Spatial navigation, cognitive coordination and behavioral flexibility belong amongst cognitive functions, which play a role in many neuropsychiatric disorders. Behavioral tasks have proved to be useful paradigms to test these functions in pharmacological or genetic animal models. First aim was to determine a potential interaction between β-adrenergic and α1-adrenergic or D2-dopaminergic systems. Spatial navigation and coordination were impaired in both studies during co-aplication of subthreshold doses of drugs. Used substances belong to group of widely prescribed drugs, thus our results could be implicated in clinical practice. Another study examined an acute effect of MK-801 (animal model of schizophrenia) on behavioral flexibility in Carousel maze and the Morris water maze (MWM). Carousel maze showed higher sensitivity with impairments from 0.08 mg.kg-1 compared to 0.10 mg.kg- 1 in MWM. The final experiment aimed at testing the effect of reduced expression of Nogo-A protein on spatial navigation and behavioral flexibility of rats. A battery of tests in the Carousel maze revealed impairment in cognitive functions, MWM showed unaffected working memory of rats. Our results support the hypothesis linking Nogo-A knock-down rats with neuropsychiatric symptoms and cognitive disorders. Key words:...

Spatial navigation, cognitive coordination and behavioral flexibility belong amongst cognitive functions, which play a role in many neuropsychiatric disorders. Behavioral tasks have proved to be useful paradigms to test these functions in pharmacological or genetic animal models. First aim was to determine a potential interaction between β-adrenergic and α1-adrenergic or D2-dopaminergic systems. Spatial navigation and coordination were impaired in both studies during co-aplication of subthreshold doses of drugs. Used substances belong to group of widely prescribed drugs, thus our results could be implicated in clinical practice. Another study examined an acute effect of MK-801 (animal model of schizophrenia) on behavioral flexibility in Carousel maze and the Morris water maze (MWM). Carousel maze showed higher sensitivity with impairments from 0.08 mg.kg-1 compared to 0.10 mg.kg- 1 in MWM. The final experiment aimed at testing the effect of reduced expression of Nogo-A protein on spatial navigation and behavioral flexibility of rats. A battery of tests in the Carousel maze revealed impairment in cognitive functions, MWM showed unaffected working memory of rats. Our results support the hypothesis linking Nogo-A knock-down rats with neuropsychiatric symptoms and cognitive disorders. Key words:...

京都大学 / 0048 / 新制・課程博士 / 博士(医学) / 甲第19270号 / 医博第4034号 / 新制||医||1011(附属図書館) / 32272 / 京都大学大学院医学研究科医学専攻 / (主査)教授 髙橋 良輔, 教授 渡邉 大, 教授 富樫 かおり / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM

The default mode network (DMN) is a highly cited neural network whose functional roles are not well understood. Until recently, event related fMRI experiments used to study the DMN could only be conducted in an open-loop format. The purpose of this study was to demonstrate the potential statistical advantages of real-time fMRI studies to conduct closed-loop experiments to directly test putative DMN functions. Using both fMRI simulations and large archival datasets, we demonstrate that open-loop designs are less statistically powerful than closed-loop experiments that can trigger stimuli at controlled levels of brain activity. When simulating event scheduling on resting state data, DMN levels were normally distributed, but the event timing proved to be ineffective in capturing the highest and lowest DMN values on average across subjects. Statistical differences in DMN levels collected by the Human Connectome Project-Aging (HCP-A) during a Go/NoGo task were also reported, along with the network's distributional effects across subjects. When examining DMN levels in 136 subjects more prone to commission errors the mean DMN levels were reported to be higher during and prior to incorrect NoGo responses. Exploring DMN levels in these same individuals reacting to a Go task also revealed differing measurement patterns when compared to all 711 subjects in the study. Additionally, the distribution of total DMN levels across all participants, as well as during a Go or NoGo trial, showed a shift in the mean towards deactivation. Furthermore, the peak at this location was greater and revealed that increased sampling occurred at the mean and under sampling at the tails. Overall, the cumulative findings in this study were successful in providing statistical arguments to support propositions for more powerful closed-loop experimentation in fMRI. / Master of Science / Activity in a neural network is observed through the use of functional MRI (fMRI) by tracking higher levels of oxygenated blood to that region when active and lower quantities when inactive. Neural networks vary in their responsibilities, thus fMRI tasks are designed to trigger a response based on the functional role of the network. This can be exemplified by studying the blood flow to default mode network (DMN), a network responsible for mind wandering, during a task that requires focus. Researchers can then correlate moments of high activity, which indicates a greater degree of mind wandering, or low activity to a correct or incorrect response to the task. Unfortunately, the timing in which a task is presented to the participant is predetermined prior to the subject entering the MRI making it difficult to capture a correct or incorrect response at the precise moment of activation or deactivation. This concept is known as open-loop and often collects data at moments of neutral activity, neither high nor low. In contrast, a closed-loop design allows a researcher to monitor the DMN's activation levels in real time and present the task at a desired time. This provides more useful data to the experimenter as all recorded responses to the task correlate with exact moments of high and low activation. This makes claims about the neural network's role statistically more powerful as there is a greater quantity of data at these moments rather than during a neutral activation state. The purpose of this thesis is to provide statistical arguments that support propositions for more powerful closed-loop experimentation in fMRI.

The aim of the work described in this thesis is to investigate the nature and mechanisms of action of repellent cues for growing axons. In particular I try to resolve the controversy in the literature regarding the need for protein synthesis in the growth cone in response to external guidance cues. My results resolve the conflicting data in the literature on Semaphorin-3A signalling, where differing labs had shown that inhibiting protein synthesis either blocks or has no effect upon repulsion. They demonstrate the presence of at least two independent pathways, protein synthesis-dependent mTOR activation and -independent GSK3? activation. The higher sensitivity of the synthesis-dependent pathway, and its redundancy at higher concentrations where synthesis-independent mechanisms can evoke a full collapse response alone, resolve the apparent conflict. My experiments also demonstrated that Nogo-?20, a domain of Nogo-A, requires local protein synthesis to cause collapse. Unlike Semaphorin-3A, the dependence of collapse upon protein synthesis is concentration-independent and does not involve guanylyl cyclase, but it does share a dependence upon mTOR activity and the synthesis of RhoA, sufficient to cause collapse downstream of Semaphorin-3A. The other axon-repelling domain of Nogo-A, Nogo-66, is partially dependent upon the proteasome instead. It does not share a common pathway with Nogo-?20, except that both are RhoA-dependent. I further attempted to identify the nature of a repulsive activity found in grey matter, ruling out a previously suggested candidate identity. Finally, I examined the phenomenon of nitric oxide-induced growth cone collapse. My experiments revealed that S-nitrosylated glutathione causes growth cone collapse through the activity of protein disulphide isomerase. This mechanism shows only a partial dependence upon soluble guanylyl cyclase, but I argue that it has total dependence upon an S-nitrosylated donor. Coupled with its apparent relation to S-palmitoylation, the reciprocal of S-nitrosylation, I propose that nitric oxide causes collapse by crossing the cell membrane to inhibit S-palmitoylation-determined localisation of proteins. These results reveal some of the many pathways involved in growth cone collapse, whose further characterisation may provide new targets for the treatment of injuries of the central nervous system.

O trabalho objetivou analisar os fatores que influenciam a mobilização da atenção automática visual. Nas tarefas diárias, o Sistema Nervoso Central seleciona os estímulos mais relevantes para as tarefas. Para entender o quê influencia a mobilização atencional, conduzimos três experimentos com análise do tempo de reação a um estímulo vai em relação a um não-vai em voluntários humanos. Utilizamos um estímulo abrupto anterior ao aparecimento dos estímulos alvos para capturar a atenção automática na mesma posição ou na oposta ao aparecimento do estímulo alvo, para medir o efeito atencional. No 1º experimento, analisamos a influência da semelhança dos estímulos negativo e positivo e obtivemos o efeito atencional. Em seguida, pesquisamos a influência da semelhança do estímulo precedente com a do estímulo positivo e não encontramos evidências a respeito. Por último, verificamos como a estratégia atencional influencia no efeito atencional, mas não houve tal efeito. Concluímos que o fator crítico para a mobilização eficaz da atenção automática é a discriminabilidade entre os estímulos vai e não-vai. / This project investigated the important factors to mobilize the visual automatic attention. During our day, the Central Nervous System selects the most important stimulus to have a good performance in a task. For understanding which factors influence the attentional mobilization, we did three experiments analyzing the reaction time to a go stimuli comparing to a no go stimuli with human volunteers. We used an onset stimulus appearing before the go and no go stimuli at the same or at the opposite positions for having the attentional effect. At the first experiment, we researched the influence of go and no-go similarities and there was the attentional effect. Then, we investigated if the similarity between positive targets and cue is the critical factor but we didn\'t find the attentional effect. Finally, we checked the possibility of attentional effect to the CR by inducing the adoption of VL´s attentional set by volunteers, but there wasn\'t no effect. We concluded that the most important factor to an efficient mobilization of the automatic attention is the discriminability between the go and no-go stimuli.

La maladie de Parkinson est une maladie neurodégénérative secondaire à la mort des neurones dopaminergiques, entraînant un dysfonctionnement des ganglions de la base (GB), ensemble de noyaux sous corticaux impliqués dans le contrôle de la motricité. Les symptômes moteurs sont améliorés par le traitement dopaminergique et par la stimulation cérébrale profonde (SCP) du noyau subthalamique (NST). Il a été montré que le changement d’activité bêta est corrélé avec l’amélioration motrice des symptômes de bradykinésie et rigidité. L’hypothèse serait que les oscillations bêta pourraient être un physiomarqueur spécifique des symptômes moteurs de la MP. L’objectif de cette thèse est de comprendre l’activité du NST et de trouver un physiomarqueur de la MP : au repos et pendant un paradigme Go/Nogo.Dans une première partie, pour 55 patients, nous avons modélisé la puissance avec un modèle linéaire à effets mixtes dans six bandes de fréquences selon la position des électrodes, la présence de complications liées au traitement dopaminergique, de la sévérité des symptômes, et du changement de ces symptômes suite à la prise du traitement dopaminergique. Le changement le plus important entre OFF- et ON-DOPA est observé dans la bande low-bêta. Cependant, nous n’avons pas trouvé de corrélation entre la sévérité de la bradykinésie, rigidité, ou du score axial avec l’activité low-bêta. Mais, nous avons trouvé que la sévérité de la rigidité était associée aux fréquences supérieures à 20Hz. Nous avons également trouvé une corrélation positive entre la sévérité du tremblement dans toutes les bandes de fréquences, qui est très importante pour la bande thêta. Etonnement, nous avons trouvé que les complications liées au traitement dopaminergique pouvaient induire des informations dans toutes les bandes. Cet effet est très important pour la bande thêta. Nos résultats au repos suggèrent que l’activité bêta n’est pas le physiomarqueur idéal de la MP.Pendant le paradigme Go/Nogo, pour 15 patients, nous avons modélisé la puissance avec un modèle linéaire à effets mixtes pour toutes les fréquences selon la position des électrodes, la sévérité des symptômes, les données comportementales et cinétiques. Nous avons trouvé une spécificité temporelle et spatiale des activités du NST au cours du paradigme. Nos résultats montrent que le NST est impliqué dans le contrôle des différentes étapes du mouvement volontaire du membre supérieur et que le défaut de dopamine dans le circuit sensorimoteur des GB génère une série de changements oscillatoires au sein du NST lors du mouvement. Cependant, l'activité thêta est apparue comme une activité caractéristique en OFF-DOPA fortement corrélée aux paramètres comportementaux et cinétiques. Cette activité pourrait être le physiomarqueur de la MP pendant l'exécution d'un mouvement, son augmentation pourrait induire une réponse motrice et un mouvement rapide. / The Parkinson's disease is a secondary neurodegenerative disease in the death of the dopaminergic neurons, pulling a dysfunction of the ganglions of the base (GB), the set pits under cortical implied in the control of the motricity...

O trabalho objetivou analisar os fatores que influenciam a mobilização da atenção automática visual. Nas tarefas diárias, o Sistema Nervoso Central seleciona os estímulos mais relevantes para as tarefas. Para entender o quê influencia a mobilização atencional, conduzimos três experimentos com análise do tempo de reação a um estímulo vai em relação a um não-vai em voluntários humanos. Utilizamos um estímulo abrupto anterior ao aparecimento dos estímulos alvos para capturar a atenção automática na mesma posição ou na oposta ao aparecimento do estímulo alvo, para medir o efeito atencional. No 1º experimento, analisamos a influência da semelhança dos estímulos negativo e positivo e obtivemos o efeito atencional. Em seguida, pesquisamos a influência da semelhança do estímulo precedente com a do estímulo positivo e não encontramos evidências a respeito. Por último, verificamos como a estratégia atencional influencia no efeito atencional, mas não houve tal efeito. Concluímos que o fator crítico para a mobilização eficaz da atenção automática é a discriminabilidade entre os estímulos vai e não-vai. / This project investigated the important factors to mobilize the visual automatic attention. During our day, the Central Nervous System selects the most important stimulus to have a good performance in a task. For understanding which factors influence the attentional mobilization, we did three experiments analyzing the reaction time to a go stimuli comparing to a no go stimuli with human volunteers. We used an onset stimulus appearing before the go and no go stimuli at the same or at the opposite positions for having the attentional effect. At the first experiment, we researched the influence of go and no-go similarities and there was the attentional effect. Then, we investigated if the similarity between positive targets and cue is the critical factor but we didn\'t find the attentional effect. Finally, we checked the possibility of attentional effect to the CR by inducing the adoption of VL´s attentional set by volunteers, but there wasn\'t no effect. We concluded that the most important factor to an efficient mobilization of the automatic attention is the discriminability between the go and no-go stimuli.

The Nogo-A protein belongs among the most important regulatory molecules in the brain, regulating development of neuronal and glial cells, axon guidance and adult synaptic plasticity. Although it has been studied mainly as an obstacle to axon regeneration after CNS injury, it plays a role in many pathological conditions, including neurodegenerative and neuropsychiatric diseases. This work offers a literature review of the current knowledge about functions of Nogo-A and related proteins, and then recapitulates the results of experiments focused on the impact on decreased expression of Nogo-A on behavior in a transgenic rat model. The most important finding is that the Carousel Maze performance, tapping higher cognitive functions such as cognitive coordination and cognitive flexibility, is remarkably impaired in this model, while other cognitive functions, such as spatial navigation and both spatial and non-spatial memory are spared in the Nogo-A deficient rats. The results are discussed in the context of a hypothesis linking Nogo-A mutations or abnormal expression to human schizophrenia. We conclude that the Nogo-A deficient rats constitute a very promising animal model of schizophrenia and deserve further attention. Powered by TCPDF (www.tcpdf.org)

The Nogo-A protein belongs among the most important regulatory molecules in the brain, regulating development of neuronal and glial cells, axon guidance and adult synaptic plasticity. Although it has been studied mainly as an obstacle to axon regeneration after CNS injury, it plays a role in many pathological conditions, including neurodegenerative and neuropsychiatric diseases. This work offers a literature review of the current knowledge about functions of Nogo-A and related proteins, and then recapitulates the results of experiments focused on the impact on decreased expression of Nogo-A on behavior in a transgenic rat model. The most important finding is that the Carousel Maze performance, tapping higher cognitive functions such as cognitive coordination and cognitive flexibility, is remarkably impaired in this model, while other cognitive functions, such as spatial navigation and both spatial and non-spatial memory are spared in the Nogo-A deficient rats. The results are discussed in the context of a hypothesis linking Nogo-A mutations or abnormal expression to human schizophrenia. We conclude that the Nogo-A deficient rats constitute a very promising animal model of schizophrenia and deserve further attention. Powered by TCPDF (www.tcpdf.org)