No description available.

No description available.

This thesis looks at the condition under which sympathetic neurons (SCG) develop in order to understand the causes of selective vulnerability during ageing and therefore shows how pre-treatment in vivo with NGF at a specific point during development affects SCG neurons. In summary, results show that following pre-treatment in vivo there is an increase in neuronal number, with differential effect on different subpopulations of neurons (MCA versus iris projecting neurons). MCA-projecting neurons (a vulnerable subpopulation of SCG neurons) increase in growth and innervation of specific target tissues following NGF pre-treatment in vivo, showing a maintained plasticity after termination of development and therefore a potential target site for future therapeutics. NGF pre-treatment in vivo also increases neuronal survival time throughout life, showing that the limited supply of NGF in real life prime neurons to a reduced potential. The results on survival also show a difference in the mode of action between the two major survival pathways (PI3-K and ERK), with PI3-K being the predominant in adult life and ERK acting mainly in early life. This shows a double survival mechanism which is plastic and capable of shifting predominance according to factors such as NGF stimuli and/or ageing. Furthermore if the NGF pre-treatment in vivo is applied after termination of development, neurons show plasticity by developing an 'addiction' or dependance to NGF pre-treatment termination results in death of the neurons. Preliminary results show increase in Akt activity which is downstream of PT3-K, and is activated in NGF-dependent survival of SCG neurons (Pierchala et aL, 2004). Biological consequences of Akt activation are survival, increase in cell number and growth, which are all characteristics relevant also to cancer-cell growth. Further preliminary results show an inhibition of GSK-3p pathways, which is downstream of Akt and is determinant for cytoskeletal rearrangement, glucose metabolism and cell survival regulation of GSK-3p has been widely studied in relation to Alzheimer's disease. In conclusions this research shows that sympathetic neurons are plastic and by priming mem with NGF, at a critical point during development, their survivability is increased. These results support the existence of a sensitive mechanism for adjusting neuronal capacity to resist cell death in response to neurotrophic factor deprivation.

The developing mesencephalon consists of two distinct domains. The dorsal domain, the tectum, gives rise to the superior and inferior colliculi, which in the adult receives information from the optic and auditory systems respectively. The ventral domain gives rise primarily to 3 distinct nuclei which are involved in the control of motor movement, such as the mesencephalic dopaminergic neurons, which are the neurons affected in Parkinson's disease, the oculomotor complex and the red nucleus. Forkhead transcription factors of the A subgroup, Foxa1 and Foxa2, are expressed in the ventral midbrain, in addition to being expressed in the notochord, floorplate and gut during embryonic development. In this study, I focused on the role of Foxal, a member of the forkheadVwinghelix family of transcription factors in the specification of the ventral mesencephalic neurons. To address the role of Foxa1 specifically in the mesencephalon, we have generated a conditional allele of Foxa2, referred to as Foxa2ox and crossed this mouse line with Wntl-Cre transgenic animals. Inactivation of Foxa2 protein in mesencephalic progenitors of Wntl-Cre Foxa'f0 embryos occurred by E8.5. Severe reduction in the numbers of Islet 1* oculomotor, Brn3a+ red nucleus and tyrosine hydroxylase* dopaminergic neurons were observed in Foxa2 conditional mutant embryos at El2.5, which were preceded by changes in the expression of the morphogen Shh as well as Foxal and Nkx transcription factors. Detailed phenotypic characterization by histology, RNA in-situ hybridization and immunohistochemistry has revealed novel roles for Foxa2 in regulating the patterning of mesencephalic progenitors as well as their differentiation. In collaboration with another postdoctoral fellow in the laboratory, we have also shown that Foxal plays a very similar role and can compensate for the function of Foxa2 in the ventral mesencephalon.

Kainate receptors (KARs) are highly expressed during postnatal development and are likely to play an important role in the synaptic mechanisms underlying maturation of neural networks. Despite recent advances in our understanding of the molecular biology and pharmacology of KARs comparatively little is known about developmental changes in native receptors and the relative contributions of individual subunits to KAR complexes. Using antibodies specific to GluR6/7 and KA2 subunits Immuno and histoblots were used to demonstrate quantitatively that the mechanisms controlling subunit expression during postnatal development are differentially regulated in a precise temporal and region-specific manner.

This thesis focuses on the phenomena of neuromodulation — these are a set of diffuse chemical pathways that modify the properties of neurons and act in concert with the more traditional pathways mediated by synapses (neurotransmission). There is a growing opinion within neuroscience that such processes constitute a radical challenge to the centrality of neurotransmission in our understanding of the nervous system. This thesis is an attempt to understand how the idea of neuromodulation should impact on the canonical ideas of information processing in the nervous system. The first goal of this thesis has been to systematise the ideas immanent in neuromodulation such that they are amenable to investigation through both simulation and analytical techniques. Specifically, the physiological properties of neuromodulation are distinct from those traditionally associated with neurotransmission. Hence, a first contribution has been to develop a principled but minimal mechanistic description of neuromodulation. Furthermore, neuromodulators are thought to underpin a distinct set of functional roles. Hence, a second contribution has been to define these in terms of a set of dynami- cal motifs. Subsequently the major goal of thesis has been to investigate the relationship between the mechanistic properties of neuromodulation and their dynamical motifs in order to understand whether the physiological properties of neuromodulation predispose them toward their functional roles? This thesis uses both simulation and analytical techniques to explore this question. The most significant progress, however, is made through the application of dynamical systems analysis. These results demonstrate that there is a strong relationship between the mechanistic and dynamical abstractions of neuromodulation developed in this thesis. In particular they suggest that in contrast to neurotransmission, neuromodulatory pathways are predisposed toward bifurcating a system’s dynamics. Consequently, this thesis argues that a true canonical picture of the dynamics of the nervous system requires an appreciation of the interplay between the properties of neurotransmission and the properties immanent in the idea of neuromodulation.

Notre travail porte sur l'adaptation du comportement humain dans un environnement où les récompenses obtenues sont distribuées sur une échelle continue. Les travaux précédents se sont principalement intéressés aux cas de récompenses binaires (de type gagné/perdu) et ont montré qu'un algorithme d'apprentissage Bayésien pouvait rendre compte du comportement. Les algorithmes Bayésiens ne marchent pas dans un environnement continu à moins d'utiliser un modèle génératif (une série d'axiomes permettant de cadrer l'interprétation des observations). A l'inverse les algorithmes de renforcement s'y comportent bien car ils peuvent efficacement s'ajuster aux moyennes de distributions de récompense. Que fait donc l'humain ? Un modèle génératif usuel considère que les distributions de récompense associées à chaque action sont Gaussiennes. Un petit nombre d'observations permet de les caractériser en inférant leur moyenne et écart type. Nous proposons un modèle plus général postulant l'existence d'un classement stable de la valeur des différentes actions, ce qui permet d'imaginer la récompense fictive qui aurait été attribuée par les actions non choisies. Pour séparer ces deux modèles ainsi que le renforcement, nous avons construit 3 expériences comportementales dans lesquelles les distributions de récompenses sont bimodales et continues. Notre modèle rend compte du comportement des sujets à l’inverse du modèle Gaussien ou du renforcement. Notre modèle répond à des contraintes évolutionnistes car il s’adapte rapidement dans un grand nombre de contextes, y compris ceux ou les axiomes du modèle génératif ne sont pas respectés, pour déterminer à chaque fois quelles récompenses sont désirables. / Our thesis aims at understanding how human behavior adapts to an environment where rewards are continuous. Many works have studied environments with binary rewards (win/lose) and have shown that human behavior could be accounted for by Bayesian inference algorithms. A Bayesian algorithm works in a continuous environment provided that it is based on a “generative” model of the environment, which is a structural assumption about environmental contingencies. The issue we address in this thesis is to characterize which kind of generative model of continuous rewards characterizes human decision-making. One hypothesis is to consider that each action attributes rewards as noisy samples of the true action value, typically distributed as a Gaussian distribution. We propose instead a generative model using assumptions about the relationship between the values of the different actions available and the existence of a reliable ordering of action values. This structural assumption enables to simulate mentally counterfactual rewards and to learn simultaneously reward distributions associated with all actions. To validate our model, we ran three behavioral experiments on healthy subjects in a setting where actions’ reward distributions were continuous and changed across time. Our proposed model described correctly participants’ behavior in all three tasks, while other competitive models, including Gaussian failed. The proposed model extends the implementation of Bayesian algorithms and establishes which rewards are “good” and desirable according to the current context. It answers to evolutionarily constraints by adapting quickly, while performing correctly in many different settings.

Dans cette étude, nous avons utilisé un modèle de souris permettant d’induire des lésions de sévérité variable afin de mimer différentes anomalies de la myéline du cerveau que l'on peut rencontrer chez l'homme. La perte des OLs a été de 80% après 2 semaines de traitement au GCV (GCV1-14). Après l'arrêt du traitement, les processus de récupération ont conduit à une augmentation significative de la population OLs à 80% à la semaine 6 (W6). L’extension du traitement GCV à 3 semaines (GCV1-21) a entraîné une perte de 85% de la population OLs. Cependant la récupération est limitée et reste à 40% du niveau de contrôle à W6. Nous avons remarqué une augmentation rapide (de 2 fois) des cellules Olig2+ chez la souris GCV1-14 contre les souris GCV1-21 (de 1,5 fois) à W4. Nos résultats ont montré une augmentation significative des cellules Olig2-phosphorylé chez la souris GCV1-14 entre W3 et W4 après l'arrêt du traitement GCV. A l'opposé, dans le modèle GCV1-21, un très faible niveau de Olig2 phosphorylé a été observé. Nous avons observé des modifications transitoires dans l’expression de NgR et Caspr mais l’expression de P75 reste inchangée. Ensemble, ces résultats suggèrent que la reprise du déficit myéline du cerveau au cours du développement postnatal dépend de régénération suffisante des oligodendrocytes dans un laps de temps défini pour la myélinisation normale. / Abnormalities of myelination during brain development are thought to result in neurologic and psychiatric disorders. We tested the developmental time window required for oligodendrocyte generation and myelin formation in the central nervous system, using a transgenic mouse harboring HSV1-TK and eGFP genes under the control of MBP and PLP promoters respectively, to carry out the conditional ablation of oligodendrocytes. The first ablation program comprised daily injection of ganciclovir (GCV) for two weeks (GCV1-14) to induce a reversible myelin recovery. The second program comprised GCV injection for 3 weeks (GCV1-21) to create a model of irreversible myelin recovery. GCV1-14 model presented 85% reduction of oligodendrocytes at week 2 (W2) and significantly increased recovery of oligodendrocytes and myelin at W4, then slower recuperation in the following weeks after the arrest of GCV treatment. Similarly, GCV treatment for three weeks (GCV1-21) induced severe deficiency of oligodrndocytes (90%) and myelin at W3. Contrasting the GCV1-14 program, only 40-50% of oligodendrocyte population was recovered at W6 and brain remained severely deficient in myelin. Moreover, no significant recovery was observed during the following weeks and myelin at W4, then slower recuperation in the following weeks after the arrest of GCV treatment. Similarly, GCV treatment for three weeks (GCV1-21) induced severe deficiency of oligodrndocytes (90%) and myelin at W3. Contrasting the GCV1-14 program, only 40-50% of oligodendrocyte population was recovered at W6 and brain remained severely deficient in myelin. Moreover, no significant recovery was observed during the following weeks and frequently ended with premature death of mice. Since no significant changes in the expression of axonal markers including neurofilaments, NgR, P75, Caspr and neurofascin186 were detected at W5 in the two models, we conclude that an intrinsic defect of oligodendrocyte regeneration at W3-W4 underlies the irreversible model. Significant number of phosphorylated Olig2+ cells was observed at W3 in reversible model in demyelinated corpus callosum while at the same time-point, this population is absent from control and irreversible model. At the same period, the proliferation index (Ki67) of Olig2+ cells is 8 fold higher in the corpus callosum of GCV1-14 model than the control and the irreversible model. Together, these findings suggest that recovery from myelin deficit during postnatal brain development depends on sufficient regeneration of oligodendrocytes within a defined time frame for normal myelination to occur.

Les troubles du spectre autistique (TSA) sont caractérisés par des déficits des interactions sociales et de la communication et par la présence de comportements répétitifs et stéréotypés. Les TSA sont associés à une hérédité complexe et une très importante hétérogénéité étiologique impliquant plus d'une centaine de gènes et loci. Les variants génétiques identifiés sont rares voire uniques et les mutations de novo jouent un rôle considérable. Des formes autosomiques dominantes ou récessives, liées au chromosome X, à forte pénétrance ou associées à une expressivité variable ont été rapportées. Néanmoins, nos connaissances de l'architecture génétique des TSA restent très incomplètes puisque les causes connues n'expliquent la pathologie que chez environ 25 % des cas, indiquant qu'il reste encore de nombreux gènes et loci à identifier. Ce travail de thèse a consisté en l'analyse de variations du nombre de copies de gènes (copy number variations, CNVs) afin de poursuivre la dissection de l'étiologie des TSA, d'identifier de nouveaux gènes impliqués et de mieux comprendre les mécanismes physiopathologiques sous-jacents.Grâce à la participation de notre équipe au consortium international Autism Genome Project (AGP), nous avons pris part à une analyse pangénomique avec des micropuces à ADN à très haute résolution chez près de 3 000 trios parents-enfant, répartis en deux stades. Les résultats du premier stade avaient démontré le rôle considérable des CNVs rares dans l'étiologie dans les TSA, en particulier les CNVs de novo. Dans le second stade, nous avons procédé à l'analyse de la deuxième moitié des familles et réanalysé les données combinées de l'ensemble des familles des deux s / Non renseigné

Nos organes sensoriels sont sous un bombardement permanent d'informations provenant du monde extérieur dont seule une infime fraction est intéressante ou pertinente pour l'individu à chaque instant, comme par exemple le visage d'une personne recherchée au milieu d'une foule. Filtrer et extraire cette information sont des fonctions vitales du cerveau, mais les mécanismes neuronaux qui décident de la réussite ou l'échec de cette épreuve restent partiellement compris. La visée de ce projet est d'étudier la relation entre activité neurale de fond et performance comportementale dans des paradigmes nécessitant différents types d'attention, au moyen de techniques comportementales et de la neuroimagerie fonctionnelle. Le modèle théorique que j'évalue dans cette thèse postule une organisation hiérarchique de ces fonctions avec l'éveil comme fonction basique d'activation physiologique, la vigilance comme fonction intermédiaire et l'attention sélective comme niveau le plus élevé et spécifique. Nous proposons en outre que l'attention sélective et la vigilance emploient deux mécanismes orthogonaux ; ces deux versants du spectre attentionnel seront le focus des deux études expérimentales présentées dans ce manuscrit. Dans les deux cas, il s'agit de chercher un lien entre l'activité neuronale spontanée et la variabilité comportementale à travers des essais répétés.J'ai utilisé le paradigme de Stroop pour opérationnaliser l'attention sélective soumise à la distraction ; la couleur du mot écrit étant la cible et le mot lui-même un distracteur en conflit direct avec cette cible. Les résultats indiquent qu'une activité pré-stimulus plus élevée dans les aires frontales et ventrales pertinentes pertinentes pour la tâche corrèle essai par essai avec des temps de réponse plus rapides ; l’effet inverse est observé dans l’aire liée au traitement de la distraction (i.e. sensible à la forme des mots). De plus, la variabilité comportementale observée à travers les sujets corrèle avec la variabilité de l’effet préstimulus dans ces régions. Pour étudier la vigilance j’ai conçu un paradigme expérimental au cours duquel les sujets ont pour instruction de rapporter tout événement saillant dans la modalité auditive ou visuelle, sans aucun signal préparatoire permettant de prédire l’apparition du prochain stimulus ou sa nature. Confirmant nos résultats précédents, des temps de réactions plus rapides sont associés à une activité pré-stimulus plus élevée dans le réseau cingulo-thalamo-insulaire. De surcroît, une activité plus élevée dans le réseau du mode par défaut (DMN) est également associée à des réponses plus rapides alors que l’activité spontanée du réseau attentionnel dorsal (DAN) n’a aucun effet sur les temps de réaction aux essais visuels et un effet négatif sur ceux des essais auditifs. Des temps de réaction plus rapide sont également associés à une activité pré-stimulus plus élevée dans les aires sensorielles primaires, mais uniquement lorsque la modalité du stimulus subséquent est congruente avec l’aire de traitement sensoriel. Les conclusions générales qui découlent de cette thèse sont donc doubles : d’une part elle confirme la pertinence fonctionnelle des fluctuations neuronales spontanées pour le comportement, d’autre part elle apporte une première identification des structures neuronales impliquées dans la vigilance sans la confondre avec l’attention sélective. / How does the brain manage to efficiently select from the abundance of sensory input that information which is currently relevant, as, for example, a known face in a crowd? Filtering and extracting this information are essential functions of the brain, but the neural mechanisms underlying the success or failure of this cognitive operation are only partially understood. Together, the aim of this project is to study, using behavioral and imaging techniques, the relationship between spontaneous neural activity and behavioral performance in task settings involving several types of attention. The related working model I wish to assess in my thesis is that attentional functions are organized in a hierarchical manner, with arousal as a basic function, alertness as an intermediate function and selective attention as the highest and most specific level. I further propose that selective attention and tonic alertness employ two orthogonal mechanisms, those two sides of the attentional spectrum will be the focus of the two experiments presented in this manuscript. In both studies, our aim was to establish a link between spontaneous fluctuations of brain activity and behavioral variability across repeated trials I used the Stroop paradigm to operationalize selective attention under distraction, the target being the color of the ink in which the word is written, the word itself is then a distractor conflicting with the target. Results indicate that higher prestimulus activity in frontal and ventral regions relevant for the task correlates trial-by-trial with faster reaction times, the opposite effect is found in the area involved in the processing of distracting features (i.e. sensitive to the word form). Moreover, inter-subjects behavioral variability also correlated with the prestimulus effect variability in those regions. To study alertness, I designed an experimental paradigm where subjects are instructed to report whatever salient event occurs in the auditory or visual modality during the recording, without any preparatory cue allowing them to predict the timing or type of an upcoming stimulus. Confirming our previous results, faster reaction times were associated with a higher prestimulus activity in the cingulo-thalamo-insular network. Furthermore, higher prestimulus activity in the default mode network (DMN) was also tied to faster responses whereas dorsal attention network (DAN) activity was overall irrelevant and, on auditory trials, even detrimental to performance. Similarly, higher prestimulus activity in the primary sensory cortices was associated with faster responses, but those effects were confined to the respective modality or, for visual trials, most pronounced in the relevant retinotopic representation. The general conclusions resulting from this thesis are two-fold: first, it confirms the functional relevance of spontaneous neuronal fluctuations for behavior; on the other hand, it brings a first identification of the brain structures involved in alertness, without confusing it with selective attention.