A fundamental question in the neurobiological study of drug addiction concerns the mechanisms mediating the motivational effects of chronic drug withdrawal. According to one theory, drugs of abuse activate opposing motivational processes after both acute and chronic drug use. The negative experience of withdrawal is the opponent process of chronic drug use that drives relapse to drug-seeking and -taking, making the identification of the neurobiological substrates mediating withdrawal an issue of central importance in addiction research. In this thesis, I identify the involvement of the neurotransmitters dopamine (DA) and corticotropin-releasing factor (CRF) in the opponent motivational a- and b-processes occurring after acute and chronic nicotine administration. I report that acute nicotine stimulates an initial aversive a-process followed by a rewarding opponent b-process, and chronic nicotine stimulates a rewarding a-process followed by an aversive opponent b-process (withdrawal). These responses can be modeled using a place conditioning paradigm. I demonstrate that the acute nicotine a-process is mediated by phasic dopaminergic activity and the DA receptor subtype-1 (D1R) but not by tonic dopaminergic activity and the DA receptor subtype-2 (D2R) or CRF activity, and the opponent b-process is neither DA- nor CRF-mediated. I also demonstrate that the chronic nicotine a-process is DA- but not CRF-mediated, and that withdrawal from chronic nicotine (the b-process) decreases tonic but not phasic DA activity in the ventral tegmental area (VTA), an effect that is D2R- but not D1R-mediated. I show that a specific pattern of signaling at D1Rs and D2Rs mediates the motivational responses to acute nicotine and chronic nicotine withdrawal, respectively, by demonstrating that both increasing or decreasing signaling at these receptors prevents the expression of the conditioned motivational response. Furthermore, I report that the induction of nicotine dependence increases CRF mRNA in VTA DA neurons, and that blocking either the upregulation of CRF mRNA or the activation of VTA CRF receptors prevents the anxiogenic and aversive motivational responses to withdrawal from chronic nicotine. The results described in this thesis provide novel evidence of a VTA DA/CRF system, and demonstrate that both CRF and a specific pattern of tonic DA activity in the VTA are necessary for the aversive motivational experience of nicotine withdrawal.

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Ce travail de thèse avait pour objectif d'étudier le rôle de l'hippocampe (HPC) ventral et des noyaux reuniens (Re) et rhomboïde (Rh) du thalamus dans les processus cognitifs qui sous-tendent la mémoire spatiale chez le Rat. Par l'utilisation d'approches complémentaires combinant l'imagerie cérébrale, la lésion excitotoxique, l'inactivation fonctionnelle réversible et des évaluations comportementales, nos résultats ont mis en évidence : (1) l'implication spécifique de l'HPC ventral uniquement dans le rappel d'informations spatiales ; (2) un rôle-clé des noyaux Re et Rh dans la persistance d'un souvenir spatial ; (3) l'implication des noyaux Re et Rh dans le labyrinthe du double-H, un nouveau test nécessitant d'une part, l'utilisation d'informations spatiales dépendant de l'intégrité de l'HPC dorsal, et d'autre part, une flexibilité comportementale, impliquant le cortex préfrontal médian. Ainsi, l'ensemble de ces résultats permet de proposer l'existence d'un circuit HPC-préfronto-thalamique impliqué dans divers aspects du traitement des informations spatiales.

A major challenge in the field of neuroscience is to link behavior with specific neuronal circuitries and cellular events. One way of facing this challenge is to identify unique cellular markers and thus have the ability to, through various mouse genetics tools, mimic, manipulate and control various aspects of neuronal activity to decipher their correlation to behavior. The Vesicular Glutamate Transporter 2 (VGLUT2) packages glutamate into presynaptic vesicles for axonal terminal release. In this thesis, VGLUT2 was used to specifically target cell populations within the basal ganglia of mice with the purpose of investigating its connectivity, function and involvement in behavior. The motor and limbic loops of the basal ganglia are important for processing of voluntary movement and emotions. During such physiological events, dopamine plays a central role in modulating the activity of these systems. The brain reward system is mainly formed by dopamine projections from the ventral tegmental area (VTA) to the ventral striatum. Certain dopamine neurons within the VTA exhibit the ability to co-release dopamine and glutamate. In paper I, glutamate and dopamine co-release was targeted and our results demonstrate that the absence of VGLUT2 in dopamine neurons leads to perturbations of reward consumption and reward-associated memory, probably due to reduced DA release observed in the striatum as detected by in vivo chronoamperometry. In papers II and IV, VGLUT2 in a specific subpopulation within the subthalamic nucleus (STN) was identified and targeted. Based on the described role of the STN in movement control, we hypothesized that the mice would be hyperlocomotive. As shown in paper II, this was indeed the case. In paper IV, a putative reward-related phenotype was approached and we could show reduced operant-self administration of sugar and altered dopamine release levels suggesting a role for the STN in reward processes. In paper III, we investigated and identified age- and sex-dimorphisms in dopamine kinetics in the dorsal striatum of one of the most commonly used mouse lines worldwide, the C57/Bl6J. Our results point to the importance of taking these dimorphisms into account when utilizing the C57/Bl6J strain as model for neurological and neuropsychiatric disorders.

A fundamental question in the neurobiological study of drug addiction concerns the mechanisms mediating the motivational effects of chronic drug withdrawal. According to one theory, drugs of abuse activate opposing motivational processes after both acute and chronic drug use. The negative experience of withdrawal is the opponent process of chronic drug use that drives relapse to drug-seeking and -taking, making the identification of the neurobiological substrates mediating withdrawal an issue of central importance in addiction research. In this thesis, I identify the involvement of the neurotransmitters dopamine (DA) and corticotropin-releasing factor (CRF) in the opponent motivational a- and b-processes occurring after acute and chronic nicotine administration. I report that acute nicotine stimulates an initial aversive a-process followed by a rewarding opponent b-process, and chronic nicotine stimulates a rewarding a-process followed by an aversive opponent b-process (withdrawal). These responses can be modeled using a place conditioning paradigm. I demonstrate that the acute nicotine a-process is mediated by phasic dopaminergic activity and the DA receptor subtype-1 (D1R) but not by tonic dopaminergic activity and the DA receptor subtype-2 (D2R) or CRF activity, and the opponent b-process is neither DA- nor CRF-mediated. I also demonstrate that the chronic nicotine a-process is DA- but not CRF-mediated, and that withdrawal from chronic nicotine (the b-process) decreases tonic but not phasic DA activity in the ventral tegmental area (VTA), an effect that is D2R- but not D1R-mediated. I show that a specific pattern of signaling at D1Rs and D2Rs mediates the motivational responses to acute nicotine and chronic nicotine withdrawal, respectively, by demonstrating that both increasing or decreasing signaling at these receptors prevents the expression of the conditioned motivational response. Furthermore, I report that the induction of nicotine dependence increases CRF mRNA in VTA DA neurons, and that blocking either the upregulation of CRF mRNA or the activation of VTA CRF receptors prevents the anxiogenic and aversive motivational responses to withdrawal from chronic nicotine. The results described in this thesis provide novel evidence of a VTA DA/CRF system, and demonstrate that both CRF and a specific pattern of tonic DA activity in the VTA are necessary for the aversive motivational experience of nicotine withdrawal.

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.

La stimulation du cortex moteur (SCM) est une technique neurochirurgicale utilisée chez l'Homme comme traitement de dernier recours pour les douleurs neuropathiques rebelles. Elle a été développée sur des bases empiriques. Ce travail vise à une meilleure compréhension des mécanismes d'action de la SCM qui restent incomplètement élucidés à ce jour. L'objectif de cette thèse est d'étudier les effets électrophysiologiques de la SCM au niveau thalamique, chez un modèle de chat. La première partie de cette étude a consisté à établir une cartographie stéréotaxique du cortex moteur (CM) de cet animal, inexistante dans la littérature. À partir de cette cartographie, nous avons pu établir et valider un modèle de SCM chez cet animal, implanté de façon mini-invasive. La deuxième partie de ce travail a consisté à recueillir et analyser les changements électrophysiologiques de l'activité extracellulaire unitaire des cellules du noyau ventro-postéro-latéral (VPL) du thalamus, induits par différents protocoles de SCM. Nos résultats montrent une modulation de l'activité des cellules du VPL par la SCM, qui varie en fonction de la nature nociceptive ou non de la cellule thalamique. La SCM augmente l'activité des cellules non nociceptives et diminue celle des cellules nociceptives. Pour une cellule donnée, l'effet observé est indépendant de la correspondance somatotopique entre la région du CM stimulée et la localisation sur le corps du champ récepteur de la cellule enregistrée. Ce travail a ainsi permis de montrer l'existence d'une neuro-modulation différentielle du VPL par la SCM en fonction de la nature de la cellule thalamique / Motor cortex stimulation (MCS) is a neurosurgical technique developed on empirical basis and currently used as last solution for patients suffering from refractory neuropathic pain. The present work is a new attempt among other contemporary studies aiming to understand the mechanisms of action of MCS, which remain incompletely elucidated at that time. The main objective of this thesis is to study the electrophysiological effect of MCS at the thalamic level, in a cat model. The first part of this work aims to establish the stereotactic somatotopic map of the cat motor cortex (MC), not available so far in the literature. Based on this mapping, we created and validated a cat model of MCS, using a mini-invasive electrode implantation. The second part of this study included a recording and analysis of the potential changes of the unitary extracellular activity of cells located in the thalamic ventro-postero-lateral (VPL) nucleus, induced by different MCS protocols. Our results indicate a modulation of the VPL cells activity after MCS, depending on the nociceptive or non-nociceptive nature of the recorded thalamic cell. MCS increases the activity of non-nociceptive cells and decreases that of nociceptive cells. For a given cell the matching between the somatotopy of the MC stimulated region and the receptive field localization of the recorded thalamic cell is not a prerequisite for obtaining such a modulation. In conclusion, the present work has proven a neuro-modulatory differential effect of MCS on nociceptive and non-nociceptive cells in the thalamic VPL nucleus

Background: Panic disorder with agoraphobia is characterized by panic attacks and anxiety in situations where escape might be difficult. However, neuroimaging studies specifically focusing on agoraphobia are rare. Here we used functional magnetic resonance imaging (fMRI) with disorder-specific stimuli to investigate the neural substrates of agoraphobia. Method. We compared the neural activations of 72 patients suffering from panic disorder with agoraphobia with 72 matched healthy control subjects in a 3-T fMRI study. To isolate agoraphobia-specific alterations we tested the effects of the anticipation and perception of an agoraphobia-specific stimulus set. During fMRI, 48 agoraphobia-specific and 48 neutral pictures were randomly presented with and without anticipatory stimulus indicating the content of the subsequent pictures (Westphal paradigm). Results: During the anticipation of agoraphobia-specific pictures, stronger activations were found in the bilateral ventral striatum and left insula in patients compared with controls. There were no group differences during the perception phase of agoraphobia-specific pictures. Conclusions: This study revealed stronger region-specific activations in patients suffering from panic disorder with agoraphobia in anticipation of agoraphobia-specific stimuli. Patients seem to process these stimuli more intensively based on individual salience. Hyperactivation of the ventral striatum and insula when anticipating agoraphobiaspecific situations might be a central neurofunctional correlate of agoraphobia. Knowledge about the neural correlates of anticipatory and perceptual processes regarding agoraphobic situations will help to optimize and evaluate treatments, such as exposure therapy, in patients with panic disorder and agoraphobia.

Clarifying the underlying spatio-temporal mechanisms that determine body pattern is important for detailed understanding of embryonic development. A crucial question of vertebrate embryogenesis remains: when and how are single blastomeres determined for differentiation that subsequently leads to body axes specification and the formation of different tissues and organs? The answer to this question will be beneficial for primary research as well as in the field of applied medicine. The main aim of the presented thesis was to study spatio-temporal molecular gradients of cell fate determinants during early embryonic development. The African clawed frog Xenopus laevis was used as a model organism because of their large size of oocytes and external embryonic development. Due to late activation of embryonic transcription, a crucial mechanism of early blastomeres determination is dependent on asymmetric localization of maternal factors within oocyte and their uneven distribution into single blastomeres during early cell division. Two main localization patterns were identified along the animal-vegetal axis of the mature Xenopus oocyte using qPCR tomography. The localization gradient with preference in either animal or vegetal hemisphere was found for maternal mRNA as well as miRNAs. Moreover, two vegetal...