The role of mechanistic target of rapamycin (mTOR) pathway and synaptic protein GABAA-R in cortical GABAergic cell connectivity

Quelque 30 % de la population neuronale du cortex mammalien est composée d’une population très hétérogène d’interneurones GABAergiques. Ces interneurones diffèrent quant à leur morphologie, leur expression génique, leurs propriétés électrophysiologiques et leurs cibles subcellulaires, formant une riche diversité. Après leur naissance dans les éminences ganglioniques, ces cellules migrent vers les différentes couches corticales. Les interneurones GABAergiques corticaux exprimant la parvalbumin (PV), lesquels constituent le sous-type majeur des interneurones GABAergiques, ciblent spécifiquement le soma et les dendrites proximales des neurones principaux et des neurones PV+. Ces interneurones sont nommés cellules à panier (Basket Cells –BCs) en raison de la complexité morphologique de leur axone. La maturation de la connectivité distincte des BCs PV+, caractérisée par une augmentation de la complexité de l’axone et de la densité synaptique, se déroule graduellement chez la souris juvénile. Des travaux précédents ont commencé à élucider les mécanismes contrôlant ce processus de maturation, identifiant des facteurs génétiques, l’activité neuronale ainsi que l’expérience sensorielle. Cette augmentation marquante de la complexité axonale et de la synaptogénèse durant cette phase de maturation suggère la nécessité d’une synthèse de protéines élevée. La voie de signalisation de la cible mécanistique de la rapamycine (Mechanistic Target Of Rapamycin -mTOR) a été impliquée dans le contrôle de plusieurs aspects neurodéveloppementaux en régulant la synthèse de protéines. Des mutations des régulateurs Tsc1 et Tsc2 du complexe mTOR1 causent la sclérose tubéreuse (TSC) chez l’humain. La majorité des patients TSC développent des problèmes neurologiques incluant des crises épileptiques, des retards mentaux et l’autisme. D’études récentes ont investigué le rôle de la dérégulation de la voie de signalisation de mTOR dans les neurones corticaux excitateurs. Toutefois, son rôle dans le développement des interneurones GABAergiques corticaux et la contribution spécifique de ces interneurones GABAergiques altérés dans les manifestations de la maladie demeurent largement inconnus. Ici, nous avons investigué si et comment l’ablation du gène Tsc1 perturbe le développement de la connectivité GABAergique, autant in vitro que in vivo. Pour investiguer le rôle de l’activation de mTORC1 dans le développement d’une BC unique, nous avons délété le gène Tsc1 en transfectant CRE-GFP dirigé par un promoteur spécifique aux BCs dans des cultures organotypiques provenant de souris Tsc1lox. Le knockdown in vitro de Tsc1 a causé une augmentation précoce de la densité des boutons et des embranchements terminaux formés par les BCs mutantes, augmentation renversée par le traitement à la rapamycine. Ces données suggèrent que l’hyperactivation de la voie de signalisation de mTOR affecte le rythme de la maturation des synapses des BCs. Pour investiguer le rôle de mTORC1 dans les interneurones GABAergiques in vivo, nous avons croisé les souris Tsc1lox avec les souris Nkx2.1-Cre et PV-Cre. À P18, les souris Tg(Nkx2.1-Cre);Tsc1flox/flox ont montré une hyperactivation de mTORC1 et une hypertrophie somatique des BCs de même qu’une augmentation de l’expression de PV dans la région périsomatique des neurones pyramidaux. Au contraire, à P45 nous avons découvert une réduction de la densité des punctas périsomatiques PV-gephyrin (un marqueur post-synaptique GABAergique). L’étude de la morphologie des BCs en cultures organotypiques provenant du knock-out conditionnel Nkx2.1-Cre a confirmé l’augmentation initiale du rythme de maturation, lequel s’effondre ensuite aux étapes développementales tardives. De plus, les souris Tg(Nkx2.1Cre);Tsc1flox/flox montrent des déficits dans la mémoire de travail et le comportement social et ce d’une façon dose-dépendante. En somme, ces résultats suggèrent que l’activation contrôlée de mTOR régule le déroulement de la maturation et la maintenance des synapses des BCs. Des dysfonctions de la neurotransmission GABAergique ont été impliquées dans des maladies telles que l’épilepsie et chez certains patients, elles sont associées avec des mutations du récepteur GABAA. De quelle façon ces mutations affectent le processus de maturation des BCs demeuret toutefois inconnu. Pour adresser cette question, nous avons utilisé la stratégie Cre-lox pour déléter le gène GABRA1, codant pour la sous-unité alpha-1 du récepteur GABAA dans une unique BC en culture organotypique. La perte de GABRA1 réduit l’étendue du champ d’innervation des BCs, suggérant que des variations dans les entrées inhibitrices en raison de l’absence de la sous-unité GABAAR α1 peuvent affecter le développement des BCs. La surexpression des sous-unités GABAAR α1 contenant des mutations identifiées chez des patients épileptiques ont montré des effets similaires en termes d’étendue du champ d’innervation des BCs. Pour approfondir, nous avons investigué les effets de ces mutations identifiées chez l’humain dans le développement des épines des neurones pyramidaux, lesquelles sont l’endroit privilégié pour la formation des synapses excitatrices. Somme toute, ces données montrent pour la première fois que différentes mutations de GABRA1 associées à des syndromes épileptiques peuvent affecter les épines dendritiques et la formation des boutons GABAergiques d’une façon mutation-spécifique.

Literary style : and other essays /

Includes bibliographical references and index.

The participatory mind : a new theory of knowledge and of the universe /

"We have taken IQ tests but, strangely, no Compassion Aptitude Tests (CATs). Yet mind and emotions need to be seen as two different parts of the same spectrum, says holistic thinker Henryk Skolimowski, if the human psyche, having taken an unprecedented battering this century, is to be mended. This cannot be accomplished, however, either through the offices of dusty philosophical treatises or popular psychological fixes, only by our arriving at a new way of looking at the world." "In a Grand Theory of participatory mind that builds on the insights of such thinkers as Teilhard de Chardin and Bergson as well as contemporaries Dobzhansky and Bateson, Skolimowski points to a new order, one brought about by a Western mind returning to, then reintegrating, the spiritual. This quest for fresh perspectives, as we approach the twenty-first century, has now become 'the hallmark of our times'."--BOOK JACKET.

A combined analysis of two randomized controlled trials evaluating the effect of Mindfulness-Based Stress Reduction on self-reported emotional experience and physiological symptoms among Veterans with Posttraumatic Stress Disorder

Thesis (Master's)--University of Washington, 2016-06

Impure Memory, Imperfect Justice: A Comparison of Post-Repression Fiction Across the South Atlantic

Thesis (Ph.D.)--University of Washington, 2016-06

Children's auditory perception and cognitive processing skills in adverse listening situations

Thesis (Ph.D.)--University of Washington, 2016-06

The effects of different review opportunities on schematisation of knowledge

Recent research suggests that early in learning, students primarily use episodic memory when recalling information, but as learning develops and schematisation occurs, students' knowledge is likely to be dominated by semantic memory. This shift has been examined through student's memory awareness; 'remembering' is linked to episodic memory and 'knowing' is linked to semantic memory. This paper explores the effect of different review opportunities on students' memory awareness and schematisation, and reports on findings that indicate students are more likely to shift from 'remembering' to 'knowing' if they have the opportunity to review the learning material, but regularly and in different formats. (C) 2002 Elsevier Science Ltd. All rights reserved.

Clinical progression and outcome of dysphagia following paediatric traumatic brain injury: a prospective study

Objectives : To provide a preliminary clinical profile of the resolution and outcomes of oral-motor impairment and swallowing function in a group of paediatric dysphagia patients post-traumatic brain injury (TBI). To document the level of cognitive impairment parallel to the return to oral intake, and to investigate the correlation between the resolution of impaired swallow function versus the resolution of oral-motor impairment and cognitive impairment. Participants : Thirteen children admitted to an acute care setting for TBI. Main outcome measures : A series of oral-motor (Verbal Motor Production Assessment for Children, Frenchay Dysarthria Assessment, Schedule for Oral Motor Assessment) and swallowing (Paramatta Hospital's Assessment for Dysphagia) assessments, an outcome measure for swallowing (Royal Brisbane Hospital's Outcome Measure for Swallowing), and a cognitive rating scale (Rancho Level of Cognitive Functioning Scale). Results : Across the patient group, oral-motor deficits resolved to normal status between 3 and 11 weeks post-referral (and at an average of 12 weeks post-injury) and swallowing function and resolution to normal diet status were achieved by 3-11 weeks post-referral (and at an average of 12 weeks post-injury). The resolution of dysphagia and the resolution of oral-motor impairment and cognitive impairment were all highly correlated. Conclusion : The provision of a preliminary profile of oral-motor functioning and dysphagia resolution, and data on the linear relationship between swallowing impairment and cognition, will provide baseline information on the course of rehabilitation of dysphagia in the paediatric population post-TBI. Such data will contribute to more informed service provision and rehabilitation planning for paediatric patients post-TBI.

Experience as a moderator of involvement and satisfaction on brand loyalty in a business-to-business setting 02-314R

This paper examines the relative influence of two key antecedents of brand loyalty-satisfaction and involvement and the moderating role of experience, using a sample of business buyers. The central argument of this paper is that the strength of the effect of these variables on attitudinal brand loyalty will vary with the level of customer experience with purchasing the service. Building on previous research which examined low-risk, customer product settings [Kim, J., Lim, J.S., & Bhargava, M. (1998). The role of affect in attitude formation: A classical conditioning approach. Journal of the Academy of Marketing Science 26 (2): pp. 143-152; Shiv, B., & Fedorikhin, A. (1999). Heart and mind in conflict: The interplay of affect and cognition in consumer decision-making. Journal of Consumer Research 26: 278], this study shows that for a high-risk setting, involvement with the service category will be more dominant in its influence on brand loyalty than satisfaction with the preferred brand. Furthermore, it was found that experience moderated the influence of involvement and satisfaction on attitudinal brand loyalty for a high-risk business-to-business service. This study provides new insights into the theory and practice of buyer behavior and business-to-business brands. Crown Copyright (C) 2004 Published by Elsevier Inc. All rights reserved.

An Internet training intervention for people with traumatic brain injury: Barriers and outcomes

Primary objective: To test whether people with cognitive-linguistic impairments following traumatic brain injury could learn to use the Internet using specialized training materials. Research design: Pre-post test design. Methods and procedures: Seven participants were each matched with a volunteer tutor. Basic Internet skills were taught over six lessons using a tutor's manual and a student manual. Instructions used simple text and graphics based on Microsoft Internet Explorer 5.5. Students underwent Internet skills assessments and interviews pre- and post-training. Tutors completed a post-training questionnaire. Main outcomes and results: Six of seven participants reached moderate-to-high degrees of independence. Literacy impairment was an expected training barrier; however, cognitive impairments affecting concentration, memory and motivation were more significant. Conclusions: Findings suggest that people with cognitive-linguistic impairments can learn Internet skills using specialized training materials. Participants and their carers also reported positive outcomes beyond the acquisition of Internet skills.

SK channels regulate excitatory synaptic transmission and plasticity in the lateral amygdala

At glutamatergic synapses, calcium influx through NMDA receptors (NMDARs) is required for long-term potentiation (LTP); this is a proposed cellular mechanism underlying memory and learning. Here we show that in lateral amygdala pyramidal neurons, SK channels are also activated by calcium influx through synaptically activated NMDARs, resulting in depression of the synaptic potential. Thus, blockade of SK channels by apamin potentiates fast glutamatergic synaptic potentials. This potentiation is blocked by the NMDAR antagonist AP5 (D(-)-2-amino-5-phosphono-valeric acid) or by buffering cytosolic calcium with BAPTA. Blockade of SK channels greatly enhances LTP of cortical inputs to lateral amygdala pyramidal neurons. These results show that NMDARs and SK channels are colocalized at glutamatergic synapses in the lateral amygdala. Calcium influx through NMDARs activates SK channels and shunts the resultant excitatory postsynaptic potential. These results demonstrate a new role for SK channels as postsynaptic regulators of synaptic efficacy.

A MEMÓRIA DE CURTO PRAZO DO UNIVERSITÁRIO E A PRÁTICA DE JOGOS: UM ESTUDO EXPLORATÓRIO

Este estudo avalia inicialmente a memória de curto prazo de estudantes universitários; verifica a seguir as modalidades de jogos por esses universitários e a frequência com que os mesmos são praticados e, finalmente, relaciona o nível de memória de curto prazo verificado com a prática de jogos. Parte da hipótese de que a prática de jogos influencia na memória de curto prazo. Utiliza-se do Teste Pictórico de Memória TEPIC-M de Rueda, F. J. M. e Sisto, F. F., devidamente validado para nossa realidade e de escala auto-avaliativa de prática de jogos de lazer/esporte, a qual visa verificar o tipo de jogo praticado, de movimentação física, raciocínio lógico ou conhecimento e os jogos digitais. Desenvolve-se junto a 100 universitários, de ambos os sexos. Os resultados são analisados por meio do Statistical Package for Social Sciences for Windows, SPSS, versão 12.0. Os níveis de memória de curto prazo encontrados foram muito baixos: Inferior (66%), Médio Inferior (25%); Médio (2%); Médio Superior (6%) e Superior (1%). A prática de jogos em suas diversas modalidades também foi reduzida em Jogos de Movimento, JM, e em Jogos Digitais, JD (25%) e maior em Jogos de Raciocínio, JR (61%). A comparação entre os resultados do TEPIC-M e a frequência de participação em JM, revelou-se positiva, uma vez que os que não praticam nunca JM, 74%, não atingiram sequer o nível médio de memória; o mesmo sendo observado em relação à JD, com 70% dos participantes que não praticam esses jogos, sem atingir o nível médio de memória; e, em relação a JR, uma porcentagem menor (44%) dos que não praticam esses jogos, sem atingir o nível médio de memória, dados que indiretamente, comprovam a hipótese deste estudo.

The 'hard problem' and the quantum physicists. Part 1:the first generation

All four of the most important figures in the early twentieth-century development of quantum physics-Niels Bohr, Erwin Schroedinger, Werner Heisenberg and Wolfgang Pauli-had strong interests in the traditional mind-brain, or 'hard,' problem. This paper reviews their approach to this problem, showing the influence of Bohr's complementarity thesis, the significance of Schroedinger's small book, 'What is life?,' the updated Platonism of Heisenberg and, perhaps most interesting of all, the interaction of Carl Jung and Wolfgang Pauli in the latter's search for a unification of mind and matter. © 2005 Elsevier Inc. All rights reserved.