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Target Recognition and Competitive Synaptogenesis in the Drosophila Giant Fiber SystemHill, Jason Joseph 01 May 2012 (has links)
The development of complex neural networks relies on a careful balance of environmental cues to guide and shape both ends of the eventual connection. However, the correct wiring of circuits whose components share molecular profiles depends on a more elaborate phenomenon, competition. Despite being highly studied, there is still a lack of understanding as to the mechanism that allows molecularly identical cells to form exclusive connections with their targets. To address this complex question, we turned to a simple circuit within the genetically tractable fly. Responsible for the escape reflex, the Giant Fiber System is comprised of bilaterally symmetrical axons that innervate the ipsilateral "jump" motorneuron, TTMn in a 1:1 ratio. However, if a TTMn is unilaterally ablated prior to circuit formation, this ratio is disrupted and the deprived axon forms its presynaptic terminal on the opposite side.
Midline crossing by the deprived axon led to exploration of a known pathway in giant fiber development, midline repulsion via Slit and Roundabout. Axons in which Roundabout levels were reduced through a natural pathway antagonist, Commissurelesss, crossed the midline freely, confirming a native, if normally restricted ability to do so. However, unlike the overlapping giant fiber terminals seen following ablation, these axons retained their wild exclusivity, elaborating their terminals toward a single TTMn. This supported our initial aim of uncovering a competitive force in giant fiber target selection.
In addition to repulsion, I also examined the attractive pathway of Netrin and Frazzled for a possible role in target identification. Varying the levels of Frazzled receptors led to increased midline crossing and overlapped terminals, suggesting a connection between this attractive receptor and the repulsion pathway first examined. Frazzled has been shown to induce commissureless expression independent of its ligand, making it an important linchpin in the regulation of giant fiber guidance and competition. In fact, when allowed to traverse the midline, giant fibers responded to a Netrin increase with overlapping synaptic terminals. In this dissertation, I present a model in which giant fibers possess competitive machinery, driven by Netrin and triggered by Frazzled, underneath the naturally restrictive midline repulsion.
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Study of the Mechanisms Underlying Neurostimulation Induced by Low- Energy Pulsed Ultrasound : Towards Approaches for the Management of Cancer-Related Chronic Pain / Étude des mécanismes de neurostimulation par ultrasons pulsés de faible énergie et applications à la gestion des douleurs chroniques d’origine tumoraleVion, Jérémy 27 March 2019 (has links)
Les applications thérapeutiques de la neurostimulation ultrasonore représentent un terrain de recherche très prometteur, auquel il fait défaut un modèle valide décrivant les biomécanismes sous-jacents. Le premier objectif de ce travail de thèse était de proposer un modèle nerveux propice à une étude mécanistique du phénomène de neurostimulation ultrasonore. L’objectif suivant était de prouver l’intérêt d’exploiter ce modèle pour recueillir des informations concernant les interactions biophysiques ayant lieu entre les ultrasons (US) focalisés et le système nerveux. La majorité des études réalisées a porté sur le système nerveux du ver de terre commun, Lumbricus terrestris. Elles ont consisté d’une part à comparer entre elles les caractéristiques temporelles des réponses nerveuses associées à différentes modalités de stimulation, et d’autre part à évaluer l’influence de chacun des paramètres acoustiques du stimulus ultrasonore sur le taux de succès de neurostimulation (NSR). Dans les deux cas, la méthodologie suivie reposait sur l’administration de différents stimuli aléatoirement alternés. Complémentairement, le rôle joué par la cavitation acoustique a été étudié. La faisabilité de la stimulation du système nerveux du ver de terre, au moyen d’US et dans des conditions in vivo, a été prouvée. Les aires sensorielles et la dynamique de réponses associées aux trois modalités de stimulation ont été caractérisées. Il a été conclu que, dans ce modèle nerveux invertébré, pendant le phénomène de neurostimulation ultrasonore, les structures nerveuses interagissant fonctionnellement avec les US sont les nerfs afférents segmentaux. Les résultats des études paramétriques ont indiqué que le NSR augmente avec l’intensité acoustique, la durée de pulse et la fréquence de répétition des pulses. Il a été proposé que la structure nerveuse visée est sensible à la « force de radiation moyenne » transportée par le stimulus US, indépendamment des paramètres menant à cette valeur / Ultrasound neurostimulation applied to therapy is a promising field of research but still lacks of a validated model explaining the biomechanisms underlying the phenomenon. The first objective of this PhD thesis was to propose a nervous model suited for a mechanistic study of the phenomenon of ultrasound neurostimulation. In a second time, it was intended to practically prove the interest of this model by using it to gain knowledge regarding the biophysical interactions between focused ultrasound and the nervous system. Studies were performed on the nervous system of the anesthetized earthworm, Lumbricus terrestris. They consisted in either comparing the timings of the nervous responses associated with different modalities of stimulation, or evaluating the influence of each acoustic parameter on the neurostimulation success rate (NSR). In both cases, the methodology followed was to administer randomly mixed sequences of different stimuli. The feasibility of the in vivo activation of the anesthetized earthworm’s nervous system was proven. The sensory fields and response dynamics associated with the three modalities of stimulation were characterized. The parametric studies indicated that the NSR increases with pulse amplitude, pulse duration, pulse repetition frequency, but is more weakly influenced by the harmonic content and number of pulses. By applying a causal approach to interpret the results, we concluded that, in this nervous model, during the phenomenon of ultrasound neurostimulation, the structures functionally responding to the ultrasound stimulus are the segmental afferent nerves. We hypothesize that the main interaction with the axonal regions is mediated by ultrasound radiation force, without excluding the involvement of other biomechanisms
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