Detecting and interpreting sensory events, and remembering those events in in the service of future actions, forms the foundation of all behavior. Each of these pillars of the so-called "perception-action cycle" have been topics of extensive inquiry throughout recorded history, with philosophical foundations provided by early BCE and CE periods (especially during the Classic and Renaissance eras) leading to intensive empirical study in the twentieth and twenty-first centuries. Such experiments have described detailed (but incomplete) behavioral functions reflecting perception and memory, and have begun to unravel the extraordinarily complex substrates of these functions in the nervous system. The current dissertation was motivated by these findings, with the goal of meaningfully extending our understanding of such processes through a multi-experiment approach spanning the behavioral and neurophysiological levels. The focus of these experiments is on short-term memory (STM), though as we shall see, STM is ultimately inseparable from sensory perception and is directly or indirectly associated with guidance of motor responses. It thus provides a nexus between the sensory inputs and motor outputs that describe interactions between the organism and environment. In Chapter 2, previous findings from nonhuman primate literature describing relatively poor performance for auditory compared to visual or tactile STM inspired similar comparisons among modalities in humans. In both STM and recognition memory paradigms, accuracy is shown to be lowest for the auditory modality, suggesting commonalities among primate species. Chapters 3-5 examined STM processing in nonhuman primates at the behavioral and neurophysiological levels. In Chapter 3, a systematic investigation of memory errors produced by recycling memoranda across trials (proactive interference) is provided for the understudied auditory modality in monkeys. Such errors were ameliorated (but not completely eliminated) by increasing the proportions of unique memoranda presented within a session, and by separating successive trials by greater time intervals. In Chapter 4, previous results revealing a human memory advantage for audiovisual events (compared to unimodal auditory or visual events) inspired a similar comparison in monkeys using a concurrent auditory, visual, and audiovisual STM task. Here, the primary results conformed to a priori expectations, with superior performance observed on audiovisual trials compared to either unimodal trial type. Surprisingly, two of three subjects exhibited superior unimodal performance on auditory trials. This result contrasts with previous results in nonhuman primates, but can be interpreted in light of these subjects' extensive prior experience with unimodal auditory STM tasks. In Chapter 5, the same subjects performed the concurrent audiovisual STM task while activity of single cells and local cell populations was recorded within prefrontal cortex (PFC), a region known to exhibit multisensory integrative and memory functions. The results indicate that both of these functions converge within PFC, down to the level of individual cells, as evidenced by audiovisual integrative responses within mnemonic processes such as delay-related changes in activity and detection of repeated versus different sensory cues. Further, a disproportionate number of the recorded units exhibited such mnemonic processes on audiovisual trials, a finding that corresponds to the superior behavioral performance on these trials. Taken together, these findings reinforce the important role of PFC in STM and multisensory integration. They further strengthen the evidence that "memory" is not a unitary phenomenon, but can be seen as the outcome of processing within and among multiple subsystems, with substantial areas of overlap and separation across modalities. Finally, cross-species comparisons reveal substantial similarities in memory processing between humans and nonhuman primates, suggesting shared evolutionary heritage of systems underlying the perception-action cycle.

ABTRACT In order to survive, an animal must be able to integrate vital information about it's surroundings, such as information about the environment and the social interactions therein. Decades of research have established the hippocampal formation as a structure indispensable for spatial memory. It was only recently, though, that evidence has emerged suggesting that the hippocampus, most notably the dorsal CA2 region, also supports the encoding of social information. New behavioural as well as electrophysiological evidence appeared, highlighting the importance of sleep for the processing of social information. In my thesis, I used microelectrodes to record the electrophysiological activity of individual CA2 neurons from freely-moving rats, during wake as well as in sleep. In order to study the processing of social information by hippocampal neurons, I employed a novel experimental paradigm in which social stimulation, in the form of two rat conspecifics, was presented in a spatial context. I report that the discharge of some CA2 neurons was organised within the experimental maze, even after social stimulation was added. Moreover, I observed that the spatial activity of neurons changed after the addition of social stimuli, and that it further changed when the location of the two conspecifics was shuffled....

A l’heure actuelle, une des principales questions des neurosciences comportementales est de comprendre les bases neurales des apprentissages et de comprendre comment des modifications au sein de circuits neuronaux spécifiques contrôlent les changements comportementaux liés à une expérience particulière. De nombreuses études ont récemment mis en évidence le rôle important des circuits neuronaux dans les phénomènes d’apprentissages associatifs, et notamment dans la régulation des comportements de peur. Cependant, leurs caractéristiques anatomiques et fonctionnelles restent encore largement inconnues. L’une des principales fonctions des circuits neuronaux est leur capacité à adapter le comportement en fonction de la nature des informations internes ou environnementales disponibles. Malgré de nombreux progrès réalisés sur la compréhension des substrats et mécanismes neuronaux sous tendant le conditionnement de peur au sein de structures telles que l'amygdale (AMG), le cortex préfrontal dorso-médian (dmPFC) et la substance grise periaqueducale (PAG), les mécanismes neuronaux gouvernant les interactions inter-structure ainsi que le contrôle local de ces différents circuits neuronaux restent encore largement inconnus. Dans ce contexte, ce travail de thèse a eupour objectifs principaux, d’évaluer la contribution des voies de projections dmPFC-BLA et dmPFC-vlPAG dans la régulation des comportements de peur, et, d’identifier les mécanismes neuronaux sous-jacent contrôlant l'expression de la peur. Afin de répondre à ces questions, nous avons utilisé conjointement des enregistrements électrophysiologiques unitaires et de potentiels de champs couplés à des approches optogénétiques au cours de l’expression de la peur conditionnée. Nous avons pu mettre en évidence un nouveau mécanisme neuronal basé sur une oscillation cérébrale à 4 Hz entre le dmPFC et le BLA impliqué dans la synchronisation neuronale des neurones de ces deux structures nécessaire à l’expression de la peur. Nous avons aussi démontré que le dmPFC via ses projections sur le vlPAG contrôle directement l’expression de la peur. Ensemble, nos données contribuent à une meilleure compréhension des circuits neuronaux ainsi que des mécanismes du comportement de peur qui dans le futur pourront aider à une amélioration thérapeutique des troubles anxieux. / A central endeavour of modern neuroscience is to understand the neural basis of learningand how the selection of dedicated circuits modulates experience-dependent changes inbehaviour. Decades of research allowed a global understanding of the computations occurring inhard-wired networks during associative learning, in particular fear behaviour. However, brainfunctions are not only derived from hard-wired circuits, but also depend on modulation of circuitfunction. It is therefore realistic to consider that brain areas contain multiple potential circuitswhich selection is based on environmental context and internal state. Whereas the role of entirebrain areas such as the amygdala (AMG), the dorsal medial prefrontal cortex (dmPFC) or theperiaqueductal grey matter (PAG) in fear behaviour is reasonably well understood at themolecular and synaptic levels, there is a big gap in our knowledge of how fear behaviour iscontrolled at the level of defined circuits within these brain areas. More particularly, whereas thedmPFC densely project to both the basolateral amygdala (BLA) and PAG, the contributions ofthese two projections pathway during fear behaviour are largely unknown. Beside theinvolvement of these neuronal pathways in the transmission of fear related-information, theneuronal mechanisms involved in the encoding of fear behaviour within these pathways are alsovirtually unknown. In this context, the present thesis work had two main objectives. First,evaluate the contribution of the dmPFC-BLA and dmPFC-vlPAG pathways in the regulation offear behaviour, and second, identify the neuronal mechanisms controlling fear expression in thesecircuits. To achieve these goals, we used a combination of single unit and local field potentialrecordings coupled to optogenetic approaches in behaving animals submitted to a discriminativefear conditioning paradigm. Our results first, identified a novel neuronal mechanism of fear expression based on the development of 4 H oscillations within dmPFC-BLA circuits thatdetermine the dynamics of freezing behaviour and allows the long-range synchronization offiring activities to drive fear behaviour. Secondly, our results identified the precise circuitry at thelevel of the dmPFC and vlPAG that causally regulate fear behaviour. Together these data provideimportant insights into the neuronal circuits and mechanisms of fear behaviour. Ultimately thesefindings will eventually lead to a refinement of actual therapeutic strategies for pathological conditions such as anxiety disorders.

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Contexte : Les difficultés de compréhension de la parole dans le bruit représente la principale plainte des personnes malentendantes. Cependant, peu d’études se sont intéressées aux mécanismes d’encodage des sons en environnement bruyant. Ce faisant, nos travaux ont portés sur les stratégies d’encodage des sons dans le nerf auditif dans environnements calme et bruyant en combinant des techniques électrophysiologiques et comportementales chez la gerbille.Matériel et méthodes : L’enregistrement unitaire de fibres du nerf auditif a été réalisé en réponse à des bouffées tonales présentées dans un environnement silencieux ou en présence d’une bruit de fond continu large bande. Les seuils audiométriques comportementaux ont été mesurés dans les mêmes conditions acoustiques, par une approche basée sur l’inhibition du reflex acoustique de sursaut.Résultats : Les données unitaires montrent que la cochlée utilise 2 stratégies d’encodage complémentaires. Pour des sons de basse fréquence (<3,6 kHz), la réponse en verrouillage de phase des fibres de l’apex assure un encodage fiable et robuste du seuil auditif. Pour des sons plus aigus (>3,6 kHz), la cochlée utilise une stratégie basée sur le taux de décharge ce qui requiert une plus grande diversité fonctionnelle de fibres dans la partie basale de la cochlée. Les seuils auditifs comportementaux obtenus dans les mêmes conditions de bruit se superposent parfaitement au seuil d’activation des fibres validant ainsi les résultats unitaires.Conclusion : Ce travail met en évidence le rôle capital de l’encodage en verrouillage de phase chez des espèces qui vocalisent au-dessous de 3 kHz, particulièrement en environnement bruyant. Par contre, l’encodage de fréquences plus aiguës repose sur le taux de décharge. Ce résultat met l’accent sur la difficulté d’extrapoler des résultats obtenus sur des modèles murins qui communique dans les hautes fréquences (> à 4 kHz) à l’homme dont le langage se situe entre 0,3 et 3 kHz. / Background: While hearing problems in noisy environments are the main complaints of hearing-impaired people, only few studies focused on cochlear encoding mechanisms in such environments. By combining electrophysiological experiments with behavioral ones, we studied the sound encoding strategies used by the cochlea in a noisy background.Material and methods: Single unit recordings of gerbil auditory nerve were performed in response to tone bursts, presented at characteristic frequencies, in a quiet environment and in the presence of a continuous broadband noise. The behavioral audiogram was measured in the same conditions, with a method based on the inhibition of the acoustic startle response.Results: Single unit data shows that the cochlea used 2 complementary strategies to encode sound. For low frequency sounds (<3.6 kHz), the phase-locked response from the apical fibers ensure a reliable and robust encoding of the auditory threshold. For high frequencies sounds, basal fibers use a strategy based on the discharge rate, which requires a larger heterogeneity of fibers at the base of the cochlea. The behavioral audiogram measured in the same noise condition overlaps perfectly with the fibers’ threshold. This result validates our predictions made from the single fiber recordings.Conclusion: This work highlights the major role of the phase locked neuronal response for animal species that vocalize below 3 kHz (as human), especially in noisy backgrounds. At the opposite, high frequency sound encoding is based on rate information. This result emphasizes the difficulty to transpose results from murine model which communicate in the high frequencies (> 4 kHz) to human whose language is between 0.3 and 3 kHz.

Reliable chronic neural recording from focal deep brain structures is impeded by insertion injury and foreign body response, the magnitude of which is correlated with the mechanical mismatch between the electrode and tissue. Thin and flexible neural electrodes cause less glial scarring and record longer than stiff electrodes. However, the insertion of flexible microelectrodes in the brain has been a challenge. A novel insertion method is proposed, and demonstrated, for precise targeting deep brain structures using flexible micro-wire electrodes. A novel electrode guiding system is designed based on the principles governing the buckling strength of electrodes. The proposed guide significantly increases the critical buckling force of the microelectrode. The electrode insertion mechanism involves spinning of the electrode during insertion. The spinning electrode is slowly inserted in the brain through the electrode guide. The electrode guide does not penetrate into cortex. The electrode is inserted in the brain without stiffening it by coating with foreign material or by attaching a rigid support and hence the method is less invasive. Based on two new mechanisms, namely spinning and guided insertion, it is possible to insert ultra-thin micro-wire flexible electrodes in rodent brains without buckling. I have demonstrated successful insertion of 25 µm platinum micro-wire electrodes about 10 mm deep in rat brain. A novel micro-motion compensated ultra-thin flexible platinum microelectrode has been presented for chronic single unit recording. Since manual insertion of the proposed microelectrode is not possible, I have developed a microelectrode insertion device based on the proposed method. A low power low noise 16 channel programmable neural amplifier ASIC has been designed and used to record the neural spikes. The ability to record neural activity during insertion is a unique feature of the developed inserter. In vivo implantation process of the microelectrode has been demonstrated. Microelectrodes were inserted in the Botzinger complex of rat and long term respiratory related neural activity was recorded from live rats. The developed microelectrode has also been used to study brain activity during seizures. In-vivo experimental results show that the proposed method and the prototype insertion system can be used to implant flexible microelectrode in deep brain structures of rodent for brain studies.

Les comportements orientés vers un but sont complexes et font appel à un grand nombre de processus cérébraux. Le cortex préfrontal médian (mPFC) apparaît comme une structure clef dans la réalisation de ces comportements de par son rôle dans la planification. De plus, il existe au sein du mPFC des cellules signalant les lieux à forte valeur motivationnelle. L’activité de ces neurones pourrait être essentielle à la mise en place d’un comportement spatial dirigé vers un but. S’orienter vers un but nécessite aussi la construction d’une représentation stable de l’environnement, qui repose sur l’activité de l’hippocampe (HPC). Néanmoins, peu de travaux ont analysé le rôle respectif de ces deux structures, et leurs interactions, lors de l’acquisition et de la consolidation d’une stratégie comportementale orientée vers un but. L’objectif des recherches réalisées au cours de ma thèse est donc d’étudier l’implication de l’hippocampe et du cortex préfrontal médian du rat dans ce processus. Notre première étude a montré l’existence d’un codage prospectif au sein des neurones du mPFC durant la réalisation d’une tâche de mémoire de travail.L’activité des neurones signale à la fois, la séquence temporelle comportementale, et l’anticipation de la récompense, et jouerait ainsi un rôle dans les fonctions exécutives. Dans la deuxième étude, nous nous sommes intéressés aux structures cérébrales impliquées dans la mise à jour de la valence du but ainsi que dans sa rétention à long terme. Nos résultats ont montré que l’inactivation de l’hippocampe intermédiaire provoque des déficits dans le traitement à court terme d’un changement de valence. En revanche, l’inactivation du mPFC empêche le stockage à long terme de ce changement. L’activité de ces deux structures serait donc essentielle pour effectuer une mise à jour en temps réel de la valence d’un but et pour sa consolidation en mémoire à long terme. Leur interaction permettrait d’adapter rapidement et de façon durable la stratégie comportementale de l’animal face aux changements de l’environnement. / Goal-directed behaviors are complex and involve a variety of cognitive processes. Medial prefrontal cortex (mPFC) plays a key role in behavioral planning. More over, cells in the rat mPFC show specific firing modulations at location with a high motivational value. Such neuronal activity could be essential for the setting up installation of a goal-directed behavior. Further more, navigating to a spatial goal requires the building of a stable presentation of the environment which is hippocampus-dependent. So far however, only few studies have addressed the respective role of these two structures, and their interaction, during the acquisition and the consolidation of a goal directed-behavior. The work conducted during my PhD thesis aimed at studying the role of hippocampus and prefrontal cortex in this process. In a first study,we showed the existence of a prospective coding by mPFC neurons when the rat performs a working memory task. Neuronal activity signals both, the temporal sequence of the behavior, and the prediction of reward. These neurons would play a role inexecutive functions. In a second study, we focused on cerebral structures involved in the updating of the value of a goal as well as in its long-term retention. Our results showed that the inactivation of the intermediate hippocampus causes deficit in the short-term processing of a change in the goal value. On the other hand, the inactivation of the mPFC prevents long-term consolidation of this change. Integrity of this two structures would therefore be essential to perform an on-line updating of the goal value and for its long-term consolidation. Their interaction would be necessary to rapidly adapt, and in a lasting manner, the behavioral strategy of the animal when it faces an environmental change.

Le travail de recherche réalisé au cours de cette thèse s'intéresse à la nature des représentations spatiales formées par le cortex entorhinal médian (CEM). Tout d'abord, nous montrons que le CEM code spécifiquement une information de distance, l'une des composantes nécessaires pour que l'animal puisse réaliser un type de navigation reposant sur les informations idiothétiques, appelé intégration des trajets. Puis, nous observons que le système vestibulaire, une source importante d'informations idiothétiques, influence l'activité thêta du CEM et permet la modulation de ce rythme thêta par la vitesse de déplacement des animaux. Ensuite, nous montrons que l'activité du CEM est nécessaire à la stabilité de l'activité des cellules de lieu. Parallèlement, nous observons que l'activité des cellules grilles du CEM est modifiée par les informations contenues dans l'environnement (allothétiques).Dans leur ensemble, nos résultats montrent que le CEM traite et intègre des informations idiothétiques mais aussi des informations allothétiques. Ces données suggèrent que la carte spatiale du CEM ne fournit pas une métrique universelle reposant sur les informations idiothétiques, mais possède un certain degré de flexibilité en réponse aux changements environnementaux. De plus, cette carte spatiale entorhinale n'est pas requise pour la formation de l'activité spatiale des cellules de lieu, contrairement à ce que suggère l'hypothèse dominante. / The work conducted during my PhD thesis was aimed at understanding the nature of the spatial representation formed by the the medial entorhinal cortex (MEC). First, we show that the MEC codes specifically distance information which is necessary for a type of navigation based on idiothetic cues, called path integration. Then, we observe that the vestibular system, an important source of idiothetic information in the brain, influences the MEC theta rhythm and its modulation by the animal velocity. In addition, we show that MEC activity is necessary for the stability of place cells activity. Finally, we observe that entorhinal grid cells activity is modified by the information available in the environment (allothetic information).Together, our results show that the MEC processes and integrates idiothetic information as well as allothetic information. These data suggest that the entorhinal map is not a universal metric based on idiothetic information, but is flexible and dependant on the information present in the environment. In addition, the entorhinal map is not required for the generation of place cells activity, contrary to the dominant hypothesis.