Cette thèse avait pour objectif d’étudier le rôle du circuit composé de l’hippocampe (Hip), du cortex préfrontal médian (mPFC) et des noyaux reuniens et rhomboïde (ReRh) du thalamus dans les processus cognitifs qui sous-tendent la mémoire spatiale chez le Rat. Nous avons montré que les noyaux ReRh pourraient être impliqués dans la consolidation systémique, mécanisme nécessaire à la persistance des souvenirs et nécessitant un dialogue hippocampo-cortical. Nous avons mis en évidence que l’activité neuronale du mPFC durant le rappel d’une mémoire ancienne dépend des noyaux ReRh, ainsi que l’implication de ces noyaux dans une tâche de mémoire spatiale (dépendante de l’Hip) nécessitant une flexibilité comportementale (impliquant le mPFC). Enfin, nous avons montré un rôle du mPFC dans le rappel d’une mémoire spatiale récente. Ces résultats mettent en évidence l’importance de ce circuit hippocampo-cortico-thalamique dans le traitement et la persistance des informations spatiales chez le Rat. / This thesis aimed to investigate the role of a circuit encompassing the hippocampus (Hip), the medial prefrontal cortex (mPFC) and the reuniens and rhomboid nuclei (ReRh) of the thalamus in cognitive processes underlying spatial memory in rats. We first showed that ReRh nuclei may be involved in systemic consolidation, a mechanism necessary for memory persistence and requiring hippocampal-cortical interactions. We confirmed these findings in a second study showing that mPFC neuronal activity during recall of a remote spatial memory depends on ReRh thalamic nuclei. We also showed the involvement of the ReRh nuclei in a mnemonic task requiring the use of both spatial information (dependent on the Hip) and behavioral flexibility (involving the mPFC). Finally, we found a role of the mPFC in the recall of recent spatial memory. Taken together, these results highlight the importance of a hippocampo-cortico-thalamic circuit in the processing and persistence of spatial information in the Rat.

This document is a critical synopsis of prior work by Michael Dwyer submitted in support of a PhD by published work. The selected work is focused on the application of quantitative magnet resonance imaging (MRI) analysis techniques to the study of multiple sclerosis (MS). MS is a debilitating disease with a multi-factorial pathology, progression, and clinical presentation. Its most salient feature is focal inflammatory lesions, but it also includes significant parenchymal atrophy and microstructural damage. As a powerful tool for in vivo investigation of tissue properties, MRI can provide important clinical and scientific information regarding these various aspects of the disease, but precise, accurate quantitative analysis techniques are needed to detect subtle changes and to cope with the vast amount of data produced in an MRI session. To address this, eight new techniques were developed by Michael Dwyer and his co-workers to better elucidate focal, atrophic, and occult/"invisible" pathology. These included: a method to better evaluate errors in lesion identification; a method to quantify differences in lesion distribution between scanner strengths; a method to measure optic nerve atrophy; a more precise method to quantify tissue-specific atrophy; a method sensitive to dynamic myelin changes; and a method to quantify iron in specific brain structures. Taken together, these new techniques are complementary and improve the ability of clinicians and researchers to reliably assess various key elements of MS pathology in vivo.

Au Canada, les pertes de rendement en agriculture attribuées aux nématodes sont généralement associées aux nématodes des lésions du genre Pratylenchus. En 2011, la découverte d’une nouvelle espèce exotique au Canada et qualifiée de rare dans le Nord-Est américain, soit Pratylenchus alleni Ferris, a soulevé de nouvelles inquiétudes. Afin de déterminer si cette espèce représente une menace pour les productions agricoles du Québec, mon projet de maîtrise visait à recueillir des informations sur sa virulence. Dans un premier temps, le spectre d’hôtes de P. alleni a été étudié et les résultats ont montré que ce nématode se développe très bien sur la pomme de terre, mais non sur la luzerne et le trèfle rouge. Ensuite, la reproduction de P. alleni dans un contexte de changements climatiques a été étudiée. L’augmentation prévue des températures et CO2 devrait favoriser le développement de P. alleni puisqu’il possède un meilleur taux de reproduction sur le soya lorsque soumis à un régime de températures de 17/28 ˚C et à une concentration en CO2 de 1200 ppm comparativement à 12/23 ˚C (400 ppm) et 15/26 ˚C (800 ppm). Dans cette même étude, une réduction de 19 à 58 % du poids sec racinaire des plants de soya inoculés avec P. alleni a été observée comparativement aux plants témoins. De plus, une méthode moléculaire de détection et de quantification simultanée de P. alleni et P. penetrans, l’espèce de Pratylenchus la plus répandu dans l’Est canadien, par qPCR a également été développée. Pour chacune des deux espèces, une sonde TaqMan associée avec le fluorophore CY5 pour P. alleni et FAM pour P. penetrans ciblant la région D2/D3 de la grande sous-unité ribosomale (28S) ont été développées et celles-ci se sont avérées spécifiques à chaque espèce. Ces résultats amènent de nouvelles connaissances sur ce ravageur et mettent en lumière sa pathogénicité. / In Canada, yield losses attributed to nematodes are generally associated with root-lesion nematodes from the genus Pratylenchus. In 2011, a new exotic species was detected in Canada and identified as Pratylenchus alleni Ferris. Pratylenchus alleni is rare in the Northeastern U.S. and its discovery has raised new concerns. To determine whether this species is a threat to agricultural production in Québec, my project aims to collect information about its pathogenicity. First, the host range of P. alleni was studied and the results showed that the nematode was developing well on potato, but poorly performed on alfalfa and red clover. The reproduction of P. alleni has also been studied in a context of climate change. The results showed that anticipated temperature and CO2 increases should favor P. alleni since it has a better reproduction rate on soybeans subjected to a night/day temperature regime of 17/28°C and a CO2 concentration of 1200 ppm compared to 12/23˚C (400 ppm) and 15/26°C (800 ppm) regimes. In the same study, a reduction of 19 to 58 % of roots dry weight of soybeans inoculated with P. alleni was observed compared to control plants. A simultaneous molecular detection and quantification method by qPCR of P. alleni and P. penetrans, the most widespread Pratylenchus species in Eastern Canada, was also developed. For each species, a TaqMan probe associated with the CY5 fluorophore for P. alleni and FAM for P. penetrans targeting the D2/D3 expansion segments of the large ribosomal subunit (28S) were developed and proved to be specific to each species. These results bring new insights into this new pest and highlight its pathogenicity.

The capacity of the olfactory neuraxis to undergo neuronal replacement and axon targeting following injury, has led to scrutiny concerning the molecular and physical determinants of this growth capacity. This is because injury to the central nervous system, in contrast, leads to permanent disconnection of neurons with targets. Olfactory ensheathing cells (OECs), a specialized glial cell, may contribute to olfactory repair, and have been used to promote recovery from spinal cord injury. However, there mechanisms underlying OEC-induced regeneration are poorly appreciated. To understand these mechanisms, OECs from the lamina propria (LP OECs) or olfactory bulb (OB OECs) were transplanted into a lesion of the dorsolateral funiculus. While both cells demonstrated reparative capacities, LP and OB OECs differentially promoted spinal fibre growth; large-diameter neurofilament-positive, CGRP-positive, and serotonergic fibres sprouted in response to both LP and OB OEC transplantation, whereas substance-P and tyrosine hydroxylase-positive neurons grew more extensively following OB or LP OEC transplantation, respectively. To further understand the growth of spinal cord neurons in response to OECs, a proteomic analysis of OEC secreted factors was performed, identifying secreted protein acidic and rich in cysteines (SPARC) as a mediator of OEC-induced outgrowth in vitro. To test the contributions of SPARC to spinal cord repair after OEC transplantation, cultures of LP OECs from SPARC null and wildtype (WT) mice were transplanted into a crush of the dorsolateral funiculus. Substance P and tyrosine hydroxylase positive axon sprouting was significantly reduced in SPARC null OEC-treated animals, suggesting that individual factors may contribute to OEC-promoted regeneration. To investigate the effect of OECs on corticospinal (CST) neurons, an in vitro assay was developed using postnatal day 8 CST neurons. Coculture of CST neurons with OB OECs produced extensive axon elongation. Application of OB OEC secreted factors increased CST neurite branching, but did not increase axon elongation. In contrast, plating of CST neurons on OB OEC plasma membrane resulted in extensive axon elongation. Furthermore, the OB OEC plasma membrane could overcome CST neurite outgrowth inhibition induced by an outgrowth inhibitor. Together these findings provide insight into OEC mechanisms of neurite outgrowth and axon regeneration. / Medicine, Faculty of / Graduate

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Problématique : Les lésions nerveuses périphériques peuvent entraîner une allodynie mécanique (AM) qui est une douleur neuropathique provoquée par le toucher. L’AM peut limiter les activités et les habitudes de vie des patients. Les approches de stimulation tactiles sont des interventions prometteuses pour traiter l’AM. Cependant, aucune étude n’a encore investigué l’intégration d’une telle approche dans un programme de réadaptation multimodal. De plus, il n’existe aucune synthèse des connaissances sur ces approches pour le traitement de l’AM. Objectifs : 1- Décrire l’intégration d’une approche de stimulation tactile dans un programme de réadaptation multimodal; 2- Recenser les approches de stimulation tactiles et évaluer les évidences de ces approches pour traiter l’AM à la main suite à une lésion nerveuse périphérique. Méthodologie : 1- Étude de cas. 2- Recension systématique sur les approches de stimulation tactile. Résultats : L’étude de cas montre une diminution de l’AM et une amélioration des incapacités chez un patient présentant un syndrome de douleur régionale complexe qui a participé à un programme de réadaptation multimodal intégrant une approche de stimulation tactile. La recension systématique montre qu’il existe deux approches de stimulation tactiles (la désensibilisation et la rééducation sensitive de la douleur) pour traiter l’AM à la main. Ces approches ne se distinguent pas quant au niveau d’évidence de leur efficacité pour traiter l’AM suite à une lésion nerveuse périphérique. Conclusion : Les deux approches peuvent être utilisées par les cliniciens pour traiter l’AM en fonction de leur raisonnement clinique et des caractéristiques des patients. / Context: Peripheral nerve lesions can lead to mechanical allodynia (MA), that is a neuropathic pain provoked by touch. MA can limit patients’ activities and life habits. Tactile stimulations are promising approaches to treat MA. However, to our knowledge, there is no study that has investigated how such approaches can be integrated into a multimodal rehabilitation program. In addition, there is no synthesis of current knowledge on the tactile stimulation approaches for treating MA. Objectives: 1- To describe the integration of a tactile stimulation approach in a multimodal rehabilitation program; 2- To identify existing tactile stimulation approaches and to assess evidences of the use of these approaches to MA in the hand following a peripheral nerve lesion. Method: 1- Case report. 2- Systematic review on tactile stimulation approaches. Results: The case report shows an abolition of MA and an improvement of incapacities in a patient with a complex regional pain syndrome who participated in a multimodal rehabilitation program including a tactile stimulation approach. The systematic review identified two tactile stimulation approaches (desensitization and somatosensory rehabilitation of pain). Those approaches do not differ in their level of evidence in the treatment of MA following a peripheral nerve lesion. Conclusion: The two approaches can be used by clinicians to treat MA. The choice of these approaches should be based on clinical reasoning and patients’ characteristics.

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活動性拒食症(ABA)とは、食事時間の制限と過剰なランニングによって引き起こされる摂食障害である。本論文では、ABAモデルラットが示す摂食障害に、脳の孤束核がどう関わっているかを検証した。第一実験は、筆者の立てた仮説に基づき、オピオイドの役割が中枢性か末梢性かについて、孤束核にナロキソンを直接投与し、その影響を調べた。第二実験では、第一実験の結果を踏まえ、ABAラットの孤束核を破壊し、その影響を調べた。 / Active anorexia (ABA) is an eating disorder caused by restricted meal times and excessive running. This study examined the involvement of the nucleus of the solitary tract (NST) of the brain in ABA model rats. In the first experiment, based on the hypothesis previously formulated by the author, naloxone was microinjected into the NST. This was to determine whether the opioid worked in the central or peripheral mechanisms. In the second experiment, based on the results of the first experiment, the NSTs of rats were lesioned and the effects were examined. / 博士(理学) / Doctor of Philosophy in Science / 同志社大学 / Doshisha University