La neuropathie optique glaucomateuse est une pathologie du système visuel entrainant une cécité irréversible qui affectera 80 millions de personnes en 2020. Le principal facteur de risque du glaucome est l'élévation de la pression intraoculaire qui mène à la mort progressive des cellules ganglionnaires de la rétine (CGR) du nerf optique jusqu'aux voies visuelles dans le cerveau. Il a été montré que le glaucome partageait des mécanismes neuro-inflammatoires communs avec les pathologies neurodégénératives. Nous avons émis l'hypothèse que ces mécanismes contribueraient à la progression du glaucome. L'objectif de ma thèse a été d'analyser les processus neuro-inflammatoires observés de la rétine jusqu'aux colliculus supérieurs sur un modèle expérimental d'hypertension oculaire unilatérale chez le rat obtenu après la cautérisation des veines épisclérales. Par des approches de biologie cellulaire et moléculaire, nous avons montré que ce modèle animal se caractérise par 1) une atteinte neuronale des CGR de l'oeil cautérisé; 2) l'augmentation de marqueurs pro-inflammatoires dans la rétine de l'oeil cautérisé, dans la rétine de l'oeil controlatéral, dans le nerf optique et dans les colliculus supérieurs et 3) la transmission de la neuro-inflammation à l'oeil controlatéral se fait majoritairement par les fibres des CGR qui projettent dans les deux colliculus supérieurs. Toutes ces données mettent en évidence le rôle complexe joué par le colliculus supérieur chez le rat dans la propagation de la neuro-inflammation induite par l'hypertension oculaire unilatérale. / Glaucoma is a visual system disorder leading to irreversible blindness and affecting 80 millions people worldwide by 2020. The major risk factor is elevated intraocular pressure leading to progressive retinal ganglion cell (RGC) death from the optic nerve (ON) to visual pathways in the brain. Glaucoma has been reported to share neuroinflammatory mechanisms with neurodegenerative disorders. We therefore hypothesize that mechanisms in central visual pathways may contribute to the spread of glaucoma disease. The aim of the present study was to analyze the neuroinflammation processes that occur from the pathological retina to the superior colliculi (SCs) in a rat model of unilateral ocular hypertension induced by episcleral vein cauterization. By molecular and cell biology methods, we have shown that this animal model is characterized by 1) neuronal damage of CGR from the cauterized eye; 2) the increase in proinflammatory markers in the retina of the cauterized eye, in the retina of the contralateral eye, in the optic nerve and in the superior colliculus and 3) transmission of neuroinflammation in contralateral eye is done mainly by CGR fibers that project into the two superior colliculus. All these data evidence the complex role played by the SCs, in rat, in the propagation of neuroinflammatory events induced by unilateral ocular hypertension.

Detailed knowledge of the role that particular genes and factors play during the development and in the normal function of the auditory system is necessary to develop successful regenerative inner ear therapies. Islet1 transcription factor and brain derived neurothrophic factor (BDNF) have great potential to play a role in regenerative inner ear therapy as both have been shown to be sufficient for self-repair regeneration in cochlea in animal studies. In this study we looked at the roles these two factors play in the development and function of the auditory system. In the transgenic mice used in the study, overexpression of Isl1 affected cell specification during embryonic development, leading to enlargement of the cochleovestibular ganglion and accelerated nerve fiber extension and branching in mutant embryos. The hearing of young transgenic mice was not affected. However, it started to decline in 1-month-old animals. This early onset of age-related hearing loss was found to be a consequence of the neurodegeneration of the olivocochlear system caused by Pax2-driven Isl1 misexpression in the hindbrain. Our data provide the first evidence that the alternation of the olivocochlear system efferent system accelerates the age-related functional decline of hearing without the loss of OHCs. The functional role of...

Detailed knowledge of the role that particular genes and factors play during the development and in the normal function of the auditory system is necessary to develop successful regenerative inner ear therapies. Islet1 transcription factor and brain derived neurothrophic factor (BDNF) have great potential to play a role in regenerative inner ear therapy as both have been shown to be sufficient for self-repair regeneration in cochlea in animal studies. In this study we looked at the roles these two factors play in the development and function of the auditory system. In the transgenic mice used in the study, overexpression of Isl1 affected cell specification during embryonic development, leading to enlargement of the cochleovestibular ganglion and accelerated nerve fiber extension and branching in mutant embryos. The hearing of young transgenic mice was not affected. However, it started to decline in 1-month-old animals. This early onset of age-related hearing loss was found to be a consequence of the neurodegeneration of the olivocochlear system caused by Pax2-driven Isl1 misexpression in the hindbrain. Our data provide the first evidence that the alternation of the olivocochlear system efferent system accelerates the age-related functional decline of hearing without the loss of OHCs. The functional role of...

L'intégration sensorielle nécessite un alignement correct des cartes nerveuses dans le cerveau. Dans les couches superficielles du colliculus supérieur, situé dans le mésencéphale, des projections en provenance de la rétine ainsi que du cortex visuel primaire doivent être alignés, mais les mécanismes sous-jacents de ce processus demeurent à ce jour méconnus. Afin d'élucider ces mécanismes, éphrine-A3 a été sur-exprimée dans un modèle murin, dans une sous-population des cellules ganglionnaires de la rétine, induisant un disruption de l'alignement de la carte rétino-colliculaire sur la carte cortico-colliculaire. L'inactivation in vivo d'éphrine-A3 dans la rétine restaure un phénotype sauvage. Une analyse théorique utilisant un modèle informatique a permis la modélisation des donnés obtenues. Ces résultats ont permis l'identification d'un principe de base dans l'alignement des cartes et des mécanismes associés, validés par un modèle théorique. / Efficient sensory processing requires correct alignment of neural maps throughout the brain. In the superficial layers of the superior colliculus in the midbrain, projections from retinal ganglion cells and V1 cortex must be aligned to form a visuotopic map, but the basic principle and underlying mechanism are elusive and still incomplete. In a new mouse model, over-expression of ephrin-A3 in a subset of retinal ganglion cells disrupts the cortico-collicular map alignment onto the retino-collicular map, creating a visuotopic mismatch. In vivo inactivation of retinal ephrin-A3 over-expression restores a wild-type corticocollicular map. Theoretical analyses using an original algorithm models the stochastic nature of maps formation and alignment, and recapitulates our observations. Our results identify a basic principle for the alignment of converging maps and the associated mechanism, validated by a theoretical model.

Deal or no deal? Hold ‘em or fold ‘em? Buy, hold or sell? When faced with uncertainty, a wise decision-maker evaluates each option and chooses the one they deem most valuable. Scientists studying decision making processes have spent much theoretical and experimental effort formalizing a framework that captures how decision makers can maximize the amount of subjective value they accrue from such decisions. This thesis tested two hypotheses. The first was that subjective value guides our simplest and most common of motor actions similar to how it guides more deliberative economic decisions. The second was that subjective value is allocated across pre-motor regions of the brain to make our actions more efficient. To accomplish these goals, I adapted a paradigm used by behavioural economists for use in neurophysiological experiments in non-human primates. In our task, monkeys repeatedly make quick, orienting eye movements, known as saccades, to targets, which they learned through experience, had different values. In support of the hypothesis that subjective value influences simple motor actions, the speed with which monkeys responded, known as saccadic reaction time (SRT), and their saccadic choices to valued targets were highly correlated and therefore both acted as a behavioural measures of subjective value. Two complimentary results support the hypothesis that subjective value influences activity in the intermediate layers of the superior colliculus (SCi) – a well-studied brain region important to the planning and execution of saccades - to produce efficient actions. First, when saccades were elicited with microstimulation, we found that the timing and spatial allocation of pre-saccadic activity in the SC was shaped by subjective value. Second, the baseline preparatory activity and transient visual activity of SCi neurons prior to saccade generation was also influenced by subjective value. Our results can be incorporated into existing models of SC functioning that use dynamic neural field theory. I suggest that saccades of higher subjective value will result in higher activation of their associated neural field such that they will be more likely and more quickly selected. In summary, this thesis demonstrates that subjective value influences neural mechanisms, not only for deliberative decision making, but also for the efficient selection of simple motor actions. / Thesis (Ph.D, Neuroscience Studies) -- Queen's University, 2013-06-25 17:18:25.393

Adaptation is one of the basic phenomena of biology, while adaptability is an important feature for neural network. Young barn owl can well adapt its visual and auditory integration to the environmental change, such as prism wearing. At first, a mathematical model is introduced by the related study in biological experiment. The model well explained the mechanism of the sensory map realignment through axongenesis and synaptogenesis. Simulation results of this model are consistent with the biological data. Thereafter, to test the model’s application in hardware, the model is implemented into a robot. Visual and auditory signals are acquired by the sensors of the robot and transferred back to PC through bluetooth. Results of the robot experiment are presented, which shows the SC model allowing the robot to adjust visual and auditory integration to counteract the effects of a prism. Finally, based on the model, a silicon Superior Colliculus is designed in VLSI circuit and fabricated. Performance of the fabricated chip has shown the synaptogenesis and axogenesis can be emulated in VLSI circuit. The circuit of neural model provides a new method to update signals and reconfigure the switch network (the chip has an automatic reconfigurable network which is used to correct the disparity between signals). The chip is also the first Superior Colliculus VLSI circuit to emulate the sensory map realignment.

No description available.

A antinocicepção é descrita como redução na capacidade de perceber a dor, sendo importante componente para o organismo, quando este está envolvido em situações de emergência. Muitos neurotransmissores e seus receptores estão envolvidos nas diversas formas de analgesia, como por exemplo, monoaminas, acetilcolina e opióides endógenos. A analgesia pós-ictal é uma das muitas formas de antinocicepção em que o recrutamento de cada um desses neurotransmissores é descrito. Algumas evidências mostram o envolvimento de estruturas mesencefálicas em processos antinociceptivos (GEBHART & TOLEIKIS, 1978; COIMBRA e col., 1992; COIMBRA & BRANDÃO, 1997; CASTILHO e col., 1999) O colículo inferior é a estrutura mesencefálica responsável pela origem e expressão de crises audiogênicas (MCCOWN e col, 1987). Estruturas como a substância cinzenta periaquedutal, camadas profundas do colículo superior e núcleo central do colículo inferior, têm sido implicadas em processos convulsivos (DE PAULIS e col., 1990; CARDOSO e col., 1994, MCCOWN e col., 1984). Recentes relatos demonstraram que a estimulação dessas estruturas, em cujo substrato neural há neurônios positivos para beta-endorfina e leu-encefalina (EICHENBERGER e col., 2002; OSAKI e col., 2003) pode gerar processos antinociceptivos (CASTILHO e col., 1999; GEBHART & TOLEIKIS, 1978), seja de natureza opióide (NICHOLS e col., 1989), seja de natureza monoaminérgica (COIMBRA e col., 1992; COIMBRA & BRANDÃO, 1997). Neste trabalho, foi realizado o estudo periférico para investigar o envolvimento, mais especificamente, dos receptores opióides µ1 na analgesia que segue as crises convulsivas evocadas pela administração de um antagonista de canais de Cl- ligados ao GABA, como é o caso do pentilenotetrazol, administrado por via intraperitoneal, após o pré-tratamento com o bloqueador opióide específico, o naloxonazine, administrado em diferentes doses. Assim também, estudou-se a participação do colículo inferior nesse processo de inibição de dor, mensurado pelo teste de retirada de cauda. O pré-tratamento com naloxonazine, administrado por via intraperitoneal por tempo prolongado (24h), mas não agudamente (10 min), antagonizou a antinocicepção evocada por convulsões tônico-clônicas. Microinjeções de naloxonazine realizadas nos núcleos central, cortical externo e cortical dorsal do colículo inferior antagonizaram a analgesia induzida por crises convulsivas tônico-clônicas, efeito que segue uma curva dose-resposta, bem como, causaram a redução do tempo do processo convulsivo induzido pelo bloqueio ionóforo de canais de cloro ligados ao GABA. Em vista disso, podemos sugerir o envolvimento de receptores µ1-opióides e das redes neurais do colículo inferior na elaboração da analgesia pós-ictal, e na modulação de crises convulsivas tônico-clônicas. / The post-ictal analgesia is an impressive kind of antinociception, in wich the involvement of many neural systems has been demonstrated. The inferior colliculus is a brainstem structure responsible for the origin and elaboration of convulsive responses (MCCOWN e col, 1987) in the presence of audiogenic stimulus or during the treatment of supralimiar administration of GABAergic antagonists. Mesencephalic structures such as the periaqueductal gray matter, the deep layers of the superior colliculus and the central nucleus of the inferior colliculus have been implicated in convulsive processes (DE PAULIS e col., 1990; CARDOSO e col., 1994, MCCOWN e col., 1984). The stimulation of these areas, in whose neural substrates there are beta-endorphin- and leu-enkephalin-positive neurons (EICHENBERGER e col., 2002; OSAKI e col., 2003) evokes antinociceptive processes (CASTILHO e col., 1999; GEBHART & TOLEIKIS, 1978), of either opioid (NICHOLS e col., 1989) or monoaminergic COIMBRA e col., 1992; COIMBRA & BRANDÃO, 1997) nature. The aim of the present work is to investigate the involvement of the µ1-opioid receptor-mediated system in the post-ictal analgesia. The antinociceptive responses were recorded by the tail-flick test, after the pre-treatment with the specific opioid antagonist naloxonazine, administrated either by peripheral (intraperitoneally) or central (into the inferior colliculus neural network) way, in different doses. The peripheral lon-lasting (24h) but not acute (10 min) pre-treatment with naloxonazine antagonized the analgesia evoked by tonic-clonic convulsions. Microinjections of naloxonazine in the central, dorsal cortical and external cortical nuclei of inferior colliculus antagonized the analgesia induced by tonic-clonic reactions, whose effect followed a dose-response curve. Also, microinjections of naloxonazine into the inferior colliculus decrease the time of convulsions reactions. These findings suggest the involvement of µ1-opiate receptors and the neural networks of the inferior colliculus in this antinociceptive phenomenon, and, in addition, the involvement of these receptors in the modulation of tonic-clonic convulsive reactions has been suggested. In conclusion, the endogenous opioid peptides-mediated system of the neural networks of the inferior colliculus is clearly implicated in the elaboration of the post-ictal antinociception and in the modulation of tonic-clonic convulsions. In theses processes, µ1-opioid receptors of the central nucleus, as well as of the cortical dorsal and cortical external nuclei of the inferior colliculus are crucially involved.

A circuitaria neuro-anatômica envolvida com a organização de respostas de medo inclui muitos sítios subcorticais diferentes, dois dos quais são a região dorsal da matéria cinzenta periaquedutal (dPAG) e as camadas intermediárias e profundas do colículo superior (i/dlSC). Este estudo investigou como as células destas duas regiões mudam de atividade em um rato que foi colocado diante de seu predador, o gato, comparado com outras situações onde o risco menor. 11 ratos wistar machos passaram por cirurgia para implantação de um microdriver contendo 8 tetrodos, que detectou 39 células na dPAG de 7 ratos e 44 células nas i/dlSC de 4 ratos. A atividade das células foi registrada em uma condição de base e em quatro condições experimentais distintas: o rato confinado, o rato diante de uma novidade, diante de um predador e diante do contexto predatório. Os dados coletados foram analisados por scripts de MATLAB e cada célula foi classificada para sua responsividade às condições experimentais, à mudança do comportamento do rato, à velocidade e à posição do rato no aparato. Na dPAG as células se mostraram mais responsivas a condição do gato do que as demais condições experimentais, tanto em número de células como em aumento de atividade celular. Uma quantidade menor de células mostrou-se responsiva a mudanças de comportamento, particularmente os comportamentos de defesa. Nas i/dlSC as células também se mostraram mais responsivas para o gato, seguido do contexto, em ambos os casos com diminuição de atividade celular, que foi mais intensa no gato. Uma quantidade menor de células pareceu responder de forma similar para as diferentes mudanças comportamentais. Interpretamos esses dados propondo que a dPAG possui uma função sinalizadora de medo, fortemente ativada durante o gato, e que as i/dlSC são inibidas diante do gato a fim de evitar a captação de estímulos irrelevantes para lidar com a situação de risco. / The neuroanatomical circuitry involved with the organization of fear responses includes a great number of subcortical sites, two of which are the dorsal periaqueductal gray (dPAG) and the intermediate and deep layers of the superior colliculus (i/dlSC). This study investigated how the cellular activity in these regions changed in a rat that was exposed to one of its predators, a cat, when compared with lower risk situations. 11 male wistar rats underwent surgery to implant a microdriver containing 8 tetrodes, which detected 39 cells in the dPAG of 7 rats and 44 cells in the i/dlSC of 4 rats. Cell activity was registered in a basal condition and then again in for experimental conditions: the rat confined in a smaller space, the rat facing a novel stimulus, the rat facing a cat and the rat facing the predatory context. Collected data was analyzed using MATLAB and each cell was classified according to its responsivity to the experimental conditions, to the rats switches in behavior, to the rats speed and position in the experimental apparatus. In the dPAG, cells were shown to be more responsive to the cat condition over the other conditions, both in terms of number of responsive cells and intensity of increase in firing activity. A smaller number of cells were responsive to behavior switching, being especially sensitive to the initiation of defensive behaviors. In the i/dlSC, cells were more responsive to the cat, followed by the predatory context, in both cases with a general reduction of cellular activity that was more intensive for the cat. A smaller number of cells was responsive in similar ways for behavior switching across experimental conditions. We interpret this data by proposing that the dPAG acts signaling a state of fear, particularly during a high risk situation, and the i/dlSC are inhibited during riskier situations so as to block irrelevant environmental stimuli.

Dans le contexte de l'énaction et dans une approche globale de la perception, nous nous sommes intéressés à étudier calcul neuronal permettant de comprendre les relations entre les structures dans le cerveau et leurs fonctions. Nous avons d'abord examiné les problèmes calculatoires liés à la discrétisation des équations différentielles qui régissent les systèmes étudiés et aux schémas d'évaluation synchrones et asynchrones. Nous nous sommes, ensuite, intéressés à un niveau fonctionnel élémentaire: la transformation de représentations sensorielles spatiales en actes moteurs temporels dans le cadre du système visuo-moteur. Nous avons proposé un modèle minimaliste d'encodage automatique des cibles visuelles de saccades qui se concentre sur le le flux visuel de la rétine vers le colliculus supérieur. Ce modèle, basé sur sur des règles locales simples au sein d'une population homogène, permet de reproduire et d'expliquer plusieurs résultats d'expériences biologiques ce qui en fait un modèle de base efficace et robuste. Enfin, nous avons abordé un niveau fonctionnel plus global en proposant un modèle de la boucle motrice des ganglions de la base permettant d'intégrer des flux sensoriels, moteurs et motivationnels en vue d'une décision globale reposant sur des évaluations locales. Ce modèle met en exergue un processus adaptatif de sélection de l'action et d'encodage de contexte via des mécanismes originaux lui permettant en particulier de constituer la brique de base pour les autres boucles cortico-basales. Les deux modèles présentent des dynamiques intéressantes à étudier que ce soit d'un point de vue biologique ou d'un point de vue informatique computationnel / Within the context of enaction and a global approach to perception, we focused on the characteristics of neural computation necessary to understand the relationship between structures in the brain and their functions. We first considered computational problems related to the discretization of differential equations that govern the studied systems and the synchronous and asynchronous evaluation schemes. Then, we investigated a basic functional level : the transformation of spatial sensory representations into temporal motor actions within the visual-motor system. We focused on the visual flow from the retina to the superior colliculus to propose a minimalist model of automatic encoding of saccades to visual targets. This model, based on simple local rules (CNFT and logarithmic projection) in a homogeneous population and using a sequential processing, reproduces and explains several results of biological experiments. It is then considered as a robust and efficient basic model. Finally, we investigated a more general functional level by proposing a computational model of the basal ganglia motor loop. This model integrates sensory, motor and motivational flows to perform a global decision based on local assessments. We implemented an adaptive process for action selection and context encoding through an innovative mechanism that allows to form the basic circuit for other cortico-basal loops. This mechanism allows to create internal representations according to the enactive approach that opposes the computer metaphor of the brain. Both models have interesting dynamics to study from whether a biological point of view or a computational numerical one