UNIQUE FEAUTRES OF ORGANIZATION AND NEURONAL PROPERTIES IN A MULTISENSORY CORTEX Multisensory processing is a ubiquitous sensory effect that underlies a wide variety of behaviors, such as detection and orientation, as well as perceptual phenomena from speech comprehension to binding. Such multisensory perceptual effects are presumed to be based in cortex, especially within areas known to contain multisensory neurons. However, unlike their lower-level/primary sensory cortical counterparts, little is known about the connectional, functional and laminar organization of higher-level multisensory cortex. Therefore, to examine the fundamental features of neuronal processing and organization in the multisensory cortical area of the posterior parietal cortex (PPr) of ferrets, the present experiments utilized a combination of immunohistological, neuroanatomical and multiple single-channel electrophysiological recording techniques. These experiments produced four main results. First, convergence of extrinsic inputs from unisensory cortical areas predominantly in layers 2-3 in PPr corresponded with the high proportion of multisensory neurons in those layers. This is consistent with multisensory responses in this higher-level multisensory region being driven by cortico-cortical, rather than thalamo-cortical connections. Second, the laminar organization of the PPr differed substantially from the pattern commonly observed in primary sensory cortices. The PPr has a reduced layer 4 compared to primary sensory cortices, which does not receive input from principal thalamic nuclei. Third, the distribution of unisensory and multisensory neurons and properties differs significantly by layer. Given the laminar-dependent input-output relationships, this suggests that unisensory and multisensory signals are processed in parallel as they pass through the circuitry of the PPr. Finally, specific functional properties of bimodal neurons differed significantly from those of their unisensory counterparts. Thus, despite their coextensive distribution within cortex, these results differentiate bimodal from unisensory neurons in ways that have never been examined before. Together these experiments represent the first combined anatomical-electrophysiological examination of the laminar organization of a multisensory cortex and the first systematic comparison of the functional properties of bimodal and unisensory neurons. These results are essential for understanding the neural bases of multisensory processing and carry significant implications for the accurate interpretation of macroscopic studies of multisensory brain regions (i.e. fMRI, EEG), because bimodal and unisensory neurons within a given neural region can no longer be assumed to respond similarly to a given external stimulus.

Ferrets are amusing, flexible creatures that have been under represented in computer models. Because their bodies can assume almost any curved shape, splines are the natural tool for modelling ferrets. Surface pasting is a hierarchical method of modelling with spline surfaces, where features are added onto a base surface. Existing surface pasting techniques are limited to modelling rectilinear shapes. Using the task of modelling a ferret as a driving force, I propose a method of pasting cylinders in world space; I looked at methods for reducing distortion of pasted features; and I created a method for pasting trimmed features to allow for features that do not have the rectilinear shape of standard pasting. With my methods, modelling ferrets with surface pasting is easier, and the resulting models are closer to a real ferret.

Ferrets are amusing, flexible creatures that have been under represented in computer models. Because their bodies can assume almost any curved shape, splines are the natural tool for modelling ferrets. Surface pasting is a hierarchical method of modelling with spline surfaces, where features are added onto a base surface. Existing surface pasting techniques are limited to modelling rectilinear shapes. Using the task of modelling a ferret as a driving force, I propose a method of pasting cylinders in world space; I looked at methods for reducing distortion of pasted features; and I created a method for pasting trimmed features to allow for features that do not have the rectilinear shape of standard pasting. With my methods, modelling ferrets with surface pasting is easier, and the resulting models are closer to a real ferret.

Influenza is a contagious respiratory disease that has caused at least four pandemics and countless epidemics since the 20th century, impacted millions of people worldwide and the global economy. To date, the predominant influenza species circulating in humans are influenza A and B. Influenza may cause serious illness in all age groups but individuals such as the newborns and senior population whose immune systems are compromised are at higher risk for severe disease. Interestingly, during the outbreak of pandemic 2009 H1N1 (H1N1pdm), it was found that the elderly had the lowest hospitalization rate and an increased proportion of healthy adults developed severe disease. Furthermore, several clinical studies have demonstrated that most H1N1pdm infected children experienced mild to moderate illness and led to the least mortality. The difference of disease outcome in age groups between different influenza infections may be due to several factors, which include differing pathogenicity between the viruses, differential immune status and composition among the age groups, and pre-existing immunity from previous encounter(s) with a similar virus. Since the human clinical data are often complicated by secondary factors such as co-morbidities, I used the ferret model to address these questions. I first compared the clinical and pathological patterns among the pandemic and seasonal influenza strains and found H1N1pdm caused the most severe illness to healthy ferrets. Importantly, the disease severity did not correlate with viral burden but immunopathology. To study the age effect, I found that H1N1pdm infected young ferrets with mild clinical symptoms developed specialized ectopic lymphoid structures and a distinct cytokine expression profile in the lungs, which were absent in adult ferrets with severe illness. I also examined antigenic change in historical H1N1s and anti-H1 responses to explain the pre-existing immunity of H1N1pdm found in the elderly. However, low similarity was found between historical H1N1s and H1N1pdm. Lastly, I conducted a detailed influenza B comparative study. I observed the pathogenic B strain was capable to cause lower respiratory tract infection and pathology like the influenza A viruses. Overall, this thesis provides novel insights for developing therapeutic and prophylactic strategies against influenza infection.

Description of the cell cycle features of neural progenitors during late stages of neurogenesis in a gyrencephalic mammal, the ferret.

Influenza is a contagious respiratory disease that has caused at least four pandemics and countless epidemics since the 20th century, impacted millions of people worldwide and the global economy. To date, the predominant influenza species circulating in humans are influenza A and B. Influenza may cause serious illness in all age groups but individuals such as the newborns and senior population whose immune systems are compromised are at higher risk for severe disease. Interestingly, during the outbreak of pandemic 2009 H1N1 (H1N1pdm), it was found that the elderly had the lowest hospitalization rate and an increased proportion of healthy adults developed severe disease. Furthermore, several clinical studies have demonstrated that most H1N1pdm infected children experienced mild to moderate illness and led to the least mortality. The difference of disease outcome in age groups between different influenza infections may be due to several factors, which include differing pathogenicity between the viruses, differential immune status and composition among the age groups, and pre-existing immunity from previous encounter(s) with a similar virus. Since the human clinical data are often complicated by secondary factors such as co-morbidities, I used the ferret model to address these questions. I first compared the clinical and pathological patterns among the pandemic and seasonal influenza strains and found H1N1pdm caused the most severe illness to healthy ferrets. Importantly, the disease severity did not correlate with viral burden but immunopathology. To study the age effect, I found that H1N1pdm infected young ferrets with mild clinical symptoms developed specialized ectopic lymphoid structures and a distinct cytokine expression profile in the lungs, which were absent in adult ferrets with severe illness. I also examined antigenic change in historical H1N1s and anti-H1 responses to explain the pre-existing immunity of H1N1pdm found in the elderly. However, low similarity was found between historical H1N1s and H1N1pdm. Lastly, I conducted a detailed influenza B comparative study. I observed the pathogenic B strain was capable to cause lower respiratory tract infection and pathology like the influenza A viruses. Overall, this thesis provides novel insights for developing therapeutic and prophylactic strategies against influenza infection.

Master of Science in Biomedical Sciences / Department of Diagnostic Medicine/Pathobiology / Yunjeong Kim / Coronaviruses are pathogens that cause diverse diseases in humans and animals. The studies in this dissertation are focused on feline coronavirus (FCoV), ferret coronavirus (FRCoV) and mink coronavirus (MCoV). FCoV and FRCoV infections typically cause enteritis in cats and ferrets, respectively. However, a 100% fatal systemic disease called feline infectious peritonitis (FIP) can develop in some FCoV infected cats and a fatal systemic disease resembling FIP can develop in some FRCoV infected ferrets. MCoV causes enteritis which results in significant economic loss to mink farmers. No effective vaccine or treatment is available despite the increasing importance of these viral diseases. We have previously reported the synthesis of inhibitors against 3C-like protease (3CLpro) of FCoV and demonstrated the antiviral efficacy of a 3CLpro inhibitor for treating FIP. FRCoV and MCoV 3CLpro are closely related to FCoV 3CLpro. Therefore, we investigated the structure-function relationships of our 3CLpro inhibitors to identify the struc-tural requirements of inhibitors for FRCoV and MCoV. This is the first report of antiviral com-pounds against FRCoV and MCoV. We have previously conducted a field trial with a potent 3CLpro inhibitor, GC376, in cats with naturally occurring FIP. Comparison of the FCoV 3CLpro amino acid sequences from the pre- and post-treatment samples in one cat showed amino acid changes in 3CLpro. Hence, we generated recombinant 3CLpros carrying the amino acid changes and characterized the effects of these amino acid changes in FCoV 3CLpro on its susceptibility to GC376. We observed that these amino acid changes did not markedly affect the activity of GC376 in fluorescence resonance energy transfer (FRET) assay, explaining the absence of clinical drug resistance in this cat during the field trial.

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Ce travail présente une analyse de la morphologie et de la dynamique sédimentaire des systèmes turbiditiques actuels du Cap-Ferret et de Capbreton (sud du Golfe de Gascogne). La reconnaissance effectuée sur le système de Capbreton est la première à le considérer dans son ensemble. Ce travail se base sur des données acoustiques de subsurface (sondeur multifaisceaux, sondeur de sédiments Chirp) et de carottages issues de la campagne océanographique Sargass menée par l’Université de Bordeaux. L’analyse morpho-bathymétrique révèle l’organisation amont-aval des géométries sédimentaires dans ces systèmes et, couplée aux données sédimentaires, de préciser les processus de dépôts liés aux écoulements gravitaires. Le fonctionnement holocène du canyon de Capbreton montre des processus gravitaires haute fréquence, révélant son rôle de dépôt-centre pour le sud du golfe de Gascogne. Dans le système du Cap-Ferret, la zone de transition chenal-lobe a été investiguée à fine échelle, documentant ainsi des structures sédimentaires rarement identifiées avec ce niveau de détails dans les systèmes turbiditiques modernes. La dynamique sédimentaire de chacun de ces systèmes est soumise à des forçages auto-cycliques et glacio-eustatiques qui affectent chacun des systèmes de façons différentes. Ces informations ont permis de proposer un modèle régional de fonctionnement sédimentaire au cours des derniers 50 000 ans. / This work presents an analysis of the morphology and sedimentary dynamic of the Cap-Ferret and Capbreton turbidite systems (south Bay of Biscay), containing the first recognition of the whole Capbreton turbidite system. The dataset comprises subsurface geophysical data (multibeam bathymetric and imagery, Chirp sub-bottom profiler) and piston cores, acquired during the oceanographic cruise Sargass conducted by the Bordeaux University. Studied by morpho-bathymetric analyses, the upstream-downstream evolution of the sedimentary bodies joined to the sedimentological data help to understand the active gravity processes of the systems. In the Capbreton system, a special focus is made on its Holocene gravity deposits occurring at high frequencies. In the Cap-Ferret system, the channel-lobe transition zone has been investigated at high resolution and revealed sedimentary structures poorly documented at this scale of details in recent turbidite systems. The glacio-eustatic and autocyclic forcing are expressed in different ways in each turbidite sytem. A regional sedimentary dynamic model is proposed for the last 50,000 years.

Neuronal plasticity deficits underlie many of the neurobehavioral problems seen in Fetal Alcohol Spectrum Disorders (FASD). Recently, we showed that third trimester alcohol exposure lead to a persistent disruption in ocular dominance (OD) plasticity. For instance, few days of monocular deprivation results in a robust reduction of cortical regions responsive to the deprived eye in normal animals, but not in ferrets exposed early to alcohol. This plasticity deficit can be reversed if alcohol-exposed animals are treated with a phosphodiesterase type 1 (PDE1) inhibitor during the period of monocular deprivation. PDE1 inhibition can increase cAMP and cGMP levels, activating transcription factors such as the cAMP response element binding protein (CREB) and the Serum response factor (SRF). SRF is important for many plasticity processes such as LTP, LTD, spine motility and axonal pathfinding. Here we attempt to rescue OD plasticity in alcohol-treated ferrets using a Sindbis viral vector to express a constitutively active form of SRF during the period of monocular deprivation. Using optical imaging of intrinsic signals and single unit recordings we observed that overexpression of a constitutively active form of SRF (Sindbis SRF+), but neither its dominant negative (SRF-) nor GFP, restored OD plasticity in alcohol-treated animals. Surprisingly, this restoration was observed throughout the extent of the primary visual cortex and most cells infected by the virus were positive for GFAP rather than NeuN. Hence, we further tested whether overexpression of SRF exclusively in astrocytes is sufficient to restore OD plasticity in alcohol-exposed ferrets. To accomplish that, first we exposed cultured astrocytes to the SRF+, SRF- or control GFP viruses. After 24h, these astrocytes were implanted in the visual cortex of alcohol-exposed animals or saline controls one day before MD. Optical imaging of intrinsic signals showed that alcohol-exposed animals that were implanted with astrocytes expressing SRF, but not SRF- or GFP, showed robust restoration of OD plasticity in all visual cortex. These findings suggest that overexpression of SRF exclusively in astrocytes can improve neuronal plasticity in FASD.