La migration radiaire est un des processus clefs de la corticogenèse menant à l’établissement d’un cortex en six couches chez les mammifères. La compréhension de ce mécanisme complexe est nécessaire à une meilleure appréhension du développement cortical. Dans ce travail de thèse, j’ai étudié la migration des neurones pyramidaux du cortex sous deux angles distincts. La 1ère partie se place d’un point de vue développemental en appréciant comment le positionnement laminaire résultant d’une migration normale ou anormale affecte la maturation neuronale. La 2nde partie se concentre sur une pathologie migratoire, l’hétérotopie en bande sous-corticale, et les altérations cognitives parfois associées à cette malformation. Pour ces deux projets, la migration neuronale a été altérée chez le rat par knockdown (KD) in utero de la doublecortine (Dcx), un effecteur majeur de la migration. Les neurones positionnés anormalement présentent une orientation incorrecte, un arbre dendritique moins développé, une spinogenère réduite et une altération morpho-fonctionnelle de la synaptogenèse glutamatergique. De plus, notre étude a mis en évidence l’implication de Dcx dans la dendritogenèse et la régulation fine des synapses glutamatergiques in vivo. Enfin, nous avons utilisé les rats Dcx-KD comme modèle d’hétérotopie en bande afin d’étudier comment un déficit de migration neuronale impacte le fonctionnement du cortex. La caractérisation comportementale, réalisée à l’aide d’une large gamme de tests, n’a pas mis en évidence de déficits majeurs des capacités motrices, somatosensorielles ou cognitives chez ces animaux. / Radial migration is one of the key processes leading to the formation of a six-layered cortex in mammals. Understanding this mechanism is necessary to get a better grasp of cortical development. During my PhD, I studied neuronal migration of pyramidal neurons from two different points of views. The 1st part is related to fundamental biology and assesses how laminar misplacement resulting from migration failure influences neuronal maturation. The 2nd one focuses on pathology by investigating a migration disorder, subcortical band heterotopia, and associated cognitive deficits. For both projects, neuronal migration was impaired in rat through in utero knockdown (KD) of doublecortin (Dcx), a major effector of cortical migration. Misplaced neurons display an abnormal orientation, a simplified dendritic arbor, a decreased spinogenesis and morpho-functional alterations of glutamatergic synaptogenesis. Moreover, our study shows that Dcx plays a role in dendritogenesis, in shaping spine morphology and in fine-tuning glutamatergic synaptogenesis. Finally, we used Dcx-KD rats as an animal model of subcortical band heterotopia to assess how migration failure would impact cortical functions. The behavioral characterization carried out through a wide range of tests did not bring to light any major shortcoming regarding motor, somatosensory or cognitive abilities in these animals. Therefore, although Dcx-KD rats display a SBH and develop spontaneous seizures, it does not seem to recapitulate cognitive deficits found in patients.

<p> Although historically treated as separate systems, there is considerable interaction between the immune system and brain. It has become increasingly clear that immunebrain communication is important to both health and disease. An immunogenic challenge given during the first postnatal week in rodents impacts the developing central nervous system (CNS) leading to long-term behavioural and molecular alterations reflective of enhanced stress-reactivity. Anxiety and depression are stress-related pathologies with a proposed neurodevelopmental origin suggesting that perturbation to neonatal immunebrain signalling may contribute to psychopathology. The current body of work examined the long-term impact of an early immune challenge on behavioural and molecular phenotypes associated with anxiety and depression. Mice were administered lipopolysaccharide (LPS) on postnatal days three and five. The emergence of anxietyrelated behaviour was characterized along the developmental trajectory of LPS-mice concurrent with changes to serotonergic neurocircuitry. Adult depressive-related behaviour was assessed in the forced swim test (FST) along with hippocampal neurogenesis as revealed by immunoreactivity for bromodeoxyuridine (BrdU) and doublecortin (DCX). The results demonstrated a sex-specific alteration in both the temporal emergence and phenotypic variant of anxiety-related behaviours displayed by LPS-mice. This was accompanied by changes to CNS serotonergic-related gene expression that coincided with a critical developmental time window essential to the establishment of emotionality. Adult LPS-mice exhibited hyperactivity during the FST that was accompanied by increased doublecortin immunoreactivity in the dorsal and ventral hippocampus, reflecting enhanced immature neuronal differentiation. The current results demonstrate that an early immune challenge impacts the developing CNS leading to enhanced emotional-reactivity. Altered serotonergic neurocircuitry and adult hippocampal neurogenesis may underlie behavioural abnormalities. The current body of work demonstrates a preeminent role for early-life immune disturbance in psychopathology and advances understanding of how immune-brain signalling impacts the developing CNS and confers risk for later disease. </p> / Thesis / Doctor of Philosophy (PhD)

The advent of wide band-gap semiconductors in power electronics has led to the scope of efficient power conversion being pushed further than ever before. This development has allowed for systems to operate at higher and higher voltages than previously achieved. One area of consideration during this high voltage transition is the synchronous rectifier, which is traditionally designed as an afterthought. Prior research in synchronous rectifiers have been limited to low voltage, high current converters. There is practically no research in high voltage synchronous rectification. Therefore, this dissertation focuses on discovering the unknown nuances behind high voltage synchronous rectifier design, and ultimately developing a practical, scalable solution. There are three main issues that must be addressed when designing a high voltage synchronous rectifier: (1) high voltage sensing; (2) light load effects; (3) accuracy. The first hurdle to designing a high voltage SR system is the high voltage itself. Traditional methods of synchronous rectification (SR) attempt to directly sense voltage or current, which is not possible with high voltage. Therefore, a solution must be designed to limit the voltage seen by the sensing mechanism without sacrificing accuracy. In this dissertation, a novel blocking solution is proposed, analyzed, and tested to over 1-kV. The solution is practical enough to be implemented on practically any commercial drain-source SR controller. The second hurdle is the light load effect of the SR system on the converter. A large amount of high voltage systems utilize a LLC-based DC transformers (DCX) to provide an efficient means of energy conversion. The LLC-DCX's attractive attributes of soft-switching and high efficiency allure many architects to combine it with an SR system. However, direct implementation of SR on a LLC-DCX will result in a variety of light load oscillation issues, since the rectifier circuitry can excite the resonant tank through a false load transient phenomena. A universal limiting solution is proposed and analyzed, and is validated with a commercial SR controller. The final hurdle is in optimizing the SR system itself. There is an inherent flaw with drain-source sensing, namely parasitic inductance in the drain-source sense loop. This parasitic inductance causes an error in the sensed voltage, resulting in early SR turn-off and increased losses through the parallel diode. The parasitic will always be present in the circuit, and current solutions are too complex to be implemented. Two solutions are proposed depending on the rectifier architecture: (1) multilevel gate driving for single switch rectifiers; (2) sequential parallel switching for parallel switch rectifiers. In summary, this dissertation focuses on developing a practical and reliable high voltage SR solution for LLC-DCX converters. Three main issues are addressed: (1) high voltage sensing; (2) light load effects; (3) accuracy. Novel solutions are proposed for all three issues, and validated with commercial controllers. / Doctor of Philosophy / High voltage power electronics are becoming increasing popular in the electronics industry with the help of wide band-gap semiconductors. While high voltage power electronics research is prevalent, a key component of high voltage power converters, the synchronous rectifier, remains unexplored. Conventional synchronous rectifiers are implemented on high current circuits where diode losses are high. However, high voltage power electronics operate at much lower current levels, necessitating changes in current synchronous rectifier methods. This research aims to identify and tackle issues that will be faced by both systems and IC designers when attempting to implement high voltage synchronous rectifiers on LLC-DCXs. While development takes planes on a LLC-DCX, the research is applicable to most resonant converters and applications utilizing drain-source synchronous rectifier technology. This dissertation focuses primarily on three areas of synchronous rectifier developments: (1) high voltage compatibility; (2) light load effects; (3) accuracy. The first issue opens the gate to high voltage synchronous rectifier research, by allowing high voltage sensing. The second issue explores issues that high voltage synchronous rectifiers can inadvertently influence on the LLC-DCX itself - a light load oscillation issue. The third issue explores novel methods of improving the sensing accuracy to further reduce losses for a single and parallel switch rectifier. In each of these areas, the underlying problem is root-caused, analyzed, and a solution proposed. The overarching goal of this dissertation is to develop a practical, low-cost, universal synchronous rectifier system that can be scaled for commercial use.