuses on how leadership directly influences the creation and ongoing function of an adaptive organisation. The study includes the comparison of four leaders through embedded case studies as an abductive approach to initial theory building, and the follow up of two of them as a comparative method of analysis, and it generates a substantive theory of leadership cognition called emergent logic. This leadership approach is especially relevant to leading complex human systems in emergent environments, the scenario for the majority of organisations in the present day. This thesis addresses two questions: How do leaders of adaptive organisations think? And what do leaders of adaptive organisations do? Among the major findings the study reveals that a critical success factor is the leader’s capacity to create and guide a complex human system by establishing and maintaining a shared mental model of its collective purpose, guided by deeply held and articulated values. The cognitive constructs of complexity and emergent logic have a direct and indirect effect on individuals and the organisation, and facilitate the creation of an adaptive operational culture and organisational mind, and the complementary enabling structures that allow for ongoing evolution through emergence, transformation and diffusion as required. Thus the organisation and its people can progressively build more complex emergent mental models and solutions in the face of increasingly common unpredictable situations, leading to the capability for organisational adaption and evolution over time. In contributing to the theory of creating and leading adaptive organisations, supported by empirical research, this study has improved our understanding of the effect of the leader’s cognitive capacity on organisational adaptability and the level of entanglement; revealed the links between the creation of adaptive organisational structures and their culture; examined the growth of individual and collective capability to manage the increasing complexity and emergence created by successful adaption and evolution; identified the common elements of various types of complex systems that are relevant to adaptive change; presented a model of emergent logic and described the empirical use of that model over time. Thesis (Ph.D.) -- University of Adelaide, Business School, 2014

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Bayer, Ronny. "Veränderungen der adulten Neurogenese im Hippocampus von Drogenabhängigen: Immunhistochemische Untersuchungen mit ausgewählten Neurogenesemarkern." Doctoral thesis, 2014. https://ul.qucosa.de/id/qucosa%3A13236.

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Die Neubildung von Neuronen persistiert lebenslang in der Subgranularzellschicht des Hippocampus und der Subventrikularzone des Großhirns und wird als adulte Neuroge-nese bezeichnet. Es wird vermutet, dass diese beim erwachsenen Menschen einen rele-vanten Einfluss auf degenerative Veränderungen, verschiedene neurologische Krank-heitsbilder und auf die (Dys-)Funktion des Gedächtnisses hat. Im Tiermodell wurde eine Verringerung der Neurogenese nach chronischer Morphingabe nachgewiesen. Vorarbeiten zeigten einen Zusammenhang zwischen chronischem Heroinmissbrauch und reaktiver Astrogliose, Mikrogliose und einer vermehrten Expression des polysialylated neural cell adhesion molecule im humanen Hippocampus. Daraus leitet sich die Hypothese ab, dass chronischer Heroinmissbrauch, als Modell für eine Abhängigkeitserkrankung, einen Einfluss auf die adulte humane Neurogenese hat. Es wurden in Formalin fixierte Gewebeproben aus dem Hippocampus von Verstorbenen mit einer letalen Heroinintoxikation und mit bekanntem Heroinmissbrauch (n = 20) un-tersucht und mit einer nach Alter und Geschlecht angepassten Kontrollgruppe (n = 28) verglichen. Hierbei wurden spezifische Neurogenesemarker mittels immunhistochemi-scher Methoden angewendet und ausgewertet. Es bestand eine generell sehr geringe zelluläre Proliferationsrate und eine signifikante Reduktion Musashi-1 positiver neuro-naler Vorläuferzellen bei gleichzeitig unveränderter Anzahl Nestin positiver reifender und Calretinin positiver migrierender postmitotischer Neurone. Zudem wurde ein ver-ändertes Calretinin-Expressionsmuster als Hinweis auf eventuelle funktionelle neuronale Defizite bei Drogenabhängigen festgestellt. Der potentielle Einfluss von chronischem Heroinmissbrauch auf die adulte humane Neurogenese wird erstmals gezeigt. Die Ergebnisse weisen auf eine negative Beeinflus-sung im Stadium neuronaler Vorläuferzellen und der Zellfunktion migrierender Neurone in der Fallgruppe im Vergleich zu einer gesunden Kontrollgruppe hin. Diese Hemmung der Neurogenese könnte eine Erklärungsmöglichkeit für kognitive Defizite und Funktionsstörungen des Gedächtnisses infolge chronischen Drogenkonsums bieten und zugleich eine Bedeutung bei der Entstehung von Abhängigkeitserkrankungen haben. Insofern könnte sich hier ein Ansatzpunkt für zukünftige Therapiestrategien derartiger Erkrankungen oder ihrer Folgen bieten.:I. Inhaltsverzeichnis 1 II. Bibliografische Zusammenfassung 2 III. Abkürzungsverzeichnis 3 1. Einführung 4 1.1. Drogenabhängigkeit und Epidemiologie 4 1.2. Heroin 6 1.3. Hippocampus 9 1.4. Adulte Neurogenese 11 1.5. Aufgabenstellung und Ziel der Arbeit 14 2. Materialen und Methoden 18 2.1. Fall- und Kontrollgruppe 18 2.2. Toxikologisch-chemische Untersuchungen 20 2.3. Immunhistochemie 21 2.4. Immunfluoreszenz und konfokale Mikroskopie 25 2.5. Quantifizierung, Datenanalyse und Statistik 26 3. Ergebnisse 28 3.1. Deskriptive Datenanalyse 28 3.2. Musashi-1 30 3.3. Nestin 31 3.4. Calretinin 32 3.5. Ki-67 34 3.6. Doublecortin 35 3.7. Doppelimmunfluoreszenz 36 4. Diskussion 37 4.1. Neurogenese – Proliferation (Ki-67) 38 4.2. Neurogenese – Differenzierung (MSI-1, Nestin) 39 4.3. Neurogenese – Reifung (Calretinin) 42 4.4. Methodische Grenzen und Fehlerbetrachtung 43 4.5. Fazit und Ausblick 46 5. Zusammenfassung der Arbeit 48 6. Literaturverzeichnis 52 7. Anlagen 1-8 65 IV. Selbständigkeitserklärung 73 V. Curriculum vitae 74 VI. Publikationen 75 VII. Danksagung 76

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Girard, Simon L. "Étude sur le rôle des déséquilibres génomiques dans le Syndrome d’Impatiences Musculaires de l’Éveil." Thèse, 2010. http://hdl.handle.net/1866/4115.

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Le Syndrome d’Impatiences Musculaires de l’Éveil (SIME) est une maladie neurologique caractérisée par un besoin urgent de bouger les jambes. C’est également l’une des causes les plus fréquentes d’insomnie. C’est une maladie très répandue, avec une prévalence de presque 15 % dans la population générale. Les maladies multifactorielles comme le SIME sont souvent le résultat de l’évolution d’une composante génétique et d’une composante environnementale. Dans le cadre du SIME, les études d’association génomique ont permis l’identification de 4 variants à effet modéré ou faible. Cependant, ces quatre variants n’expliquent qu’une faible partie de la composante génétique de la maladie, ce qui confirme que plusieurs nouveaux variants sont encore à identifier. Le rôle des déséquilibres génomiques (Copy Number Variations ou CNVs) dans le mécanisme génétique du SIME est à ce jour inconnu. Cependant, les CNVs se sont récemment positionnés comme une source d’intérêt majeur de variation génétique potentiellement responsable des phénotypes. En collaboration avec une équipe de Munich, nous avons réalisé deux études CNVs à échelle génomique (biopuces à SNP et hybridation génomique comparée (CGH)) sur des patients SIME d’ascendance germanique. À l’aide d’une étude cas-contrôle, nous avons pu identifier des régions avec une occurrence de CNVs différentes pour les patients SIME, comparés à différents groupes contrôles. L’une de ces régions est particulièrement intéressante, car elle est concordante à la fois avec des précédentes études familiales ainsi qu’avec les récentes études d’associations génomiques. Restless Legs syndrome (RLS) is a neurological disorder characterized by the urge to move one’s limbs. It is also one of the most frequent causes of insomnia. The prevalence of RLS is estimated to be around 15% in the general population. Complexes disorders like RLS are often the result of the evolution of genetic and environmental components. For RLS, recent Genome Wide Association Study (GWAS) have identified four variants with mild to moderate effects. However, those four variants explain only a small part of the disease heritability and thus, we expect that many new variants are still to be found. The impact of Copy-Number Variation (CNV) in the genetic mechanism of RLS is still unknown. However, many studies have recently position the CNVs as a significant source of genetic variation potentially responsible of phenotypes. In collaboration with a team from Munich, we conducted two genome-wide CNVs studies (Genome Wide SNP chips and Comparative Genomic Hybridization (CGH)) on RLS patients from Germany. Using cases-controls studies, we identified regions with a different occurrence of CNVs for RLS patients, compared to different groups of controls. One of these regions is particularly interesting, as it has already been identified by both linkage and association studies.

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