Paradoxical results on object-recognition delayed nonmatching-to-sample (DNMS) tasks have been found in monkeys and rats that receive either partial, ischemia-induced hippocampal lesions or complete hippocampal ablation. Ischemia results in severe DNMS impairments, which have been attributed to circumscribed CA1 cell loss. However, ablation studies indicate that the hippocampus plays only a minimal role in the performance of the DNMS task. Two hypotheses have been proposed to account for these discrepant findings (Bachevalier & Mishkin, 1989). First, the "hippocampal interference" hypothesis posits that following ischemia, the partially damaged hippocampus may disrupt activity in extrahippocampal structures that are important for object-recognition memory. Second, previously undetected ischemia-induced extrahippocampal damage may be responsible for the DNMS impairments attributed to CA1 cell loss. To test the "hippocampal interference" hypothesis, the effect of partial NMDAinduced lesions of the dorsal hippocampus were investigated on DNMS performance in rats. These lesions damaged much of the same area, the CA1, as did ischemia; but did so without depriving the entire forebrain of oxygen, thereby reducing the possibility of extrahippocampal damage. In Experiment 1, rats were trained on the DNMS task prior to receiving an NMDA-lesion. Postoperatively, these rats reacquired the nonmatching rule at a rate equivalent to controls and were unimpaired in performance at delays up to 300 s. In Experiment 2, naive rats were given NMDA-lesions and then trained on DNMS. These rats acquired the DNMS rule at a rate equivalent to controls and performed normally at delays up to 300 s. These findings suggest that interference from a partially damaged hippocampus cannot account for the ischemia-induced DNMS impairments and that they are more likely produced by extrahippocampal neuropathology. In Experiment 3, rats from the previous study were tested on the Morris water-maze. Compared to sham-lesioned animals, rats with partial lesions of the dorsal hippocampus were impaired in the acquisition of the water-maze task. Thus, subtotal NMDA-lesions of the hippocampus impaired spatial memory while leaving nonspatial memory intact. Mumby et al. (1992b) suggested that the ischemia-induced extrahippocampal damage underlying the DNMS deficits is mediated or produced by the postischemic hippocampus. To test this idea, preoperatively trained rats in Experiment 4 were subject to cerebral ischemia followed within 1hr by hippocampal aspiration lesions. It was hypothesized that ablation soon after ischemia would block the damage putatively produced by the postischemic hippocampus and thereby prevent the development of postoperative DNMS deficits. Unlike "ischemia-only" rats, the rats with the combined lesion were able to reacquire the nonmatching rule at a normal rate and performed normally at delays up to 300 s. Thus, hippocampectomy soon after ischemia eliminated the pathogenic process that lead to ischemia-induced DNMS deficits. Experiment 5 investigated the role of ischemiainduced CA1 cell death as a factor in the production of extrahippocampal neuropathology. Naive rats were given NMDA-lesions of the dorsal hippocampus followed 3 weeks later by cerebral ischemia. If the ischemia-induced CA1 neurotoxicity is responsible for producing extrahippocampal damage then preischemic ablation should attenuate this process and prevent the development of DNMS impairments. This did not occur: Rats with the combined lesion were as impaired as the "ischemia-only" rats in the acquisition of the DNMS task. This suggests that the ischemia-induced pathogenic processes that result in extrahippocampal neuropathology comprise more than CA1 neurotoxicity. The findings presented in this thesis are consistent with the idea that ischemiainduced DNMS deficits in rats are the result of extrahippocampal damage mediated or produced by the postischemic hippocampus. The discussion focuses on three main points: 1) How might the post-ischemic hippocampus be involved in the production of extrahippocampal neuropathology? 2) In what brain region(s) might this damage be occurring? 3) What anatomical, molecular, or functional neuropathology might ischemia produce in extrahippocampal brain regions? The results are also discussed in terms of a specialized role for the hippocampus in mnemonic functions and the recently emphasized importance of the rhinal cortex in object-recognition memory. / Arts, Faculty of / Psychology, Department of / Graduate

Machine Learning (ML) is a transformative technology at the forefront of many modern research endeavours. The technology is generating a tremendous amount of attention from researchers and practitioners, providing new approaches to solving complex classification and regression tasks. While concepts such as Deep Learning have existed for many years, the computational power for realising the utility of these algorithms in real-world applications has only recently become available. This dissertation investigated the efficacy of a novel, general method for deploying ML in a variety of complex tasks, where best feature selection, data-set labelling, model definition and training processes were determined automatically. Models were developed in an iterative fashion, evaluated using both training and validation data sets. The proposed method was evaluated using three distinct case studies, describing complex classification tasks often requiring significant input from human experts. The results achieved demonstrate that the proposed method compares with, and often outperforms, less general, comparable methods designed specifically for each task. Feature selection, data-set annotation, model design and training processes were optimised by the method, where less complex, comparatively accurate classifiers with lower dependency on computational power and human expert intervention were produced. In chapter 4, the proposed method demonstrated improved efficacy over comparable systems, automatically identifying and classifying complex application protocols traversing IP networks. In chapter 5, the proposed method was able to discriminate between normal and anomalous traffic, maintaining accuracy in excess of 99%, while reducing false alarms to a mere 0.08%. Finally, in chapter 6, the proposed method discovered more optimal classifiers than those implemented by comparable methods, with classification scores rivalling those achieved by state-of-the-art systems. The findings of this research concluded that developing a fully automated, general method, exhibiting efficacy in a wide variety of complex classification tasks with minimal expert intervention, was possible. The method and various artefacts produced in each case study of this dissertation are thus significant contributions to the field of ML.

La polarité cellulaire planaire (PCP) est une voie de signalisation conservée au fil de l’évolution et qui joue un rôle crucial dans l’établissement de la polarité des cellules et tissues en régulant la dynamique du cytosquelette. De nombreuses études ont démontré l’implication de la PCP dans les mécanismes développementaux importants comme la gastrulation ou la neurulation chez les mammifères, et la mutation des gènes centraux qui composent la PCP mène à de sévères malformations de nombreux organes, et par conséquent une mort néonatale. Van Gogh-like 2 (vangl2) est un des gènes centraux de la PCP et code pour une protéine transmembranaire de la voie de la PCP, et sa mutation conduit à une absence de fermeture de la gouttière neurale et la mort à la naissance chez les mammifères, y compris l'homme. Certaines études suggèrent que Vangl2 jouerait un rôle dans le guidage axonal, mais aussi l’arborisation dendritique des neurones de l’hippocampe et le nombre des épines dendritiques.Dans ce travail, je montre que Vangl2 est enrichi dans l’hippocampe adulte de souris, et plus précisément dans le gyrus denté (DG) et le stratum lucidum du CA3. De nombreuses études suggèrent que le réseau formé par ces sous-structures sous-tend des processus cognitifs spécifiques impliqués dans l’encodage et le rappel de la mémoire : le pattern separation et le pattern completion. Le pattern separation est un processus d’encodage d’informations similaires en représentations différentes, permettant la formation de souvenirs distincts malgré les similitudes entre les évènements. Le processus de pattern completion permet, à partir de stimuli partiels, de se remémorer un souvenir dans son intégralité. De récentes études suggèrent que la maturation des nouveaux neurones issus de la neurogenèse adulte dans le DG joue un rôle critique dans le maintien d'une balance qui existerait entre ces deux processus cognitifs. Bien que les mécanismes qui sous-tendent les deux processus soient encore mal compris, la connectivité du DG et du CA3 semble essentielle.J’ai ainsi formulé et testé l'hypothèse selon laquelle l'absence d'expression de Vangl2 affecterait ces processus mnésiques. Pour ceci, j'ai généré plusieurs mutants murins n'exprimant pas le gène vangl2 dans différentes régions du cerveau, que j'ai ensuite testé dans des paradigmes comportementaux requérant l’utilisation des processus de pattern separation et de pattern completion. Mes résultats suggèrent que Vangl2 dans le DG est essentiel dans le maintien d'une balance existante entre les deux processus, en régulant la maturation des neurones du DG. / Planar cell polarity (PCP) signaling is an evolutionary conserved pathway known to play a crucial role in the establishment of tissue polarity via a regulation of cytoskeleton dynamics. PCP signaling is essential during critical developmental stages, such as gastrulation or neurulation, to shape tissues and organs, and disruption of core PCP genes in mammals leads to severe malformations and neonatal death. Van Gogh-like 2 (vangl2) is one of the core PCP genes coding for a transmembrane protein, and its mutation leads to a failure of the neural tube closure in mammals, including humans. It has also been suggested that Vangl2 plays a role in axonal guidance, dendritic arborization of hippocampal neurons and dendritic spines number. I showed that Vangl2 protein is enriched in the hippocampus in the adult stage, precisely in the dentate gyrus (DG) and CA3 stratum lucidum subregions. These subregions have been proposed to sustain two cognitive processes involved in memory functions: pattern separation and pattern completion. Pattern separation allows the encoding of similar or overlapping inputs in distinct neuronal representations, allowing formation of new memory without interference of a previous similar encountered event. Pattern completion is described as the ability to guide the recall of an entire memory using partial sensory cues. Recent studies suggest a critical role for the maturation of adult-born granule neurons of the DG in the balance that may exist between pattern completion and pattern separation. Although the mechanisms of both cognitive processes are still debated, the connectivity between DG and CA3 appears to be essential. I thereby tested the hypothesis that in absence of Vangl2 in the brain, these two processes would be affected. I generated several conditional mutant mice in order to excise vangl2 gene in specific areas of the hippocampus, and tested them in behavioral paradigms requiring pattern separation or pattern completion processes. My data support my hypothesis that Vangl2 in the DG is essential for a balance between pattern separation and pattern completion, through the regulation of the maturation of DG neurons.

Nous traitons dans cette thèse des différents aspects de la manipulation de maillages, et de la façon dont ces opérations peuvent être effectuées en parallèle, ou en mémoire distribuée, à l’heure où les GPUs comme les super-calculateurs deviennent de plus en plus utilisés. Ainsi, nous présentons des algorithmes de lissage surfacique et volumique, inspirés d’algorithmes de traitement d’images (filtre bilatéral, histogrammes locaux). Après ces manipulations de géométrie, nous abordons des problématiques topologiques comme le remaillage local, dans le but de générer, à partir d’un maillage tétraédrique, une couche limite de cellules prismatiques et hexaédriques de bonne qualité, permettant des simulations de mécanique des fluides dans ces ones proches de la surface. Enfin, nous décrivons une technique de maillage basée sur des interactions particulaires, permettant de générer des maillages à dominante quadrangulaire. / This thesis deals with different aspects of mesh processing, and the way those operations can be done in parallel, or using distributed memory, when GPUs and supercomputers are more and more commonly used. We present surfacic and volumetric mesh smoothing algorithms, based upon image processing techniques (bilateral filter, local histograms). After those geometric considerations, we talk about topologic methods, as local remeshing, enabling one to generate, from a tetrahedral mesh, one layer of good quality prisms and hexahedron, allowing fluid mechanics simulations in those near-surface areas. Finally, we present a meshing technique based upon particular interactions, in order to construct quad-dominant meshes.

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Many young adult university students engage in frequent alcohol bingeing and have high depression scores, both of which are factors that can reduce hippocampal neurogenesis in rodents. Rodents with depleted neurogenesis exhibit selective deficits on high interference memory tasks including visual and spatial pattern separation. We predicted that young adult humans with high bingeing and depression scores would exhibit similarly impaired spatial pattern separation as a result of neurogenesis reductions. The relationships between alcohol bingeing, depression, and spatial pattern separation have, to this point, not been investigated in humans. We developed a novel computerized memory task for assessing spatial pattern separation in humans, loosely based on the “Concentration” memory card game. To further identify how sensitive this pattern separation function is to spatial separation between two stimuli, we developed the spatial separation recognition task (SSRT). We found that young adults with elevated depression and alcohol consumption scores exhibited impaired spatial pattern separation, in spite of intact performance on control tasks, consistent with a selective neurogenesis reduction. Further, this difference in performance seemed to be driven by performance at relatively larger separations. / Thesis / Master of Science (MSc)

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