A recent model of Parkinson’s disease (PD) suggests that the neuropathological, behavioural and cognitive symptoms progress in stages. There is substantial evidence for a prodromal stage of PD, during which time pre-motor symptoms develop. Rapid eye movement (REM) sleep behaviour disorder (RBD) is a risk factor for developing PD and may be part of the pre-motor stage. In both disorders, neuropathological α-synuclein aggregates are thought to be a direct cause of the resulting symptoms. One model has shown that in rats, proteasome inhibition produced by systemic exposure to environmental toxins results in α-synuclein pathology and motor behaviour dysfunction that mimics the progression of PD in humans. The present study examined the hypothesis that the systemic proteasome inhibition model would produce pre-Parkinsonian RBD-like pathology in rats. It was expected that sleep disturbances would be seen prior to behavioural disturbances in rats treated systemically with PSI (a proteasome inhibitor). Following baseline sleep recording and training on the inclined beam-traverse task, rats were injected with PSI (a proteasome inhibitor) or ethanol (control), 6 times over 2 wk. Sleep recording over 8 wk and behavioural testing over 16 wk provided no evidence of sleep disturbances or motor dysfunction. Post-mortem immunohistochemical analyses of brain tissue provided no evidence of PSI-associated α-synuclein aggregates in the locus coeruleus, subcoeruleus (dorsal part), or substantia nigra (areas involved in RBD and/or PD). These results did not provide support for RBD as a prodromal phase of PD within the systemic proteasome inhibitor-based model and add to a growing body of research reporting inconsistent findings using this model. We suggest that systemic PSI exposure in rats does not produce a viable model of RBD or PD. Whether RBD is an early symptom in the progression of PD remains to be established. / Thesis (Master, Neuroscience Studies) -- Queen's University, 2010-04-28 12:04:50.613

Mémoire numérisé par la Division de la gestion de documents et des archives de l'Université de Montréal

Si les connaissances anatomiques supportent l'élaboration des techniqueschirurgicales, peu d'informations étaient disponibles sur l'anatomie et la physiologie del'innervation pelvi-périnéale. La détermination précise de l'origine, du trajet péri-viscéral, desrapports anatomiques avec les organes et les vaisseaux de voisinage et de la terminaison deces nerfs au niveau d'organes dont ils commandent la fonction était jusqu'alors peu accessibleaux techniques anatomiques classiques de dissection macroscopique sur sujet cadavérique.Dans le domaine de la chirurgie pelvienne pour cancer, l'amélioration de la qualité de vie desmalades passe par la préservation de ces structures nerveuses, la dimension fonctionnelle étantdésormais indissociable des impératifs carcinologiques. En effet, l'intégrité de ces nerfs estindispensable aux fonctions de continence sphinctérienne et de sexualité. Par ailleurs, lamajorité des travaux s'intéressant aux séquelles fonctionnelles postopératoires sont réaliséschez l'homme et très peu de travaux concernent exclusivement les femmes dont les troublessexuels sont plus difficiles à identifier. La réduction de ces troubles fonctionnelspostopératoires passe donc par une meilleure compréhension de l'anatomie nerveuse pelvipérinéale,qui peut être éclaircie par de nouvelles techniques d'étude

Doctor of Philosophy(PhD) / Two recently identified transient receptor potential (TRP) channels, TRPM8 and TRPA1, have been proposed to play an important role in mammalian cool and cold peripheral sensory transduction. When expressed in cell-lines the cloned TRPM8 and TRPA1 receptors have distinct pharmacological and temperature response characteristics. Although these receptors are also transported to the central terminals of primary afferents, little is known about their centrally mediated actions. In this thesis, I use an in vitro electrophysiological approach to investigate the dorsal horn processing of cool afferent modalities and the role of TRP ion channels. The results of this thesis provide further information on thermal processing, indicate direction for further research and suggest possible therapeutic targets for the management of abnormal cold sensory processing. Initial experiments demonstrate that the cooling agents and known TRPM8 and TRPA1 agonists, menthol and icilin, inhibit primary afferent evoked excitatory postsynaptic currents (EPSCs) in rat spinal cord dorsal horn neurons. In addition, temperature reduction, menthol and icilin increase the frequency of miniature EPSCs without affecting amplitude distribution or kinetics. Little or no direct postsynaptic effect on dorsal horn neurons, GABAergic or glycinergic transmission was found. In combination, these observations demonstrate that temperature reduction, menthol and icilin act presynaptically to increase the probability of glutamate release from primary afferent fibres. Further examination of the changes in glutamatergic synaptic transmission induced by temperature reduction, menthol and icilin reveals a subset of neurons sensitive to innocuous cool (< 29 oC) and low concentrations of icilin (3-10 µM) which closely match the temperature activation and pharmacological profile of TRPM8. In addition, the majority of lamina I and II neurons displayed characteristics partly consistent with TRPA1-activation, including a concentration-dependent response to icilin and blockade by ruthenium red. The present experiments did not allow thermal characterisation of these TRPA1-like responses. Together these observations indicate that the effects of menthol and icilin on glutamatergic synaptic transmission in the superficial dorsal horn are mediated by TRPM8 and possibly by TRPA1. Examination of the anatomical location of neurons activated by temperature reduction, menthol, icilin and capsaicin allowed the central termination pattern of thermoreceptive primary afferent fibres with specific TRP-like response characteristics to be determined. TRPM8-like presynaptic activation was confined to a subpopulation of neurons located in lamina I and outer lamina II, while the majority of neurons throughout laminae I and II received inputs sensitive to menthol, high concentrations of icilin and capsaicin. These findings suggest that innocuous cool sensation projects to a specific subpopulation of superficial dorsal horn neurons unlike other modalities (mediated by TRPV1, possibly TRPA1 and other receptors), which non-selectively engage circuits within the entire superficial dorsal horn. No morphological specificity was identified for recovered neurons after electrophysiological characterisation. Finally, mu-opioids were shown to inhibit basal glutamatergic synaptic transmission as well as menthol- and icilin-induced transmission in the superficial dorsal horn. Of particular interest, delta-opioids selectively inhibited icilin-induced synaptic transmission within the same location. The selective effect of delta-opioids suggests a possible role in modulating receptors activated by icilin (TRPM8 and TRPA1). Overall, this thesis provides further evidence that TRPM8 is responsible for the transduction of innocuous cold sensation in mammals and is a potential therapeutic target in humans with cold hyperaesthesia secondary to abnormal thermal processing. The use of delta-opioid agonists warrants further investigation in cold hypersensitivity states and potentially other forms of pain.

Diss. (sammanfattning) Umeå : Umeå universitet, 2010.

L'allodynie mécanique est un symptôme cardinal des douleurs persistantes. Elle est due à l’activation de circuits, habituellement bloqués, des couches superficielles de la corne dorsale spinale ou du sous-noyau caudal du trijumeau (Sp5C), par lesquels les afférences mécaniques à bas seuil peuvent accéder aux neurones nociceptifs de projection de la couche I. Un élément déterminant de ces circuits est une classe d’interneurones excitateurs de la couche II interne (IIi) exprimant l'isoforme gamma de la protéine kinase C (PKCγ), et recevant des afférences des mécanorecepteurs à bas seuil. La modulation de l’inhibition tonique de ces interneurones PKCγ contribue à l’apparition de l’allodynie mécanique. Cependant la morphologie, les propriétés électrophysiologiques et les caractéristiques des afférences excitatrices et inhibitrices de ces interneurones PKCγ ne sont toujours pas connues. Utilisant des techniques d’électrophysiologie (enregistrements patch-clamp) et d'immunohistochimie sur tranches de Sp5C, nous avons caractérisé les propriétés des interneurones PKCγ de la couche IIi du Sp5C chez le rat adulte et comparé ces propriétés avec celles d’interneurones voisins n’exprimant pas la PKCγ.Cette étude révèle que l’arborisation neuritique des interneurones PKCγ s’étend largement au sein de la couche IIi, et peut se prolonger du coté dorsal jusqu’à la couche II externe, sans jamais atteindre la couche I. En outre, en fonction de cette extension neuritique, au moins deux sous-populations d'interneurones PKCγ peuvent être dissociées – centrales et radiales – qui s’avèrent être aussi fonctionnellement différentes. Comparés aux autres neurones non-PKCγ de la conche IIi, les interneurones PKCγ, dans leur ensemble, présentent un seuil de déclenchement des potentiels d’action plus bas et, souvent associée, plus fréquemment une réponse tonique à un courant dépolarisant, indiquant ainsi qu’ils sont plus facilement excitables. Cependant, ils reçoivent inversement une excitation synaptique plus faible. Quant aux afférences inhibitrices, la plupart des interneurones PKCγ expriment des synapses mixtes associant récepteurs GABAAergiques (GABAAR) et récepteurs glycinergiques (GlyR). Seul un petit nombre d’entre eux exprime des synapses uniquement GABAAR ou GlyR. Pourtant, tous les interneurones PKCγ reçoivent non seulement des mIPSCs mixtes GABAAR-GlyR, mais aussi des mIPSCs uniquement GABAAR ou uniquement GlyR. / Mechanical allodynia, a cardinal symptom of persistent pain, is associated with the unmasking of usually blocked local circuits within the superficial spinal or medullary dorsal horn (MDH), through which low-threshold mechanical inputs can gain access to the lamina I nociceptive output neurons. Key determinants of these circuits are lamina II (IIi) excitatory interneurons that selectively concentrate the gamma isoform of protein kinase C (PKCγ) and receive low-threshold mechanical receptor (LTMR) inputs. Tonic inhibition of PKCγ interneurons is thought to gate circuits underlying mechanical allodynia. However, the morphology, electrophysiological properties and excitatory and inhibitory synaptic inputs on these PKCγ interneurons are still unknown. Using whole-cell patch-clamp recordings and immunohistochemical techniques in slices of adult rat MDH, we characterized these lamina IIi PKCγ interneurons and compared them with neighboring non-PKCγ interneurons. Our results reveal that the neurites of PKCγ interneurons arborize extensively within lamina IIi, can spread dorsally into lamina IIo, but never reach lamina I. In addition, according to cell bodies and the orientation and extent of dendritic arbors, at least two morphologically different classes of PKCγ interneurons can be identified – central and radial – which appear to be also functionally different. Compared with neighboring lamina IIi non-PKCγ interneurons, PKCγ interneurons exhibit a lower threshold for action potentials, consistent with a more frequent tonic spike discharge to depolarizing step current, indicating that they are more excitable than other lamina IIi neurons. On the other hand, they receive a weaker excitatory synaptic drive. According to inhibitory inputs, most PKCγ interneurons display mixed-GABAA (GABAAR) and glycine (GlyR) receptor synapses with only very few of them displaying also GABAAR-alone or GlyR-alone synapses. Interestingly, all PKCγ interneurons exhibit mixed GABAAR–GlyR as well as GABAAR-only and GlyR-only mIPSCs. Altogether, this study indicates that PKCγ interneurons within lamina IIi of MDH are different from other lamina IIi neighboring neurons according to morphology, electrophysiological properties and synaptic inputs. This is consistent with their specific role in the gating of dorsally directed circuits within the MDH underlying mechanical allodynia. Moreover, we have identified two morphological and functional subclasses of PKCγ interneurons which might thus differently contribute to this gating.

Introduction: (Experimental part). Hypothesis evaluates the quasi-static risk of transpedicular fixation failure in the spinal cadaver with anterior column defect due to the fixation extension and defines the risk of transpedicular fixation failure due to screw convergence in cyclic loading. (Clinical part). Hypothesis evaluates the risk of isolated dorsal approach to ventral lumbar spondylodiscitis due to clinic and radiopraphic results and the risk of anterior radical debridement due to using titanium implant in the site of bone infection. Methods: (Experimental part). Four anatomically preparated spinal cadavers with anterior spinal column defect transpediculary instrumented were quasi-statically tested on MTS 858,2 Mini-Bionix. Concept of cyclic loading part were based on ASTM standard F1717. (Clinical part). The group A consisting of 23 patients was treated only by dorsal transmuscular approach and the second group B consisting of 8 patients was treated by two-stage postero- anterior surgery in lumbar spondylodiscitis. Results: (Experimental part). There were progress in all assessed parametres with considerable asymmetry direction in extension to flexion and duction in spinal column loading with anterior defect during quasi-static loading. The rod deformation decrease with extent of...

L’objectif de ces travaux a été d’étudier, à partir des potentiels évoqués, l’implication des voies ventrale (qui sous-tend le traitement expert de l’écrit) et dorsale (qui sous-tend des processus phonologiques et attentionnels) lors de la reconnaissance visuelle des mots chez des adultes dyslexiques. Les spécificités des sujets dyslexiques ont été isolées en les comparant à deux groupes contrôles, appariés sur : l’âge (i.e., des lecteurs experts) et sur le niveau de lecture (i.e., des mauvais lecteurs). Les résultats montrent des déficits du traitement expert de l’écrit, phonologiques et de la détection du conflit spécifiques aux sujets dyslexiques. Nos données montrent aussi des déficits du traitement expert des mots familiers et d’orientation de l’attention communs aux sujets dyslexiques et mauvais lecteurs. Les résultats sont discutés dans le cadre du modèle LCD, de la théorie du mapping phonologique et d’une implication précoce de l’orientation attentionnelle dans la lecture. / The aim of this project was to examine with event related potentials ventral (involved in expertise for print) and dorsal (involved in phonological and attentional processes) pathways implication in visual word recognition in dyslexic adults. The specificity of dyslexics was determined by comparing them to age-matched controls (i.e., expert readers) and reading-level matched controls (i.e., poor readers). Results showed impaired expertise for print, decoding abilities and conflict detection which were specific to dyslexics. Our data also revealed impaired expertise for familiar words and attention orienting in both dyslexics and poor readers. Results are discussed in the context of the LCD model, the phonological mapping theory and an early involvement of attention orienting in reading.

Extensos dados na literatura têm assinalado a importância da serotonina (5-HT) na modulação de comportamentos de medo e ansiedade em roedores, a grande maioria utilizando ratos machos como sujeitos experimentais. No presente trabalho, foi analisada a influência da neurotransmissão 5-HT periférica e central sobre a expressão da resposta de medo condicionado e incondicionado de ratos machos e fêmeas, previamente selecionados pelo fenótipo como animais de baixa (BA) ou de alta (AA) reatividade emocional. Para este fim foi utilizado o teste do sobressalto potencializado pelo medo (SPM). A influência global e central de 5-HT foi avaliada pela utilização da administração sistêmica ou intraventricular aguda do inibidor irreversível da enzima triptofano hidroxilase PCPA (p-clorofenilalanina) nas doses de 200 mg/mL (i.p.) e 200 µg/5 µL (i.v.), ou através de infusões locais de 5-HT (10 nmol/0.2 µL) ou do agonista seletivo de receptores 5-HT1A 8-hidroxi-2-(di-n-propilamino)-tetralina (8-OH-DPAT) na dose de 0,3 µg/0.2 µL, diretamente em áreas encefálicas conhecidas por sua influência na modulação do medo e ansiedade a saber: o córtex pré-limbico (CPL), o núcleo basolateral da amígdala (BLA), e a substância cinzenta periaqueductal dorsal (SCPd) do mesencéfalo. As variáveis dependentes registradas foram a amplitude e a latência das respostas incondicionadas e condicionadas de sobressalto e a amplitude do SPM. / Extensive data in the literature have signaled the importance of serotonin (5-HT) on the modulation of fear and anxiety-like behaviors in rodents. In the present study, we have analyzed the influence of peripheral and central 5-HT neurotransmission on the expression of the conditioned and unconditioned fear, and on the fear-potentiated startle in male and female rats previously selected as low- (LA) or high-anxiety (HA). For this purpose, we used the fear-potentiated startle (FPS) test. The global and central influence of 5-HT was evaluated by using the acute systemic or intraventricular administration of the irreversible tryptophan hydroxylase inhibitor PCPA (p-chlorophenylalanine - 200 mg/mL i.p., or 200 µg/5 µL i.v.). Local effects were evaluated through local infusions of 5-HT itself (10 nmol/0.2 µL) or the selective 5-HT1A receptors agonist 8-hydroxy-2-(di-n-propylamino)-tetralin (8-OH-DPAT 0.3 µg/0.2 µL) in the prelimbic cortex (PrL), basolateral amygdala (BLA) or the dorsal periaqueductal gray (DPAG). These brain regions were chosen for the present study based on their great importance in the modulation and expression of conditioned and unconditioned fear. Dependent variables recorded were the amplitude and latency of unconditioned and conditioned fear, and fear-potentiated startle (FPS).

La perception d’un mouvement biologique correspond à l’aptitude à recueillir des informations (comme par exemple, le type d’activité) issues d’un objet animé en mouvement à partir d’indices visuels restreints. Cette méthode a été élaborée et instaurée par Johansson en 1973, à l’aide de simples points lumineux placés sur des individus, à des endroits stratégiques de leurs articulations. Il a été démontré que la perception, ou reconnaissance, du mouvement biologique joue un rôle déterminant dans des activités cruciales pour la survie et la vie sociale des humains et des primates. Par conséquent, l’étude de l’analyse visuelle de l’action chez l’Homme a retenu l’attention des scientifiques pendant plusieurs décennies. Ces études sont essentiellement axées sur informations cinématiques en provenance de différents mouvements (comme le type d’activité ou les états émotionnels), le rôle moteur dans la perception des actions ainsi que les mécanismes sous-jacents et les substrats neurobiologiques associés. Ces derniers constituent le principal centre d’intérêt de la présente étude, dans laquelle nous proposons un nouveau modèle descriptif de simulation bayésienne avec minimisation du risque. Ce modèle est capable de distinguer la direction d’un ballon à partir d’un mouvement biologique complexe correspondant à un tir de soccer. Ce modèle de simulation est inspiré de précédents modèles, neurophysiologiquement possibles, de la perception du mouvement biologique ainsi que de récentes études. De ce fait, le modèle présenté ici ne s’intéresse qu’à la voie dorsale qui traite les informations visuelles relatives au mouvement, conformément à la théorie des deux voies visuelles. Les stimuli visuels utilisés, quant à eux, proviennent d’une précédente étude psychophysique menée dans notre laboratoire chez des athlètes. En utilisant les données psychophysiques de cette étude antérieure 3 et en ajustant une série de paramètres, le modèle proposé a été capable de simuler la fonction psychométrique ainsi que le temps de réaction moyen mesurés expérimentalement chez les athlètes. Bien qu’il ait été établi que le système visuel intègre de manière optimale l’ensemble des indices visuels pendant le processus de prise de décision, les résultats obtenus sont en lien avec l’hypothèse selon laquelle les indices de mouvement sont plus importants que la forme dynamique dans le traitement des informations relatives au mouvement. Les simulations étant concluantes, le présent modèle permet non seulement de mieux comprendre le sujet en question, mais s’avère également prometteur pour le secteur de l’industrie. Il permettrait, par exemple, de prédire l’impact des distorsions optiques, induites par la conception de verres progressifs, sur la prise de décision chez l’Homme. Mots-clés : Mouvement biologique, Bayésien, Voie dorsale, Modèle de simulation hiérarchique, Fonction psychométrique, Temps de réaction / The ability to recover information (e.g., identity or type of activity) about a moving living object from a sparse input is known as Biological Motion perception. This sparse input has been created and introduced by Johansson in 1973, using only light points placed on an individual's strategic joints. Biological motion perception/recognition proves to play a significant role in activities that are critical to the survival and social life of humans and primates. In this regard, the study of visual analysis of human action had the attention of scientists for decades. These studies are mainly focused on: kinematics information of the different movements (such as type of activity, emotional states), motor role in the perception of actions and underlying mechanisms, and associated neurobiological substrates. The latter being the main focus of the present study, a new descriptive risk-averse Bayesian simulation model, capable of discerning the ball’s direction from a set of complex biological motion soccer-kick stimuli is proposed. Inspired by the previous, neurophysiologically plausible, biological motion perception models and recent studies, the simulation model only represents the dorsal pathway as a motion information processing section of the visual system according to the two-stream theory, while the stimuli used have been obtained from a previous psychophysical study on athletes. Moreover, using the psychophysical data from the same study and tuning a set of parameters, the model could successfully simulate the psychometric function and average reaction time of the athlete participants of the aforementioned study. 5 Although it is established that the visual system optimally integrates all available visual cues in the decision-making process, the results conform to the speculations favouring motion cue importance over dynamic form by only depending on motion information processing. As a functioning simulator, the present simulation model not only introduces some insight into the subject at hand but also shows promise for industry use. For example, predicting the impact of the lens-induced distortions, caused by various lens designs, on human decision-making. Keywords: Biological motion, Bayesian, Dorsal pathway, Hierarchical simulation model, Psychometric function, Reaction time