The motor nervous system is one of the main systems of the body and is our principle means ofbehavior. Some of the most debilitating and wide spread disorders are motor systempathologies. In particular the basal ganglia are complex networks of the brain that control someaspects of movement in all vertebrates. Although these networks have been extensively studied,lack of proper methods to study them on a system level has hindered the process ofunderstanding what they do and how they do it. In order to facilitate this process I have usedcomputational models as an approach that can faithfully take into account many aspects of ahigh dimensional multi faceted system.In order to minimize the complexity of the system, I first took agnathan fish and amphibians asmodeling animals. These animals have rather simple neuronal networks and have been wellstudied so that developing their biologically plausible models is more feasible. I developedmodels of sensory motor transformation centers that are capable of generating basic behaviorsof approach, avoidance and escape. The networks in these models used a similar layeredstructure having a sensory map in one layer and a motor map on other layers. The visualinformation was received as place coded information, but was converted into population codedand ultimately into rate coded signals usable for muscle contractions.In parallel to developing models of visuomotor centers, I developed a novel model of the basalganglia. The model suggests that a subsystem of the basal ganglia is in charge of resolvingconflicts between motor programs suggested by different motor centers in the nervous system.This subsystem that is composed of the subthalamic nucleus and pallidum is called thearbitration system. Another subsystem of the basal ganglia called the extension system which iscomposed of the striatum and pallidum can bias decisions made by an animal towards theactions leading to lower cost and higher outcome by learning to associate proper actions todifferent states. Such states are generally complex states and the novel hypothesis I developedsuggests that the extension system is capable of learning such complex states and linking themto appropriate actions. In this framework, striatal neurons play the role of conjunction (BooleanAND) neurons while pallidal neurons can be envisioned as disjunction (Boolean OR) neurons.In the next set of experiments I tried to take the idea of basal ganglia subsystems to a new levelby dividing the rodent arbitration system into two functional subunits. A rostral group of ratpallidal neurons form dense local inhibition among themselves and even send inhibitoryprojections to the caudal segment. The caudal segment does not project back to its rostralcounterpart, but both segments send inhibitory projections to the output nuclei of the rat basalganglia i.e. the entopeduncular nucleus and substantia nigra. The rostral subsystems is capableof precisely detecting one (or several) components of a rudimentary action and suppress othercomponents. The components that are reinforced are those which lead to rewarding stateswhereas those that are suppressed are those which do not. The hypothesis explains neuronalmechanisms involved in this process and suggests that this subsystem is a means of generatingsimple but precise movements (such as using a single digit) from innate crude actions that theanimal can perform even at birth (such as general movement of the whole limb). In this way, therostral subsystem may play important role in exploration based learning.In an attempt to more precisely describe the relation between the arbitration and extensionsystems, we investigated the effect of dynamic synapses between subthalamic, pallidal andstriatal neurons and output neurons of the basal ganglia. The results imply that output neuronsare sensitive to striatal bursts and pallidal irregular firing. They also suggest that few striatalneurons are enough to fully suppress output neurons. Finally the results show that the globuspallidus exerts its effect on output neurons by direct inhibition rather than indirect influence viathe subthalamic nucleus. / <p>QC 20131209</p>

Techn. Universiẗat, Diss., 2005--Darmstadt.

Contrairement aux mammifères, le système nerveux central du poisson téléostéen adulte possède un potentiel énorme de neurogenèse et de régénération après une lésion cérébrale. Chez le poisson zèbre adulte, de nouveaux neurones peuvent être régénérés à partir de progéniteurs constitutifs ou latents. Au cours de mon doctorat, je me suis intéressée aux capacités de régénération neuronale du cerveau moyen dorsal (le toit optique, TO) chez le poisson zèbre. Le TO présente à sa périphérie une zone de progéniteurs de type neuroépithélial à l’origine des neurones et des cellules épendymogliales qui le constituent. J’ai tout d’abord identifié un enhancer potentiel du gène meis2a, qui m’a permis d’effectuer des lignages cellulaires de progéniteurs neuroépithéliaux. En contexte homéostatique, j’ai montré que ces progéniteurs construisent la totalité du TO pendant le développement et soutiennent sa neurogenèse continue pendant la croissance post-embryonnaire. A la suite d’une lésion cérébrale chez la larve et l’adulte, le TO à la capacité de générer de nouveaux neurones, toutefois sa structure topographique n’est pas restaurée. Chez l’adulte, j’ai montré que les progéniteurs constitutifs neuroépithéliaux et des progéniteurs latents épendymogliaux sont activés lors du processus de régénération. / Unlike mammals, the adult teleost brain exhibits widespread neurogenic activity and can regenerate after injury. The adult zebrafish has the capacity to regenerate neurons from constitutive or latent progenitors. During my PhD, I studied the neuronal regeneration in the zebrafish dorsal midbrain (optic tectum, OT). At adult stage, neuroepithelial-like progenitors at the OT periphery contribute to neuronal and glial lineages during homeostasis.I identified a putative enhancer of meis2a, which allowed me to trace the progeny of neuroepithelial-like progenitors. In a non-regenerative context I showed that enhancer-targeted progenitors were at the origin of the whole structure during development and of its continued neurogenesis during post-embryonic growth.Following lesion, OT displayed reactive neurogenesis, at larval and adult stages, nevertheless its topographical structure remained altered. In adults, I showed that both constitutive neuroepithelial-like progenitors and latent ependymoglial progenitors were activated in a regenerative context.

One of the major goals of developmental biology is to understand how specialized groups of cells arise from an initially unspecified cell population. The vertebrate hindbrain is transiently segmented along its anterior-posterior axis into lineage-restricted compartments called rhombomeres, making it an excellent model in which to study the genetic mechanisms of axial patterning. Hox homeodomain transcription factors (TF), in close partnership with the Pbx and Meis families of TALE-class homeodomain proteins, impart unique molecular identities to the hindbrain rhombomeres, thereby specifying functionally specialized neurons within each segment. The broad goals of this thesis are to clarify the roles of Meis1 and Tshz3b TFs in Hox-dependent hindbrain patterning, and to examine the Hox-independent roles of Pbx and Meis proteins in axial patterning of the visual system. While it is clear that Hox-Pbx-Meis complexes regulate hindbrain segmentation, the contributions of individual Meis proteins are not well understood. I have shown that Meis1-depleted embryos exhibit neuronal patterning defects, even though the hindbrain retains its segmental organization. This suggests that Meis1 is making important contributions to neuronal development downstream of rhombomeric specification. A zinc-finger TF called Teashirt (Tsh) cooperates with Hox-Pbx-Meis complexes to establish segmental identity in Drosophila, but this role not been tested in vertebrates. I found that overexpression of tshz3b produces segmentation defects reminiscent of Hox-Pbx-Meis loss of function phenotype, likely by acting as a transcriptional repressor. Thus, Tshz3b may be a negative regulator of Hox- dependent hindbrain patterning. Like the hindbrain, visual system function requires that positional information be correctly specified in the retina and midbrain. I found that zebrafish Pbx and Engrailed homeodomain TFs are biochemical DNA binding partners, and that this interaction is required to maintain the midbrain as a lineage- restricted compartment. Additionally, I show that Meis1 specifies positional information in both the retina and midbrain, thereby helping to organize the axonal connections between the eye and brain. Taken together, this thesis clarifies our understanding of Hox-dependent hindbrain patterning, and makes the claim that Pbx and Meis perform a general axial patterning function in anterior neural tissues such as the hindbrain, midbrain and retina. / Molecular Biology and Genetics

No description available.

Comment la taille d'un organisme est-elle régulée au cours du développement embryonnaire ? Quels sont les mécanismes génétiques à l'origine de l'arrêt de la prolifération pendant la croissance d'un organisme pluricellulaire ? Afin d'identifier des acteurs de la sortie du cycle cellulaire au cours du développement, mon travail s’est orienté sur l’étude de gènes suppresseurs de tumeurs pendant la croissance du toit optique (TO) du médaka Oryzias latipes. Le TO, structure dorsale du cerveau moyen des Vertébrés, est un modèle particulièrement adapté à l’étude de la régulation de la prolifération. Trois zones de la marge vers le centre du TO sont discernables : une zone périphérique de prolifération, une zone intermédiaire de cellules sortant du cycle cellulaire et une zone centrale de cellules différenciées. Un crible d'expression par hybridation In Situ a été réalisé et a permis d'identifier 28 gènes exprimés dans le TO, suggérant leur implication dans le contrôle de la sortie du cycle cellulaire au cours du développement. Dans le but de caractériser in vivo la fonction de gènes issus de ce crible, le gène BTG1 (B-cell Translocation Gene 1) et les membres de sa famille, ont été étudiés au cours du développement du médaka. J’ai mené des expériences fonctionnelles sur BTG1, permettant de mettre en évidence son rôle central pour la morphogenèse du système nerveux central. De plus, une autre partie de mon travail s’est penchée sur l’étude de l’expression des membres de la voie de signalisation Hippo, bien connue et caractérisée chez la drosophile et les Mammifères pour son rôle dans le contrôle de la taille des organes via une régulation de l’arrêt de la prolifération. A l’issu de notre travail, une fonction de la voie de signalisation Hippo dans la formation du TO et des somites a pu être mise en évidence au cours du développement du médaka. / How is an organisms’ size regulated during embryonic development? What are the genetic mechanisms that control the proliferation arrest during multicellular organisms growth? In order to identify a cell cycle exit developmental actor genes, I have analysed the role of tumor suppressor genes (TSGs) in the optic tectum (OT) of the medaka Oryzias latipes. This structure is particularly suited for this kind of studies because, during its morphogenesis, there is a strict correlation between the position of a cell and its degree of differentiation. 3 zones can be easily distinguished from the border to the center: a marginal zone made of proliferative cells, an intermediate zone in which cells exit the cycle, and a central zone made of postmitotic cells. Using this criterium, I have performed an in situ hybridization expression screen on 150 TSGs on medaka embryos. The expression patterns of 28 TSGs in the OT suggest their implication in the OT proliferation arrest mechanisms. I focused my study on the BTG1 gene, implicated in many cancers, and for which few developmental data are available. A functional analysis on developing medaka embryos has been performed and permitted to highlight the essential role of BTG1 in central nervous system morphogenesis. Furthermore, I performed an expression study on Hippo signalling pathway components. Hippo pathway is well caracterised for its organ size control function in drosophila and Mammals. Our results show that this pathway could act in OT formation and somitogenesis in medaka fish.

Patterned neuronal activity driven by the sensory environment plays a key role in the development of precise synaptic connectivity in the brain. It is well established that the action potentials (‘spikes’) generated by individual neurons are crucial to this developmental process. A neuron’s spiking activity is jointly determined by its synaptic inputs and its intrinsic excitability. It is therefore important to ask how a neuron develops these attributes, and whether the emergence of spiking might itself be governed by activity-dependent processes. In this thesis, I address these questions in the retinotectal system of Xenopus laevis. First, I investigate the extent to which visuospatial information is available to the developing retinotectal system. I show that the eyes of developing Xenopus larvae are hyperopic at the onset of vision, but rapidly grow towards correct vision. Despite its imperfect optics, the Xenopus eye is able to generate spatially restricted activity on the retina, which is evident in the spatial structure of the receptive fields (RFs) of tectal neurons. Using a novel method to map the visually driven spiking output and synaptic inputs of the same tectal neuron in vivo, I show that neuronal spiking activity closely follows the spatiotemporal profile of glutamatergic inputs. Next, I characterise a population of neurons in the developing optic tectum that does not fire action potentials, despite receiving visually evoked glutamatergic and γ-aminobutyric acid (GABA)ergic synaptic inputs. A comparison of visually spiking and visually non-spiking neurons reveals that the principal reason these neurons are ‘silent’ is that they lack sufficient glutamatergic synaptic excitation. In the final section of the thesis, I investigate whether visually driven activity can play a role in the ‘unsilencing’ of these silent neurons. I show that non-spiking tectal neurons can be rapidly converted into spiking neurons through a visual conditioning protocol. This conversion is associated with a selective increase in glutamatergic input and implicates a novel, spike-independent form of synaptic potentiation. I provide evidence that this novel plasticity process is mediated by GABAergic inputs that are depolarising during early development, and can act in synergy with N-methyl-D-aspartate receptors (NMDARs) to strengthen immature glutamatergic synapses. Consistent with this, preventing the depolarising effects of GABA or blocking NMDARs abolished the activity-dependent unsilencing of tectal neurons. These results therefore support a model in which GABAergic and glutamatergic transmitter systems function synergistically to enable a neuron to recruit the synaptic excitation it needs to develop sensory-driven spiking activity. This represents a transition with important consequences for both the functional output and the activity-dependent development of a neuron.

No description available.

No description available.