A Cetamina, antagonista não competitivo de receptores de glutamato do tipo NMDA, é uma substância com propriedades dissociativas originalmente utilizada como anestésico que apresenta a característica de intensificar as experiências sensoriais. Apesar de seus conhecidos efeitos sobre os aspectos cognitivos e comportamentais, poucos estudos préclínicos foram conduzidos para tentar detectar os efeitos físicos e/ou comportamentais da abstinência de Cetamina após consumo prolongado. Partindo do princípio de que os efeitos da Cetamina sobre a neurotransmissão glutamatérgica induzem alguns dos sintomas observados durante surtos esquizofrênicos, como as alucinações auditivas, e sabendo que o colículo inferior tem sua função ligada ao processamento da informação sensorial a estímulos sonoros, neste estudo avaliamos os efeitos da modulação glutamatérgica na área cortical pré-límbica (PrL) sobre os potenciais evocados auditivos eliciados (PEAs) no colículo inferior. As medidas foram realizadas no fim do tratamento, ou seja, no 14° dia, 24 horas e 6 dias após a retirada da cetamina. Em nossos resultados obtivemos que a administração local de NMDA, foi capaz de diminuir a amplitude dos PEAs, os quais foram recuperados 24 horas após. A cetamina sistêmica não foi capaz de diminuir os PEAs, uma provável consequência da interação com outros receptores além do NMDA. Os testes realizados 6 dias após a interrupção ao tratamento crônico de cetamina, demonstraram uma forma inesperada de U, diferente da curva padrão de U invertido. Além disso, encontramos que as alterações provocadas pela cetamina são dependentes dos níveis dos mecanismos dopaminérgico e glutamatérgicos. Estes resultados demonstram que o processamento auditivo no colículo inferior está sob controle direto no Pré límbico e permitem ampliar o conhecimento atual da neurobiologia por evidenciar novas informações do efeito crônico da cetamina. / Ketamine is a non-competitive NMDA receptor antagonist. It is a substance with dissociative properties originally used as anesthetic, which can intensify sensory experiences, being also capable of accentuating the psychotic state in patients with schizophrenia. Despite its known effect on cognitive aspects and behavior, there are few preclinical studies conducted to identify physical and behavioral effects of ketamine withdrawal after its long-term use. Moreover, little is known about the impact of repetitive use of ketamine on brain structures and their functioning. The inferior colliculus, part of the midbrain tectum, is mainly related to auditory information processing, sending information to the motor centers and participating in the modulation and expression of specific behaviors, such as attack and predatory. Therefore, it is related to the biological importance of sounds to survival. The auditory hallucinations induced by schizophrenic psychotic crisis has as neural correspondent the activation of inferior colliculus and cortical areas. It is not yet known which cortical area is connected to the modulation of alterations induced by electrophysiological potential registered in inferior colliculus. Considering that the effects of ketamine on glutamate neurotransmission induces the symptoms observed during schizophrenic psychotic crisis, such as auditory hallucinations, and that inferior colliculus is related to the sensory information processing and auditory pathways, the present work evaluates the effects of glutamate modulation on pre-limbic cortical area on auditory evoked potential startle in inferior colliculus of rats tested during and after interruption of chronic treatment with ketamine

Les saccades sont de brefs mouvements des yeux dont le but est d'amener les objets visuels périphériques sur la partie fovéale de la rétine pour une analyse détaillée. L'ensemble des modèles considère que la programmation de la métrique des saccades reflète en premier lieu le codage spatial distribué au sein du colliculus supérieur (CS), et n'est que secondairement modulée par des processus cognitifs endogènes. De plus, la majorité considère que les interactions latérales entre les neurones du CS (locales et excitatrices ou distantes et inhibitrices) déterminent où mais aussi quand les yeux bougent. Nos études visaient à (1) tester et préciser la relation entre codage spatial distribué et métrique des saccades, (2) re-examiner si des stratégies visuelles peuvent déterminer où les yeux bougent, et (3) tester le rôle des interactions latérales. Elles reposaient sur l'enregistrement des mouvements oculaires de participants humains lors de la visée d'une cible visuelle, présentée seule ou accompagnée d'un distracteur. Nos résultats ont premièrement confirmé l'hypothèse de codage spatial distribué ; les champs d'intégration spatiale estimés à partir de la distance maximale entre deux stimuli pour l'exécution d'une saccade vers une position intermédiaire (ou effet global; Findlay, 1982) présentent des propriétés similaires aux champs récepteurs des neurones du CS. Deuxièmement, en désaccord avec l'hypothèse générale, des stratégies visuelles peuvent aussi amener le regard au centre de gravité de la configuration visuelle. Enfin, contrairement à l'hypothèse d'interactions latérales, l'effet d'un distracteur sur la latence des saccades (Walker et al., 1997) est indépendant de la distance qui le sépare de la cible. La variable critique étant l'excentricité des stimuli, ce serait plutôt la balance entre les activités de fixation et de mouvement qui déterminerait quand les yeux bougent. Notre travail présente l'intérêt d'avoir établi un nouvel ensemble de contraintes pour la modélisation des bases neurales et cognitives de la programmation saccadique.

Ce mémoire d'Habilitation à Diriger des Recherches synthétise les travaux que j'ai menés dans le domaine des neurosciences computationnelles. Ils traitent de trois thématiques principales en interaction: la sélection de l'action, la navigation et l'exécution motrice. Le substrat neural de ces fonctions, et principalement les ganglions de la base et le colliculus supérieur, ont été modélisés sous forme de réseaux de neurones contraints par les données issues de la neuro-anatomie et de l'électrophysiologie. Les résultats présentés résument mes contributions portant sur : les processus de sélection, d'apprentissage par renforcement et de modulation motivationnelle dans les ganglions de la base, le rôle de l'incertitude dans la sélection de l'action, la sélection de stratégies de navigation, l'intégration de chemin pour la stratégie de retour au point de départ, et la transformation spatio-temporelle pour la génération de saccades oculaires. Enfin, les liens reliant l'ensemble de ces études sont mis en exergue afin de délimiter le programme de recherche qui en découle.

Many cells in the inferior colliculus (IC) are excited by contralateral and inhibited by ipsilateral stimulation and are thought to be important for sound localization. These excitatory-inhibitory (EI) cells comprise a diverse group, even though they exhibit a common binaural response property. Previous extracellular studies proposed specific excitatory and/or inhibitory events that should be evoked by each ear and thereby generate each of the EI discharge properties. The proposals were inferences based on the well established response features of neurons in lower nuclei, the projections of those nuclei, their excitatory or inhibitory neurochemistry, and the changes in response features that occurred when inhibition was blocked. Here we recorded the inputs, the postsynaptic potentials, discharges evoked by monaural and binaural signals in EI cells with in vivo whole cell recordings from the inferior colliculus (IC) of awake bats. We also computed the excitatory and inhibitory synaptic conductances from the recorded sound evoked responses. First, we showed that a minority of EI cells either inherited their binaural property from a lower binaural nucleus or the EI property was created in the IC via inhibitory projections from the ipsilateral ear, features consistent with those observed in extracellular studies. Second, we showed that in a majority of EI cells ipsilateral signals evoked subthreshold EPSPs that behaved paradoxically in that EPSP amplitudes increased with intensity, even though binaural signals with the same ipsilateral intensities generated progressively greater spike suppressions. These ipsilateral EPSPs were unexpected since they could not have been detected with extracellular recordings. These additional responses suggested that the circuitry underlying EI cells was more complex than previously suggested. We also proposed the functional significance of ipsilaterally evoked EPSPs in responding to moving sound sources or multiple sounds. Third, by computing synaptic conductances, we showed the circuitry of the EI cells was even more complicated than those suggested by PSPs, and we also evaluated how the binaural property was produced by the contralateral and ipsilateral synaptic events. / text

Natural sound, such as conspecific vocalizations and human speech, represents an important part of the sensory signals animals and humans encounter in their daily lives. This dissertation investigates the neural mechanisms involved in creating response selectivity for complex features of natural acoustic signals and demonstrates that selectivity for spectral motion cues provides a neural mechanism to encode communication signals in the auditory midbrain. Spectral motion is defined as the movement of sound energy upward or downward in frequency at a certain velocity, and is believed to provide the auditory system with an important perceptual cue in the processing of human speech. Using the Mexican free-tailed bat, tadarida brasiliensis, as a model system, this research examined the role of selectivity for spectral motion cues, such as direction and velocity, in creating response selectivity for specific features of the social communication signals emitted by these animals. We show that auditory neurons in the midbrain nucleus of the inferior colliculus (IC) are specifically tuned for the frequency-modulated (FM) direction and velocities found in their conspecific vocalizations. This close agreement between neural tuning and features of natural conspecific signals shows that auditory neurons have evolved to specifically encode features of signals that are vital for the survival of the animal. Furthermore, we find that the neural computations resulting in selectivity for spectral motion are analogous to mechanisms observed in selectivity for visual motion, suggesting the evolution of similar neural mechanisms across sensory modalities. / text

A Cetamina, antagonista não competitivo de receptores de glutamato do tipo NMDA, é uma substância com propriedades dissociativas originalmente utilizada como anestésico que apresenta a característica de intensificar as experiências sensoriais. Apesar de seus conhecidos efeitos sobre os aspectos cognitivos e comportamentais, poucos estudos préclínicos foram conduzidos para tentar detectar os efeitos físicos e/ou comportamentais da abstinência de Cetamina após consumo prolongado. Partindo do princípio de que os efeitos da Cetamina sobre a neurotransmissão glutamatérgica induzem alguns dos sintomas observados durante surtos esquizofrênicos, como as alucinações auditivas, e sabendo que o colículo inferior tem sua função ligada ao processamento da informação sensorial a estímulos sonoros, neste estudo avaliamos os efeitos da modulação glutamatérgica na área cortical pré-límbica (PrL) sobre os potenciais evocados auditivos eliciados (PEAs) no colículo inferior. As medidas foram realizadas no fim do tratamento, ou seja, no 14° dia, 24 horas e 6 dias após a retirada da cetamina. Em nossos resultados obtivemos que a administração local de NMDA, foi capaz de diminuir a amplitude dos PEAs, os quais foram recuperados 24 horas após. A cetamina sistêmica não foi capaz de diminuir os PEAs, uma provável consequência da interação com outros receptores além do NMDA. Os testes realizados 6 dias após a interrupção ao tratamento crônico de cetamina, demonstraram uma forma inesperada de U, diferente da curva padrão de U invertido. Além disso, encontramos que as alterações provocadas pela cetamina são dependentes dos níveis dos mecanismos dopaminérgico e glutamatérgicos. Estes resultados demonstram que o processamento auditivo no colículo inferior está sob controle direto no Pré límbico e permitem ampliar o conhecimento atual da neurobiologia por evidenciar novas informações do efeito crônico da cetamina. / Ketamine is a non-competitive NMDA receptor antagonist. It is a substance with dissociative properties originally used as anesthetic, which can intensify sensory experiences, being also capable of accentuating the psychotic state in patients with schizophrenia. Despite its known effect on cognitive aspects and behavior, there are few preclinical studies conducted to identify physical and behavioral effects of ketamine withdrawal after its long-term use. Moreover, little is known about the impact of repetitive use of ketamine on brain structures and their functioning. The inferior colliculus, part of the midbrain tectum, is mainly related to auditory information processing, sending information to the motor centers and participating in the modulation and expression of specific behaviors, such as attack and predatory. Therefore, it is related to the biological importance of sounds to survival. The auditory hallucinations induced by schizophrenic psychotic crisis has as neural correspondent the activation of inferior colliculus and cortical areas. It is not yet known which cortical area is connected to the modulation of alterations induced by electrophysiological potential registered in inferior colliculus. Considering that the effects of ketamine on glutamate neurotransmission induces the symptoms observed during schizophrenic psychotic crisis, such as auditory hallucinations, and that inferior colliculus is related to the sensory information processing and auditory pathways, the present work evaluates the effects of glutamate modulation on pre-limbic cortical area on auditory evoked potential startle in inferior colliculus of rats tested during and after interruption of chronic treatment with ketamine

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<p dir="ltr">Localizing movements in the external space is crucial for animals to navigate safely, find food, avoid predators, and interact with their surroundings. Efficient localization during body movements requires the brain to distinguish between externally generated movements and self-generated ones. This involves integrating external stimulation with a continuous estimate of one's body position, to isolate external motion by suppressing sensations arising from self-motion.</p><p dir="ltr">To explore the neural mechanisms underlying object localization during active touch, we focused on the mouse superior colliculus (SC), which harbors multiple egocentric maps of sensorimotor space. Our studies revealed that SC neurons exhibit a rapidly adapting tactile response during externally generated touch. The response is significantly attenuated during self-generated touch, thus enhancing the ability to distinguish between external and self-induced tactile stimuli. Additionally, the direction of external motion is precisely encoded in the firing rates of these tactile-responsive neurons, indicating a specialized localization mechanism within the SC.</p><p dir="ltr">In scenarios devoid of external stimuli, SC neural activity accurately reflects the kinematics of self-motion, such as whisker position and locomotion speed, capturing past, present, and future body positions. Half of the neurons that encode self-motion also respond to external tactile stimuli. This dual functionality suggests that these neurons not only track self-motion but also engage in the processing of external tactile information. The magnitude of the external tactile response in these neurons is modulated by the state of self-motion upon touch. These results suggest that SC neurons integrate internal estimates of body movements with external tactile inputs to compute the egocentric distance of objects.</p>

Thèse numérisée par la Division de la gestion de documents et des archives de l'Université de Montréal.

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