Contexte : Les répercussions de l’alcool au niveau des fonctions cognitives sont bien documentées. Certaines hypothèses suggèrent que l’alcool affecte des fonctions cognitives spécifiques alors que d’autres avancent l’hypothèse de déficits diffus. Cependant, une ambigüité persiste concernant quelles fonctions cognitives sont le plus touchées par l’alcool, et à quel point la durée d’abstinence affecte la récupération cognitive. Nous avons procédé à une des premières méta-analyses qui s’intéresse aux différentes fonctions cognitives touchées par la consommation problématique d’alcool et à la durée d’abstinence requise pour une récupération au niveau des cognitions. Méthodes : Une recherche de la littérature a permis d’identifier 62 études évaluant les cognitions chez les personnes présentant des troubles liés à l’utilisation d’alcool. Les estimations de la taille d’effet ont été calculées avec la Comprehensive Meta Analysis –V2 pour les 12 domaines cognitifs suivants : quotient intellectuel, fluidité verbale/langage, vitesse de traitement de l’information, mémoire de travail, attention, résolution de problème/fonctions exécutives, inhibition/impulsivité, apprentissage verbal, mémoire verbale, apprentissage visuel, mémoire visuelle, habiletés visuo-spatiales. Parmi ces 12 domaines cognitifs, 3 estimations de la taille d’effet ont été calculées selon les durées d’abstinences suivantes : court- (<1 mois), moyen- (2 à 12 mois) et long- (>1 an) termes. Résultats : Les résultats ont révélé la présence de dysfonctions modérées dans 11 domaines cognitifs durant l’abstinence à court terme, et dans 10 domaines cognitifs pour le moyen-terme. Des dysfonctions cognitives minimales furent notées durant l’abstinence à long-terme. Conclusions : Ces résultats révèlent des déficits cognitifs significatifs et diffus durant la première année d’abstinence. Déficits qui se normalisent après un an. Ces résultats soutiennent l’hypothèse de déficits cognitifs diffus reliés à l’alcoolisme et suggèrent que la cognition devrait faire partie intégrante du traitement d’alcoolisme. / Background: The cognitive repercussions of alcoholism are well documented. However, the literature remains somewhat ambiguous with which distinct cognitive functions are more susceptible to impairment in alcoholism and to how duration of abstinence affects cognitive recovery. Some theories claim alcohol negatively affects specific cognitive functions while others assert that deficits are more diffuse in nature. We performed the first meta-analysis to examine cognition in alcoholism and how duration of abstinence affects cognitive recovery. Methods: A literature search yielded 62 studies assessing cognitive dysfunction among alcoholics. Effect size estimates were calculated using the Comprehensive Meta-Analysis V2, for the following 12 cognitive domains: intelligence quotient, verbal fluency/language, speed of processing, working memory, attention, problem solving/executive functions, inhibition/impulsivity, verbal learning, verbal memory, visual learning, visual memory, and visuo-spatial abilities. Within these 12 domains, 3 effect size estimates were calculated based on abstinence duration and partitioned into short- (<1 month), intermediate- (2 to 12 months) and long- (>1 year) term abstinence. Results: Findings revealed moderate impairment across 11 cognitive domains during short term abstinence with moderate impairment across 10 domains during intermediate term abstinence, and overall small effect size estimates during long term abstinence. Conclusions: Results suggest significant cognitive dysfunction during the first year following abstinence from alcohol and that long term abstinence yields near normalisation of cognitive function. These findings support the diffuse brain deficits hypothesis. Clinical implications suggest that cognition may need to be considered an integral part of the treatment of alcoholism.

Hi ha nombrosos estudis que fan constar la diversitat de déficits cognitius que pateixen les persones amb esquizofrènia. Aquests déficit es troben en diverses àrees (atenció, llenguatge, memòria i especialment les funcions executives = FE), i conseqüentment afecta al funcionament de la vida diària d'aquestes persones.Muñoz i Tirapu (2001) definiren "la síndrome disexecutiva" com una constel.lació d'alteracions cognitiva-conductuals relacionades amb l'afectació de les FE i que en persones amb esquizofrènia afecta als següents elements: dificultat per centrar-se en una tasca i finalitzar-la sense un control ambiental extern; presència d'un comportament rígid, perseverant i en ocasions amb conductes estereotipades; dificultats en l'establiment de nous repertoris conductuals juntament amb una absència d'estratègies operatives, de creativitat i amb una mancança de flexibilitat cognitiva. Entre els diferents models de rehabilitació, hi ha autors com (Roder i cols. 1996) que proposen models integradors (programa ITP) suggerint un programa terapèutic tenint present la influència interactiva de les variables biològiques, cognitives i ambientals.Els objectius generals d'aquest estudi són: avaluar l'eficàcia del programa d'entrenament cognitiu de les funcions executives i el manteniment dels resultats obtinguts després del programa al cap de sis mesos d'haver finalitzat aquest. Els criteris d'inclusió dels subjectes a l'estudi són: diagnòstic d'esquizofrènia (DSM-IVTR). La mostra estava formada per 19 subjectes: el grup d'estimulació cognitiva (GEC) amb 12 pacients i el grup control (GC) format per 7 pacients. Els dos grups només es diferenciaven perquè en el grup GEC es va aplicar el programa d'entrenament cognitiu de sis mesos, i el grup GC no va rebre cap tipus de programa terapèutic.Es va administrar a tots els subjectes tres avaluacions cognitives aplicant les mateixes proves en tres moments diferents (la primera avaluació: abans d'iniciar el programa, la segona avaluació que s'administrava immediatament després d'haver finalitzat el programa, i la tercera avaluació administrada sis mesos després d'haver finalitzat els sis mesos de programa d'entrenament cognitiu). Les proves consistien en diferents mesura d'avaluació, entre d'altres, de la qualitat de vida, simptomatologia, rendiment executiu i funcional (DEX, PANSS, QLS, Test of Porteus, Tower of London i WCST).El programa d'entrenament de sis mesos de duració administrat al grup GEC consistia en tres fases: la primera fase estava formada per exercicis de raonament abstracte i formació conceptual; la segona fase per tasques de planificació i seqüenciació de diverses accions; i la tercera consistia en la resolució de problemes reals dels pacients.Els resultats obtinguts mostra efectivitat en el programa d'entrenament cognitiu de les funcions executives, i en concret, en el raonament conceptual i abstracte, planificació i seqüenciació, i resolució de problemes. Aquesta millora es manté sis mesos després d'haver finalitzat el programa.Probablement els efectes obtinguts en el programa han generat una influència positiva en la disminució de la simptomatologia i un augment en el rendiment funcional executiu i de qualitat de vida. / "Study of the efficacy of an executive training program (ETP) applied to people with schizophrenia"TEXT:It was carried out/applied a cognitive training program to schizophrenic people. Muñoz i Tirapu (2001) defined the "disexecutive syndrome" in reference to the fact that these patients have difficulties in concentrating on an activity, in planning and in having lack of creativity and mental flexibility. Some authors propose integrating models (Roder et al. 1996). Following this approach, this training program of the executive functions has been developed (ETP). The objectives of this study were two: firstly to evaluate the efficiency of an ETP applied to people with schizophrenia and secondly to evaluate the maintenance of the results after the program.To people with schizophrenia were divided into two groups (19 patients): the cognitive training group (CTG) (12 patients) and the control group (CG) (7 patients). All subjects underwent three cognitive evaluations (initial, 6 months and 12 months) that assessed symptoms, quality of life, functional performance and executive functions. The tests carried out, among others, were: DEX, PANSS, QLS, Test of Porteus, Tower of London and WCST.The ETP lasted 6 months and included exercises of planning, problem solving and abstract reasoning. For example, several exercises of planning (journeys, culinary dishes and some other sequential actions), and reasoning exercises about daily life situations and problem-solving trainingThe CTG obtained better scores immediately after the ETP. The patients of this group partially maintained these results in the evaluation done 6 months after the finishing of the program. These positive results are mainly observed in the capacity of planning, mental flexibility, abstract reasoning and problem solving. An improvement was also observed in the rest of parameters that were evaluated.The results show the effectiveness of the cognitive training program that not only appeared immediately after the program, but with the 12 months followup.The effects of the ETP may have had a positive influence in the decreased of the schizophrenic symptomathology and, therefore, an increase of quality of life and functional performance.

Chez la personne atteinte d'hémiplégie, la restauration des capacités posturales est considérée comme un des objectifs majeurs du processus de réhabilitation. Aujourd'hui, les grandes caractéristiques de la posture érigée chez le patient hémiplégique sont bien connues. Cependant, un certain nombre d'interrogations, relatives à la nature des mécanismes déficitaires et au type de rééducation à développer, subsiste. Au cours de ce travail doctoral, nous avons utilisé les concepts et les outils de l'approche dynamique des systèmes sensori-moteurs pour étudier les déficits posturaux de cette population. Dans ce cadre, ces déficits sont assimilés aux anomalies spatio-temporelles observables dans les coordinations hanche/cheville. Dans un premier temps, nous avons cherché à quantifier la nature des modifications de la dynamique posturale consécutives à une lésion cérébrale. Nous avons étudié, d'une part, la dynamique spontanée lors d'une tâche de poursuite de cible, et d'autre part, la dynamique intentionnelle en présence d'une information comportementale spécifiant la coordination à produire. A travers ces deux expérimentations, une disparition de l'attracteur en phase et une diminution de la stabilité de l'attracteur en anti-phase ont pu être mises en évidence. Dans un second temps, sur la base de ces résultats, nous avons proposé un (ré)apprentissage des deux modes de coordination préférentiels à l'aide d'un dispositif de biofeedback. L'objectif était de déterminer si la restauration d'une dynamique posturale dite "normale" était possible en dépit de la pathologie. Les résultats montrent un (ré)apprentissage du patron en phase suite au protocole; (ré)apprentissage qui s'accompagne d'une amélioration du niveau d'indépendance fonctionnelle des patients. Dans leur ensemble, ces résultats contribuent à une plus grande compréhension des déficits posturaux du patient hémiplégique et proposent des pistes de réflexion intéressantes pour la mise en place de futurs protocoles de rééducation. / The improvement of postural capacities is regarded as one of the major goals of rehabilitation of hemiplegic patients. Today, the main characteristics of the upright posture are well-known. However, many questions concerning the nature of affected mechanics and possible physical therapies remain open. In this work, we studied postural deficits in a hemiplegic population following the concepts and tools of the dynamical approach of sensori-motor systems. Deficits were considered as spatio-temporal anomalies of the organization of the postural system and analyzed through ankle/hip coordination patterns. First, we investigated modifications of postural dynamics following stroke in two different experiments. We observed both spontaneous dynamics during a tracking task and intentional dynamics using behavioral information specifing the to be produced coordination pattern. Results of both studies showed disappearance of the in-phase pattern and less stable performance in the anti-phase pattern. Second, based on gained knowledge, we proposed a (re)learning task of the two preferred postural patterns using a biofeedback design. The aim was to assess the success of this protocol for the recovery of "normal" dynamics and to explore the effect of this (re)learning on postural and functional abilities. Results suggested that the recovery of the in-phase pattern is possible and seemed to improve independence of patients. Summarized, this work proposes a new way to investigate postural deficits in post-stroke population and provided a base for the development of new therapies.

Conselho Nacional de Desenvolvimento Científico e Tecnológico / A diminuição do aporte de oxigênio e nutrientes na vida perinatal resulta em danos, como astrogliose, morte de neurônios e de células proliferativas. Déficits cognitivos podem estar relacionados a danos no hipocampo. Neste trabalho avaliamos a citoarquitetura do giro dentado (DG) durante o desenvolvimento e a memória de ratos submetidos à HI. Para tal, utilizamos a técnica de imunohistoquímica para marcador de proliferação celular (KI67), neurônio jovem (DCX), de astrócitos (GFAP) e de óxido nítrico sintase neuronal (NOSn). Para avaliar a memória de curta e de longa duração foi utilizado o teste de reconhecimento de objetos (RO). Ratas Wistar grávidas em E18 foram anestesiadas (tribromoetanol) e as quatro artérias uterinas foram ocluídas com grampos de aneurisma (Grupo HI). Após 45 minutos, os grampos foram removidos e foi feita a sutura por planos anatômicos. Os animais do grupo controle (SHAM) sofreram o mesmo procedimento, excetuando a oclusão das artérias. Os animais nasceram a termo. Animais com idades de 7 a 90 dias pós-natal (P7 a P90), foram anestesiados e perfundido-fixados com paraformaldeído a 4%, e os encéfalos submetidos ao processamento histológico. Cortes coronais do hipocampo (20m) foram submetidos à imunohistoquímica para KI67, DCX, GFAP e NOSn. Animais P90 foram submetidos ao RO. Os procedimentos foram aprovados pelo comitê de ética (CEA/019/2010). Observamos menor imunomarcação para KI67 no giro dentado de animais HI em P7. Para a marcação de DCX nesta idade não foi observada diferença entre os grupos. Animais HI em P15, P20 e P45 tiveram menor imunomarcação para DCX e Ki67 na camada granular. Animais P90 de ambos os grupos não apresentaram marcação para KI67 e DCX. Vimos aumento da imunomarcação para GFAP nos animais HI em todas as idades. A imunomarcação para NOSn nos animais HI foi menor em todas as idades. O maior número de células NOSn positivas foi visto em animais P7 em ambos os grupos na camada polimórfica. Em P15, animais HI apresentam células NOSn+ em todo o DG. Em P30 animais HI apresentam células NOSn+ nas camadas polimórfica e sub-granular. Animais adultos (P90) de ambos os grupos apresentam células NOSn positivas apenas nas camadas granular e sub-granular. Embora animais HI P90 não apresentaram déficits de memória, estes apresentaram menor tempo de exploração do objeto. Comportamento correspondente a déficits de atenção em humanos. Nossos resultados sugerem que HI perinatal diminui a população de células proliferativas, de neurônios jovens, de neurônios NOSn+, além de causar astrogliose e possivelmente déficits de atenção. O modelo demonstrou ser útil para a compreensão dos mecanismos celulares das lesões hipóxico-isquêmicas e pode ser usado para testar estratégias terapêuticas. / The supply of oxygen and nutrients decreasing in perinatal life may results in CNS damage such as deficits in memory and attention and increased susceptibility to epileptic disorders in adulthood. Perinatal hypoxia-ischemia ( HI ) results in astrogliosis in white matter and loss of cortical neurons (Robinson et al, 2005). Cognitive deficits may be related to hippocampal damage. In this study we evaluate the cytoarchitecture of the dentate gyrus (DG) during development and memory in rats submeted to HI. We used the immunohistochemistry marker of cell proliferation (Ki67), young neuron (DCX), astrocytes (GFAP) and neuronal nitric oxide synthase (nNOS). To evaluate the short-memory and long-lasting the recognition of objects (RO) test was used. Pregnant Wistar rats on E18 were anesthetized (tribromoethanol) and the four uterine arteries were occluded with aneurysm clips (Group HI). After 45 minutes, the clips were removed and the incision was sutured to the anatomical planes. The control group (SHAM) underwent the same procedure, except the occlusion of arteries. The animals were born at term. Animals aged 7 to 90 days postnatal (P7 to P90) were anesthetized and perfused-fixed with 4% paraformaldehyde, and their brains were subjected to histological processing. Coronal sections of the hippocampus (20&#956;m) were subjected to immunohistochemistry for Ki67, DCX, GFAP and nNOS. Animals were subjected to RO P90. The procedures were approved by the ethics committee ( CEA/019/2010 ). We observed lower Ki67 immunostaining in the dentate gyrus of animals HI at P7. For marking DCX at this age is no difference between the groups was observed. HI animals at P15, P20 and P45 had less immunostaining for DCX and Ki67 in the granular layer. Animals P90 in both groups showed no labeling for Ki67 and DCX. We have seen an increase in GFAP immunostaining HI in animals at any age. The immunostaining for nNOS in HI animals was lower at all ages. The greater number of positive cells was seen in nNOS P7 animals in both groups in the polymorphic layer. In P15 animals HI nNOS + cells present in the whole DG. In P30 animals HI feature nNOS + cells in the polymorphic layer and sub-granular. Adult animals (P90) of both groups have positive nNOS granular cell layers, and only in the sub-granular. Although HI P90 animals showed no memory deficits, these patients had shorter holding the object. Corresponding to attention deficits in human behavior. Our results suggest that perinatal HI decreases the population of proliferative cells, young neurons, nNOS+ neurons, and astrocytic and possibly cause attention deficits. The model proved to be useful for understanding the cellular mechanisms of hypoxic- ischemic injury and can be used to test therapeutic strategies.

La thèse se concentre sur la problématique très actuelle des déséquilibres macroéconomiques à laquelle on rattache l'existence des déficits jumeaux. La méthode innovante basée sur la métrique des distances, inspirée par la théorie des espaces métriques, permet de mettre en évidence les sources des divergences macroéconomiques qui sont, dans notre cas d'étude, la balance courante et l'endettement. Ces facteurs sont à la source de la divergence macroéconomique dans le monde ainsi qu'en Europe, ce qui souligne l'importance de l'analyse des déficits jumeaux. L'analyse dite de « text-mining », l'analyse du contenu des articles scientifiques sur les déficits jumeaux et leur classement révèlent la prédominance dans la recherche actuelle de l'approche théorique du modèle de Mundell-Fleming et de l'équivalence Ricardienne, qui sont confirmées notamment dans les pays développés. La validité de l'hypothèse des déficits jumeaux pour 14 pays de l'UE-15 dans le contexte de l'endettement public important est testée par l'estimation du modèle à effet de seuil des données de panel. Le modèle permet de conclure que l'hypothèse des déficits jumeaux est confirmée uniquement lorsque la dette publique se trouve dans l'intervalle de 40.2% à 96.6% du PIB. L'équivalence Ricardienne est valide dans le régime de la dette publique supérieure à 96.6% (le modèle à effet de seuil) ou bien 93% (le modèle dynamique qui explique l'impact asymétrique de la dette publique sur la croissance économique) du PIB. Ici, un déficit ne provoque pas l'autre; toutefois, l'efficacité de la politique budgétaire expansionniste pour rétablir la croissance économique est limitée. / The thesis presents highly topical macroeconomic imbalances problem and the related twin deficit phenomenon. Innovative distance-based methodology inspired by an algebraic term of the metric space allows to identify sources of the macroeconomic divergence, which are, in our case, the current account and the indebtedness. These factors are responsible for macroeconomic divergence in the world as well as in Europe, which suggests an importance of the twin deficit analysis. Text-mining, analysis of the content and systematic classification of the scientific papers on twin deficits reveal a dominance of the Mundell-Fleming approach and the Ricardian equivalence, confirmed mainly in developed countries. Twin deficit hypothesis in 14 countries of the EU15 in the context of the important public debt is tested by panel data threshold model. The model confirms twin deficit hypothesis only if a public debt-to-GDP ratio is of the range from 40.2% to 96.6%. The Ricardian equivalence is valid in the regime of the public debt-to-GDP higher than 96.6% (threshold model) or 93% (dynamic model explaining an asymmetric impact of the public debt on economic growth). One deficit does not deepen the second one, but efficiency of the expansionary fiscal policy to reestablish an economic growth is importantly reduced at this indebtedness level.

Le 10 janvier 1994, suite à l’échec des Politiques d’ajustement structurel proposées par les bailleurs de fonds extérieurs et à la dévaluation du Franc CFA qui en a suivi, a été signé, à Dakar, le Traité instituant l’Union Economique et Monétaire Ouest Africaine (UEMOA) par sept Etats : le Bénin, le Burkina Faso, la Côte d’Ivoire, le Mali, le Niger, le Sénégal et le Togo. Le 2 mai 1997, la Guinée Bissau deviendra le huitième Etat de l’Union. Ce Traité entérine la transformation de l’Union Monétaire Ouest Africaine, regroupant les anciennes colonies françaises ouest africaines partageant la même monnaie commune (le Franc CFA), en une union économique. Pour éviter de revivre la même situation qui a amené à dévaluer la monnaie commune, l’Union a décidé d’assainir les finances publiques des Etats membres, enmettant en place un cadre juridique approprié et une Surveillance Multilatérale de leurs politiques budgétaires. L’objectif des pères fondateurs était d’arriver,par cet arsenal juridique, à harmoniser les législations budgétaires et comptables nationales, mais aussi d’y instaurer une réelle discipline budgétaire en appui à la politique monétaire commune. Très vite, l’UEMOA se dotera de deux directives clés portant respectivement Lois de finances et Règlement général sur la comptabilité publique, mais également d’un Pacte de convergence et d’un Code de transparence dans la gestion des finances publiques. Comparée à la situation antérieure, on a noté une nette amélioration dans la gestion des finances publiques au sein de l’Union, même si tous les Etats n’avancent pas au rythme dans le respect des critères de convergence, surtout concernant la réduction des déficits publics. C’est ainsi que, l’UEMOA, avec le soutien des bailleurs de fonds multilatéraux (FMI et Banque mondiale) qui cherchent à promouvoir dans les pays où ils interviennent de nouveaux outils financiers (Gestion axée sur la performance, Pluriannualité dans la programmation budgétaire, etc.…), va réformer, en 2009, son cadre juridique des finances publiques afin de l’adapter aux nouveaux standards de gestion internationaux. / January 10, 1994, following the failure of structural adjustment policies proposedby the external donors and the devaluation of the CFA Franc which followed, was signedin Dakar, the Treaty establishing the West African Economic and Monetary Union byseven countries: Benin, Burkina Faso, Côte d'Ivoire, Mali, Niger, Senegal and Togo. OnMay 2, 1997, Guinea Bissau will become the eighth State of the Union. The Treatyconfirms the transformation of the West African Monetary Union, comprising the formerFrench colonies in West Africa share the same common currency (the CFA), in aneconomic union. To avoid repeating the same situation that led him to devalue thecurrency, the West Africa has decided to consolidate public finances of Member States,by establishing an appropriate legal framework and multilateral surveillance of fiscalpolicies. The objective of the founding fathers was to arrive by this legal arsenal,harmonize national budget and accounting laws, but also to establish a real fiscaldiscipline in support of the common monetary policy. Soon, WAEMU will develop two keydirectives dealing respectively Finance Laws and the General Public Accounting, but alsoa Pact of convergence and a code of transparency in the management of public finances.Compared to the previous situation, there was a marked improvement in the managementof public finances in the EU, even if all states are not moving at the pace in compliancewith the convergence criteria, especially regarding the reduction of deficits public. Thus,UEMOA, with support from multilateral donors (IMF and World Bank) seeking to promotein the countries where they operate a new financial tools (performance-basedmanagement, the multiannual budgetary planning etc ....), will reform in 2009, its legalframework of public finance in order to adapt to new international management standards.

La voie de signalisation mTORC1 (mechanistic target of rapamycin complex 1) est cruciale pour la croissance de l’organisme. Dans les neurones matures, mTORC1 régule la synthèse des protéines ainsi que la plasticité synaptique à la base de l’apprentissage et de la formation de la mémoire. Des dérégulations de mTOR constituent la cause de plusieurs maladies monogéniques (mTORpathies) et sont impliquées aussi bien dans des troubles neurodéveloppementaux que neuropsychiatriques. L’une des mTORpathies, la sclérose tubéreuse, est causée par des mutations des gènes codant pour les inhibiteurs de mTORC1, les complexes 1 et 2 de la sclérose tubéreuse (Tsc1 et Tsc2). Elle est associée à l’épilepsie, l’autisme et aux déficiences intellectuelles. Le rôle de mTORC1 dans les neurones excitateurs est largement connu, pourtant, son implication dans la modulation des circuits inhibiteurs corticaux a été très peu investiguée. Dans le cerveau, les interneurones inhibiteurs GABAergiques (cellules produisant l’acide gamma-aminobutyrique) sont caractérisés par leur grande diversité de morphologies, connectivités et propriétés électrophysiologiques. Les Basket Cells qui expriment la parvalbumine (PV) ciblent spécifiquement le soma et les dendrites proximales de centaines de neurones excitateurs. Cela étant, les cellules PV sont positionnées de façon stratégique pour contrôler la génération des potentiels d’actions. En particulier, l’arborisation axonale ainsi que la densité synaptique des cellules PV subissent des changements drastiques dans le jeune cerveau en développement. Par ailleurs, des altérations dans le fonctionnement des cellules PV ont été associées aux maladies du spectre de l’autisme. Les mécanismes moléculaires et cellulaires sous-jacents le développement de la connectivité des cellules PV sont très peu investigués. En particulier, dans quelle mesure et comment une dérégulation de la voie de signalisation mTORC1 affecterait le développement des cellules PV est inconnue. D’un autre côté, il a été rapporté qu’en plus de dysfonctionnements cognitifs, les maladies du spectre de iv l’autisme sont également caractérisées par des déficits dans le traitement sensoriel. Environ 90% des patients de cette pathologie subissent des expériences sensorielles atypiques telles qu’une hyper et hypo-réactivité et des réponses anormales aux stimuli tactiles. À cet égard, les anomalies sensorielles font désormais partie intégrante des critères de diagnostic de l’autisme. Pourtant, les mécanismes neurobiologiques à l’origine des déficits sensoriels demeurent encore mal connus. Vu l’importance de la voie mTORC1-TSC1 dans la physiologie neuronale et du fait que les mutations de TSC1 génèrent des traits autistiques, nous proposons l’hypothèse selon laquelle la dérégulation Tsc1-dépendante de la voie mTOR dans les cellules PV engendre une perturbation de la connectivité de ces dernières, provoquant une altération des comportements relatifs à la sclérose tubéreuse. Les résultats présentés dans cette thèse démontrent qu’une haploinsuffisance ou une absence totale de TSC1 soit dans des cellules PV isolées, en cultures organotypiques, ou dans toute la population de cellules PV in vivo entraîne une croissance précoce des branchements axonaux et de la densité des boutons synaptiques formés par les cellules mutantes, ce qui est suivie par une perte exagérée de leur innervation chez les souris adultes. Par ailleurs, les souris hétérozygotes PV-Cre;Tsc1flox/+ et knock-out PV-Cre;Tsc1flox/flox comparativement aux souris saines présentaient des déficits dans les comportements sociaux. Aussi, nous avons identifié les dysfonctionnements dans l’autophagie comme mécanismes moléculaires sous-jacents la perte des synapses PV chez les souris mutantes. Enfin, nous avons démontré l’existence d’une période critique se situant entre les 2e et 3e semaines postnatales durant laquelle un traitement à la Rapamycine qui inhibe l’hyperactivation de mTORC1 découlant de l’haploinsuffisance de TSC1 est suffisante pour renverser de façon permanente les déficits synaptiques et comportementaux des animaux mutants. Aussi, l’haploinsuffisance de TSC1 dans les cellules PV entraîne une augmentation de la discrimination tactile chez les animaux mutants. Par ailleurs, nous avons trouvé que les v connectivités glutamatergiques aussi bien intra-corticales que thalamocorticales sur les cellules PV sont réduites chez les adultes mutants comparativement aux contrôles alors que chez les souris pré-adolescentes, elles ne sont pas affectées. Finalement, une restriction sensorielle par l’intermédiaire de la coupe de moustaches pendant la fenêtre critique identifiée est suffisante pour renverser le phénotype d’hypersensibilité de ces animaux. Dans son ensemble, cette thèse apporte les preuves du rôle particulier de la signalisation mTORC1 dans la régulation du développement et du maintien de la connectivité des cellules PV et établit le ciblage de ces dernières comme bases mécanistiques d’un renversement des déficits dans les comportements sociaux et la discrimination sensorielle relatifs à l’autisme dans la sclérose tubéreuse. / Mechanistic target of rapamcyin (mTORC1) is a central player in cell growth throughout the organism. However, mTORC1 takes on additional, more specialized roles in the brain, for example, regulating neuron differentiation and glutamatergic synapse formation. In addition, in mature neuron, mTORC1 regulates protein synthesis-dependent and synaptic plastic changes underlying learning and memory. mTOR dysfunctions are the root cause of several monogenetic disorders (mTORpathies) and are implicated in both neurodevelopmental and neuropsychiatric disorders. One of the most studied mTORpathy is Tuberous Sclerosis, which is caused by mutations in the mTORC1-negative regulators Tuberous Sclerosis Complex 1 or 2 (TSC1 or TSC2). Tuberous Sclerosis is associated with neurological problems, including epilepsy, autism and intellectual disabilities. The role of mTORC1 in excitatory neurons has been extensively investigated, on the other hand whether and how it modulates cortical inhibitory circuit formation is not known. Within the forebrain, inhibitory GABAergic (γ-aminobutyric acid producing) interneurons possess the largest diversity in morphology, connectivity, and physiological properties. Cortical parvalbumin (PV)-positive basket cells (BC) specifically target the soma and proximal dendrites of excitatory neurons. PV cells are strategically positioned to control the generation of action potentials and are also strongly interconnected, which promotes their synchronous activity. The correct development of inhibitory interneurons is crucial for functional circuits. In particular, the axonal arborisation and synapse density of PV interneurons change in the postnatal brain. Interestingly, altered PV cells function has been associated to neurodevelopmental disorders, such as autism spectrum disorders (ASDs), both in human and animal models. How and whether mTORC1 signaling affects PV cell development is unknown. In addition to cognitive impairments, ASDs often result in sensory processing deficits. About 90% of ASD individuals have atypical sensory experiences, described as both hyper- and hypo-reactivity, with abnormal responses to tactile stimulation representing a very frequent finding. In fact, sensory abnormalities are now commonly recognized as diagnostic criteria in ASDs. However, the neurobiological mechanisms that underlie impaired sensory processing associated with ASDs are poorly understood. Mindful of the importance of TSC1-mTOR pathway for neuronal physiology and since mutations in Tsc1 give rise to autistic traits, we questioned whether and how Tsc1 deletion selectively in PV cells affects their connectivity, and whether and to what extent these alterations in cortical PV cell circuits might be contributing to changes in behaviours downstream of altered mTOR signaling. The results presented in this thesis show that Tsc1 haploinsufficiency causes a premature increase in terminal axonal branching and bouton density formed by mutant PV cells, followed by a loss of perisomatic innervation in adult mice. Further PV cell-restricted Tsc1 haploinsufficient and knockout mice, respectively PV-Cre;Tsc1flox/+ and PV-Cre;Tsc1flox/flox mice show deficits in social behaviour. Moreover, we identify autophagy dysfunctions as molecular mechanisms underlying PV synapses loss in PV-Cre;Tsc1flox/+ and PV-Cre;Tsc1flox/flox mice. Finally, we identify a sensitive period during the third postnatal week during which treatment with the mTOR inhibitor Rapamycin rescues deficits in both PV cell innervation and behavioral deficits in adult conditional haploinsufficient mice. We further find that PV-Cre;Tsc1flox/+ mice show increased texture discrimination. Our data also demonstrate that mutant PV cells show reduced cortical and thalamocortical glutamatergic inputs in adult mice, whereas they do not exhibit any alterations of these inputs in pre-adolescent mice. Finally sensory modulation by whisker trimming during the third postnatal week rescues texture discrimination hypersensitivity in adult conditional haploinsufficient mice. Altogether, this thesis demonstrates the crucial role of mTORC1 signaling in the regulation of the developmental time course and maintenance of cortical PV cell connectivity and support a mechanistic basis for the targeted rescue of social behaviors and sensory processing in disorders associated with deregulated mTORC1 signaling.

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

A partir de alguns estudos sobre a Academia Brasileira de Letras entidade fundada no Rio de Janeiro, em 1897 , é possível chegar a uma imagem já muito conhecida, porém pouco questionada: a de um espaço cuja compleição é marcadamente androcêntrica. Ainda que a associação entre Academia e dominação masculina possa parecer um tanto apressada, há um conjunto de implicações sociológicas nela inscritas que merecem ser descortinadas e problematizadas. Cabe-nos, assim, percorrer os caminhos teórico-analíticos que nos possibilitem apreender os matizes que tal correlação encoberta, tendo em vista as prerrogativas de gênero. Para tanto, nosso ponto de partida, situado no encalço de alguns déficits documentais, será o período de consolidação da ABL, que assiste à cogitação do nome de uma mulher para figurar entre seus membros fundadores. Trata-se da escritora Júlia Lopes de Almeida que, logo em seguida, viu-se excluída da relação final de agremiados. Também dedicaremos especial atenção a 1930, ano em que a escritora Amélia Beviláqua propõe candidatura à Academia, obtendo como resposta um sonoro não. Além destes episódios, que representam verdadeiros vazios institucionais, buscaremos evidenciar as mudanças que se processaram na Casa de Machado de Assis ao longo do tempo, tendo como ponto de inflexão o ano de 1976, momento em que é aprovada a elegibilidade feminina, alteração regimental esta que fora sucedida pela exígua presença de mulheres até os dias atuais, mais especificamente, pelo ingresso de seis escritoras: respectivamente Rachel de Queiroz, Dinah Silveira de Queiroz, Lygia Fagundes Telles, Nélida Piñon, Zélia Gattai e Ana Maria Machado. A partir do quadro construído, procuraremos mostrar se a referida modificação no Regimento Interno foi sintomática de uma alteração nos contornos tradicionais e conservadores da ABL, ou se as circunstâncias e motivações que orientaram tais ingressos resultam de forças sociais ratificadoras do cânon literário. / From some studies about the Brazilian Academy of Letters an institute established in Rio de Janeiro in 1897 , we can see an image that is widespread but not questioned, i.e., that of a space that tends to be visibly male chauvinist. Although the association of the Brazilian Academy and the male domination may seem to be simplistic, there is in it, in fact, a series of sociological implications that must be scrutinized and questioned. Thus, taking a theoretical and analytical approach vis-à-vis the gender, the aim of this study is to capture the nuances that such an association veils. Therefore, our starting point, which takes into consideration the absence of some documents, will be the period of consolidation of the ABL, when the name of a woman is considered to emerge among its founding members. This woman was the writer Júlia Lopes de Almeida, who immediately afterwards saw herself excluded from the final list of members. Also we will dedicate special attention to 1930, year in which the writer Amélia Beviláqua proposed her candidacy to the ABL and got a sound no as a reply. Besides these occurrences, which represent a true institutional emptiness, we will seek to elucidate the changes that took place in the House of Machado de Assis throughout the years, having as a turning point the year 1976, period in which women eligibility was approved. We will see that such an alteration has been followed, until now, by a rare presence of women, more specifically, by the admission of six writers: Rachel de Queiroz, Dinah Silveira de Queiroz, Lygia Fagundes Telles, Nélida Piñon, Zélia Gattai and Ana Maria Machado. From the resulting frame, we will find out whether the changes made in its statute in 1976 were, finally, indicative of a shift in the traditional and conservative structure of ABL or whether the circumstances and motivation that oriented the attainment of prestige and, consequently, a chair in the Brazilian Academy of Letters was the result of social forces which ratify the literary canon.

A partir de alguns estudos sobre a Academia Brasileira de Letras entidade fundada no Rio de Janeiro, em 1897 , é possível chegar a uma imagem já muito conhecida, porém pouco questionada: a de um espaço cuja compleição é marcadamente androcêntrica. Ainda que a associação entre Academia e dominação masculina possa parecer um tanto apressada, há um conjunto de implicações sociológicas nela inscritas que merecem ser descortinadas e problematizadas. Cabe-nos, assim, percorrer os caminhos teórico-analíticos que nos possibilitem apreender os matizes que tal correlação encoberta, tendo em vista as prerrogativas de gênero. Para tanto, nosso ponto de partida, situado no encalço de alguns déficits documentais, será o período de consolidação da ABL, que assiste à cogitação do nome de uma mulher para figurar entre seus membros fundadores. Trata-se da escritora Júlia Lopes de Almeida que, logo em seguida, viu-se excluída da relação final de agremiados. Também dedicaremos especial atenção a 1930, ano em que a escritora Amélia Beviláqua propõe candidatura à Academia, obtendo como resposta um sonoro não. Além destes episódios, que representam verdadeiros vazios institucionais, buscaremos evidenciar as mudanças que se processaram na Casa de Machado de Assis ao longo do tempo, tendo como ponto de inflexão o ano de 1976, momento em que é aprovada a elegibilidade feminina, alteração regimental esta que fora sucedida pela exígua presença de mulheres até os dias atuais, mais especificamente, pelo ingresso de seis escritoras: respectivamente Rachel de Queiroz, Dinah Silveira de Queiroz, Lygia Fagundes Telles, Nélida Piñon, Zélia Gattai e Ana Maria Machado. A partir do quadro construído, procuraremos mostrar se a referida modificação no Regimento Interno foi sintomática de uma alteração nos contornos tradicionais e conservadores da ABL, ou se as circunstâncias e motivações que orientaram tais ingressos resultam de forças sociais ratificadoras do cânon literário. / From some studies about the Brazilian Academy of Letters an institute established in Rio de Janeiro in 1897 , we can see an image that is widespread but not questioned, i.e., that of a space that tends to be visibly male chauvinist. Although the association of the Brazilian Academy and the male domination may seem to be simplistic, there is in it, in fact, a series of sociological implications that must be scrutinized and questioned. Thus, taking a theoretical and analytical approach vis-à-vis the gender, the aim of this study is to capture the nuances that such an association veils. Therefore, our starting point, which takes into consideration the absence of some documents, will be the period of consolidation of the ABL, when the name of a woman is considered to emerge among its founding members. This woman was the writer Júlia Lopes de Almeida, who immediately afterwards saw herself excluded from the final list of members. Also we will dedicate special attention to 1930, year in which the writer Amélia Beviláqua proposed her candidacy to the ABL and got a sound no as a reply. Besides these occurrences, which represent a true institutional emptiness, we will seek to elucidate the changes that took place in the House of Machado de Assis throughout the years, having as a turning point the year 1976, period in which women eligibility was approved. We will see that such an alteration has been followed, until now, by a rare presence of women, more specifically, by the admission of six writers: Rachel de Queiroz, Dinah Silveira de Queiroz, Lygia Fagundes Telles, Nélida Piñon, Zélia Gattai and Ana Maria Machado. From the resulting frame, we will find out whether the changes made in its statute in 1976 were, finally, indicative of a shift in the traditional and conservative structure of ABL or whether the circumstances and motivation that oriented the attainment of prestige and, consequently, a chair in the Brazilian Academy of Letters was the result of social forces which ratify the literary canon.