Introduction : Les encéphalopathies épileptiques (EE) constituent un groupe de pathologies où l’activité épileptique (répétition des crises épileptiques et/ou anomalies électroencéphalographies) est responsable d’une atteinte cognitive, sensorielle et motrice. Les EE sont définies selon leurs caractéristiques cliniques et EEG dans la classification élaborée par Ligue Internationale contre les Epilepsies (Berg et al. 2010). La distinction en différentes formes d’EE selon le phénotype clinique-EEG reflète des mécanismes physiopathologiques différents. Une base génétique est suspectée comme étant responsable de la majorité des cas d’EE. Méthodes : Ce travail débute d’une analyse clinique avec la constitution des groupes homogènes de patients grâce un phénotypage extensif. Des nouvelles techniques de séquençage à haut débit ont été appliquées à l’étude des cohortes homogènes des patients atteints d’EE afin de mieux en comprendre les bases génétiques. Résultats : Cette approche nous a permis d’identifier, à partir d’une cohorte de patients atteints de crises focales migrantes du nourrisson (MFSI), KCNT1 comme le gène impliqué dans plus de la moitié des cas de MFSI. Nous avons identifié également un autre gène, QARS, impliqué dans une forme familiale des MFSI associée à une microcéphalie progressive. Nous avons analysé les caractéristiques électro-cliniques des patients porteurs d’une mutation du gène STXBP1 permettant de mieux détailler le phénotype associé à ces mutations et de préciser donc, quels patients sont candidats à l’étude de ce gène. Enfin, nous avons décrit un cas d’épilepsie myoclono-astatique chez lequel une mutation du gène CHD2 a été identifiée. Conclusions : L’interaction dynamique et réciproque entre clinique et génétique constitue une approche fondamentale pour mettre en place des études génétiques rationnelles et ciblées et afin de pouvoir détecter, comprendre et interpréter les résultats génétiques dans des maladies rares, les EE, pour lesquelles nous ne disposons pas de larges familles “multiplex”. Une fois une anomalie génétique identifiée, le “retour à la clinique” est indispensable afin de pouvoir détailler le phénotype électroclinique associé à chaque anomalie génétique. / Introduction: Epileptic encephalopathies (EE) are a group of conditions in which cognitive, sensorial, and motor functions deteriorate as a consequence of epileptic activity (recurrence of epileptic seizures and EEG abnormalities) (Nabbout, 2003). EE are classified according to clinical and EEG features in the «Revised terminology and concepts for organization of seizures and epilepsies: Report of the ILAE Commission on Classification and Terminology, 2005-2009» (Berg et al. 2010). The distinction of different forms of EE according to the electro-clinical phenotype reflects different pathophysiological mechanisms. A genetic basis is supposed to cause the majority of EE. Methods: This work starts from the clinics with the constitution of homogeneous cohorts of patients affected by EE. The new technics of next generation sequencing have been applied to the study of homogeneous cohorts of patients with EE in order to gain insight into their genetic bases and pathophysiological mechanisms. Results: This approach allowed the identification of KCNT1 as the major gene causing migrating focal seizures of infancy (MFSI) in more than half of patients. We also identified QARS as a gene involved in a familial form of MFSI with a progressive microcephaly.
We finally analyzed electro-clinical phenotype of patients with STXBP1 mutations in order to better detail their phenotype and better select patients who are candidate to STXBP1 analysis. Finally, we reported a patient affected by myoclonic astatic epilepsy and harboring a CHD2 gene mutation. Conclusions: The dynamic and reciprocal interaction between clinics and genetics constitutes a necessary approach to target genetic studies and to gain insight into genetic and pathophysiological mechanisms of rare conditions such as EE, where large “multiplex” families are lacking. Once a genetic abnormality identified, it is essential to come back to clinics in order to detail the electroclinical phenotype associated with a genetic abnormalities and to performed genotype-phenotype correlations.

Pas de résumé / The aim of the study was to evaluate in controlled retinal risk LED lighting conditions compared to other common household lighting such as CCFL or CFL, in standard lighting conditions, on different animal species pigmented and non-pigmented. At first, we characterized the conditions of adaptation before enlightenment. We found that housing conditions before the light exposure is a source of artifact. Indeed, the location of the cages in a ventilated cabinet and the period before stalling before illumination generates a variable response to retinal light toxicity. Then, we tested the relative sensitivity of the albino strains and pigmented. After 3 weeks of stabulation, the animals were exposed for 24 hours to cold white LED at a luminance of 6000 lux, with dilation of pupils, and the retinas were examined in a week. In these extreme illumination conditions, retinas showed a significant loss of photoreceptors in superior retina, not only in albino animals, but also in pigmented animals. In another experiment, we tested different luminance in cages provided for this purpose. We have used as control a compact fluorescent lighting at 500 lux, with a homogeneous on the floor of the cage. An illumination of 24 hours dilation was performed after the time of dark adaptation. A luminance of 500 lux is a classic condition of a good visual quality domestic lighting. Unlike a compact fluorescent lighting at 500 lux, white LEDs result in a significant loss of photoreceptor nuclei of retinal pigmented rats (LE) 500 lux with an increasing toxicity in function of the luminance of the LED lighting. Finally, to assess the effects prolonged exposure we exposed the rats for one week or one month, but in alternating illumination only during the day, and without dilated pupils (day / night cycle 12h / 12h, no dilated pupils) with LED different spectra. We have compared these lighting conditions to a compact fluorescent lighting at 500 lux and non-illuminated rats. After one week, only albino rats showed a loss of photoreceptors and only after exposure to blue LEDs. These results show that the blue LEDs are more toxic than the white LEDs confirming the effects of short wavelengths. After 1 month of illumination, a significant loss of photoreceptors is observed in the retinas of non-pigmented rats, not only with the blue LEDs, but also with green LEDs and cool white LEDs. An increase of the exposure time under standard conditions leads to a loss of photoreceptors accumulated suggesting a potentially toxic effect of LED light, not observed with a compact fluorescent lighting even luminance.

The study of expertise and superior performance can be more imperative when performance is assessed in real-life conditions and professions. The present study’s aim was to capture the performance of expert marksmanship through the observation of error-detection awareness—an essential anticipatory and cognitive skill in expert performance. Two research paradigms were employed to study this phenomenon: (a) neuro-cognitive tracking, and (b) think aloud protocol. The neuro-cognitive paradigm consisted of tracking brain activity via the use of neuro-imaging technology (electroencephalography, EEG). The “think aloud” paradigm consisted of tracking thoughts and sensation expressed during shooting preparation. Both approaches relied on chronometric experimental procedures using a warning stimulus and subsequent imperative stimulus (using Tenenbaum & Summers’ model, 1997) to uncover the temporal progression of error-detection. The magnitude of error-detection signals associated with specific actions by observing the error-related negativity (ERN, a neural signal related to the commission of errors), along with the overt verbal report from performers (see Ericsson & Simon’s think aloud protocol, 1984) were measured. The results suggested that the expert shooters relied less on visual feedback in order to detect performance error. / A Dissertation submitted to the Department of Educational Psychology and Learning Systems in partial fulfillment of the requirements for the degree of Doctor of Philosophy. / Summer Semester 2017. / July 17, 2017. / Anticipatory skills, Error-Detection, Error-Renated Negativity, Expertise, Expert Performance, Motor Learning / Includes bibliographical references. / Gershon Tenenbaum, Professor Co-Directing Dissertation; Jonathan R. Folstein, Professor Co-Directing Dissertation; Anders K. Ericsson, University Representative; Graig Michael Chow, Committee Member.

Pas de résumé / No abstract available

D’une organisation très complexe, le cortex résulte de différents processus coordonnés qui comprennent la neurogenèse, la migration et la différenciation neuronales. L’altération d’un ou plusieurs de ces processus peut entrainer chez l’homme l’apparition de malformations du développement cortical (MDC).L’identification de mutations chez des patients présentant des MDC dans les gènes DCX et LIS1 codant des protéines s’associant directement ou indirectement aux microtubules a montré le rôle primordial du cytosquelette dans le développement cortical. Ce constat fut renforcé par la découverte de mutations dans des gènes codant des sous-unités tubulines elles-mêmes (TUBA1A, TUBB2B et TUBB5), unités structurelles et fonctionnelles des microtubules.Notre étude apporte des contributions à cette observation importante. En effet, nous avons tout d’abord identifié l'existence de six mutations faux-sens dans le gène TUBB3, chez douze patients, incluant un cas fœtal. Les mutations ont été trouvées principalement à l'état hétérozygote et peuvent être de novo ou transmises selon un mode autosomique dominant. Tous les patients ont en commun des anomalies complexes du développement du cortex, évocatrices de polymicrogyries frontales ou de désorganisations et simplifications gyrales en combinaison avec des anomalies du corps calleux et de la capsule interne des ganglions de la base ainsi qu'une hypoplasie du pont et du cervelet. La deuxième partie de ce travail s’intéresse à l’effet de la perte d’expression de la tubuline β3 et des mutations responsables de MDC sur les processus de la migration radiaire des neurones pyramidaux par une approche d’électroporation in utero chez la souris. L’inactivation de Tubb3 entraine un défaut de migration drastique : la majorité des cellules électroporées sont présentes dans la zone sous ventriculaire et la zone intermédiaire. Des explorations montrent une diminution du nombre de cellules multipolaires présentant des processus multiples et bien élongés, et une augmentation du nombre de cellules rondes ne présentant pas ou peu de processus. Ces résultats laissent penser que la diminution de Tubb3 entraine des défauts du contrôle des étapes de multipolarisation et rebipolarisation des neurones pyramidaux lors de la migration radiale. Nous avons également mis en évidence une augmentation de la population de progéniteurs intermédiaires électroporés avec l’ARNsh anti-Tubb3. Cette augmentation est accompagnée d’une forte diminution de leur division cellulaire. Ce résultat soulève de nombreuses questions sur le rôle potentiel de Tubb3 dans cette population. Enfin, nous avons pu constater que l’arrêt de migration observé peut être sauvé par une surexpression du transcrit de TUBB3 alors que les tubulines TUBB1, TUBB2B et TUBB4A sont dans l’incapacité de restaurer pleinement la migration radiaire des neurones sous exprimant Tubb3. Ces observations tendent à étayer l’hypothèse selon laquelle les sous unités tubulines possèdent des spécificités fonctionnelles.Dans l’ensemble, nos travaux montrent donc que des mutations de TUBB3 sont liées à des formes de MDC et que Tubb3 joue un rôle important dans la migration des neurones pyramidaux chez la souris, notamment par le contrôle des changements morphologiques qui interviennent dans la phase multipolaire. Enfin, nous apportons une nouvelle proposition d’interdépendance entre l’arrêt de migration neuronale et la division des progéniteurs neuronaux dans le développement cortical. / Over the last years, the critical role of the cytoskeletal network in the proper cortical development has been established. The importance of microtubules was further emphasized with the association of mutations in gene encoding for alpha-tubulin (TUBA1A, TUBA8), beta-tubulin (TUBB2B) in malformations of cortical development (MCD) including lissencephalies and polymicrogyria (Keays 2007, Poirier 2007, Jaglin 2009, Abdollahi 2009) and TUBB5 in microcephaly with cortical gyration abnormalities. We report the implication of TUBB3 missense mutations in polymicrogyria and cortical simplifications in 6 different families including a foetal case harboring a severe micerolissencephaly.We investigated the properties of MT network in patients' fibroblasts and revealed that MCD-related mutations can alter the resistance of microtubules to depolymerisation. These results led us to hypothesise that either microtubule dynamics or their interactions with various MT interacting proteins could be differently affected by TUBB3 variations, thus resulting in distinct alteration of downstream processes and therefore explaining the phenotypic diversity of the TUBB3-related spectrum. In a second time, we investigate further the association between TUBB3 mutations and MCDs by analyzing the consequences of Tubb3 knockdown on cortical development in mice. Using the in utero electroporation approach, we demonstrate that Tubb3 knockdown leads to delayed bipolar morphology and radial migration with evidence suggesting that the neuronal arrest is a transient phenomenon overcome after birth. Silenced blocked cells display a round shape and decreased number of processes and a delay in the acquisition of the bipolar morphology. Also, more Tbr2 positive cells are observed, although less cells express the proliferation marker Ki67, suggesting that Tubb3 inactivation might have an indirect effect on intermediate progenitor proliferation. Furthermore, we show by rescue experiments the non interchangeability of other beta-tubulins which are unable to rescue the phenotype. Our study highlights the critical and specific role of Tubb3 on the stereotyped morphological changes and polarization processes that are required for initiating radial migration to the cortical plate.

No description available.

No description available.

<p> A change in a stimulus response relationship implies that there has been a change in the internal state of the relevant behavior-generating network. Frequently, network states are persistent, biasing responses for some time following stimulus exposure. This benefits subsequent behavioral performance when the same stimulus is re-encountered. Alternatively, it can also negatively impact initiation of a second (distinct) task, i.e. there can be a task-switch cost. Recently, work from a few invertebrate model systems has begun to determine how experience dependent network states are mediated on a cellular/molecular level. A fundamental question I have addressed is, does the establishment of one network-state remove a prior state, or can two network states overlap and interact? In this thesis I provide data that indicate that in the feeding circuit of <i>Aplysia,</i> network states that promote incompatible behaviors can indeed overlap. In addition, I describe a novel role for a cyclic nucleotide gated ion-current, as supporting an experience dependent network state through a persistent modulation of cell excitability. </p>

<p> Many individuals with diabetes use medications or exercise to control blood glucose concentrations, which can lead to episodes of hypoglycemia. Although chronic hyperglycemia leads to many diabetic complications, hypoglycemia is an acute threat to the health of individuals, and can lead to myocardial ischemia and arrhythmias, as well as increasing inflammation, oxidative stress, and thrombotic and fibrinolytic processes. Either antecedent exercise or antecedent hypoglycemia lead to a blunted counter-regulatory response to a subsequent hypoglycemia episode. Acute exercise has been shown to increase monocarboxylate transport proteins (MCTs) in the ventromedial hypothalamus (VMH) of the brain, which is involved in regulating the counter-regulatory response to restore euglycemia. The MCTs shuttle lactate in and out of cells, however when is lactate infused into the VMH has been shown to interfere with the counter-regulatory response. Additionally, antecedent recurrent hypoglycemia has been shown to increase lactate transport in the brain. Therefore, the current studies investigated what effect exercise training or recurrent antecedent hypoglycemia had on MCT proteins in the VMH. Adult male Sprague-Dawley rats were used for both studies, randomized to receive either 6-7 weeks of aerobic training, sedentary behavior, 3 days of insulin induced hypoglycemia, or 3 days of saline injection. The increases in cytochrome c oxidase activity among the aerobically trained group showed that training adaptations occurred, however, there were no significant differences in MCT proteins within the VMH between the trained versus sedentary rats. While each of the 3 days of hypoglycemia or saline injection showed differences in 30 minute post-injection glucose concentrations, no significant differences in MCTs were observed in the VMH between the 2 groups on day 4.</p>

Cette thèse s’inscrit dans le domaine des neurosciences computationnelles dont le but est de modéliser des fonctions cognitives complexes par le biais de simu¬lations informatiques et numériques en s’inspirant du fonctionnement cérébral. Les modèles et simulations proposées reposent sur le paradigme des champs neuronaux, que nous exploitons pour étudier dans quelle mesure des capacités cognitives complexes peuvent être le résultat émergeant de l’interaction de cel¬lules élémentaires simples. Nous nous intéressons dans cette thèse à la modélisation de l’attention vi-suelle, avec ou sans mouvement oculaire. Pour guider le développement de nos modèles, nous proposons dans une première partie une revue de données psychologiques et physiologiques sur l’attention visuelle avant de proposer un modèle computationnel de l’attention visuelle sans saccade oculaire. Puis, nous nous intéressons dans une seconde partie à la manière dont on peut intégrer les saccades oculaires dans nos modèles en s’inspirant des données anatomiques et physiologiques sur le contrôle des saccades oculaires chez le primate. Les per¬formances des différents mécanismes proposés sont évalués en simulation en les appliquant à des tâches de recherche visuelle. Nos travaux de thèse permettent également d’étudier un paradigme de calcul original qui repose sur des calculs locaux, numériques, distribués et adaptatifs qui permettent d’envisager le déploiement des mécanismes proposés dans ce cadre sur des supports de calculs parallèles. / This thesis belongs to the computational neuroscience domain in which we aim at understanding complex cognitive functions with computer simulations built on the current knowledge of the brain. The proposed models and simula¬tions are built on the paradigm of dynamic neural ?elds, that we use in order to study in which way complex congitive capabilities can be the emergent result of the interaction of elementary units. In this thesis, we are interested in the modelisation of visual attention, with and without eye movements. To guide the development of these models, we propose in the ?rst part a review of the current psychological and physiologi¬cal data on visual attention, before proposing a computational model of visual attention without saccadic eye movement. Then, we study in the second part the way we can integrate saccadic eye movements in our models based on the current anatomical and physiological data on the oculomotor control in the pri-mate. The performances of the different proposed mechanisms are evaluated by simulating visual search tasks with saccadic eye movements. This work also makes us able to study a computational paradigm that relies on distributed, asynchronous, numerical and adaptive computation which per¬mits to consider further developments of the proposed mechanisms on parallel architectures.