Opioid Receptors (ORs) are involved in the pathophysiology of several neuropsychiatric conditions yet remain an untapped therapeutic resource. Although only mu-, delta-, and kappa-OR types have been cloned, additional subtypes result from complexes generated by direct receptor-receptor interactions. Mu- and delta-ORs form a heteromeric receptor complex with unique pharmacological and signalling properties distinct from those of mu- and delta-OR homomers. In these studies, we sought to characterize the ligand binding pocket and agonist-induced internalization profile of the mu-delta heteromer, to investigate mu-delta heteromer-specific signalling in brain, and to interrogate the contribution of this receptor complex to opioid-mediated behavioural effects. In competition radioligand binding studies, delta-agonists displaced high affinity mu-agonist binding from the mu-delta heteromer but not the muOR homomer, suggestive of delta-agonists occupying or allosterically modulating the muOR ligand binding pocket within the heteromer. Delta-agonists induced internalization of the mu-delta heteromer in a dose-dependent, pertussis toxin resistant, and muOR- and deltaOR-dependent manner from the cell surface via the clathrin and dynamin endocytic machinery. Agonist-induced internalization of the mu-delta heteromer persisted following chronic morphine treatment conditions which desensitized the muOR homomer. Using Galpha-specific GTPgammaS binding assays, we demonstrated that mu-delta heteromer signalling previously characterized in cell lines was present in the striatum and hippocampus, and did not desensitize following prolonged morphine treatment conditions which desensitized muOR homomer-mediated signalling. Since delta-agonists which also target the mu-delta heteromer possess antidepressant-like and anxiolytic-like properties, we investigated the role of this receptor complex in mood regulation. We devised a strategy to selectively analyze the effects of the mu-delta heteromer by dissociating it using a specific interfering peptide aimed at a sequence implicated in mu-delta heteromerization. The interfering peptide abolished the unique pharmacological and trafficking properties of delta-agonists at the mu-delta heteromer and dissociated this receptor complex in vitro. Intra-accumbens administration of the interfering peptide disrupted the mu-delta interaction in vivo and allowed for isolation of the mu-delta heteromer contribution to the mood-regulatory effects of a delta-agonist with activity at the heteromer. Activation of the mu-delta heteromer in the nucleus accumbens produced antidepressant-like and anxiolytic-like actions in animal models of depression and anxiety.

La presente tesis doctoral ofrece una edición actualizada de la lista lexical paleo babilónica Ugu mu,ejemplo de producción lexicográfica utilizada en los procesos de aprendizaje y entrenamiento de los escribas mesopotámicos. En este trabajo se incorporan los nuevos textos catalogados desde 1967, año de la primera edición de la lista, tanto en su versión monolingüe sumeria como en aquella bilingüe sumerio-acadia, incluyendo tres textos inéditos procedentes de la colección Schøyen (OsloyLondres). Puesto que Ugu-muelenca términos anatómicos y alusivos al cuerpo humano, el grueso del trabajo se ha focalizado en el tratamiento de las categorías partonómicas en sumerio y en acadio y en el análisis semántico del vocabulario de la lista, así como en los procesos de formación de nomenclatura anatómica, los contextos de uso de la terminología incluida en Ugu-mu, y en las ideas, conceptos y prácticas vinculadas al cuerpo humano presentes en el corpus de textos cuneiformes. / This PhD dissertation offers an updated version of the Old Babylonian lexical list Ugumu, a source that was used as a learning and teaching device for the training in cuneiform writing of the Mesopotamian scribes.This work includes the new Ugu-mu texts, both monolingual (Sumerian) and bilingual (Sumerian-Akkadian), catalogued from 1967 on, when the first edition of the list was published. Besides, the unpublished texts of the list from the Schøyencollection (Osloand London) are edited and analysed as well. Since Ugu-mu lists anatomical and body-related terms, a significative part of this dissertation has focused on Sumerian and Akkadian partonomic categories, as well as in the semantic analysis of the vocabulary in Ugu-mu, its use in context, and the ideas, concepts and practices linked to the human body within the corpus of mesopotamian cuneiform texts.

Σκοπός της παρούσας διπλωματικής εργασίας είναι η μελέτη του αντίστροφου καθορισμού πηγής (inverse source localization problem) και του ρυθμού μ (mu). Έχοντας ως δεδομένο το σήμα του ΗΕΓ γίνεται προσπάθεια µέσω της εφαρμογής της μεθόδου Ανάλυσης Ανεξάρτητων συνιστωσών (ICA) να προσδιοριστούν οι συνιστώσες οι οποίες σχετίζονται με τις περιοχές του εγκεφάλου που ενεργοποιούνται από την κίνηση των χεριών. Με βάση τη λειτουργία της αισθητηριοκινητικής περιοχής του εγκεφάλου και τις ιδιότητες του ρυθμού μ, γίνεται μια μελέτη πάνω στις συνιστώσες που προκύπτουν από την ICA τόσο σε δεδομένα από πραγματική κίνηση, όσο και σε δεδομένα από νοερή κίνηση, καθώς και στην εφαρμογή που μπορεί να υπάρχει σε συστήματα Διεπαφής Εγκεφάλου – Υπολογιστή. / The subject of this diploma thesis is the study of the inverse source localization problem and the mu rhythm. Performing Independent Component Analysis (ICA) on EEG data, we try to specify the components that are related to the brain areas activated by hand movement. By focusing on the function of the somatosensory brain area and the properties or mu rhythm, we study the components resulting from Independent Component Analysis on data of both real and imaginary movement, as well as the possible implementations on Brain – Computer Interface systems.

Of all motor skills, manual reaching might be the one ability that matters most for infants’ perceptual, cognitive and social development. Reaching allows infants to learn about object properties, but also gives opportunities for socializing with others. The general aim of the present thesis was to study the importance of manual motor development in infancy from different perspectives; first, through examining stereopsis as a prerequisite for efficient reaching development, second, with regard to understanding others goal-directed reach actions by means of the mirror neuron system (MNS), and third, in relation to possible atypical development, with a specific focus on autism spectrum disorder (ASD). Study I shows that under monocular viewing conditions, infants at six, eight and 10 months of age perform slower and less accurate reaches. Longer times to object contact during monocular trials specifically imply that motor prediction is less effective when depth and distance information is compromised. Study II demonstrates that, by eight months of age, infants seem to have a MNS that functions in a similar manner to the adult MNS, thus activity can be registered over the motor cortex when infants simply observe an action they can master themselves. This activation is predictive, indicating anticipation of the goal of the observed reach. Study III indicates that infants at elevated familial risk for ASD present with reduced prospective motor control at 10 months of age. Compared to a low-risk control sample, high-risk infants perform reactive rather than predictive reach actions. Follow-up assessment at 36 months will show whether this measure can be used as a predictive diagnostic marker for ASD. The main contribution given by this work is the insight that it is important to take manual motor aspects into account when considering typical as well as atypical cognitive and social development, and in addition, that motor prediction is a key factor behind being able to timely execute and understand reaching actions.

Amidst the upheaval of the French Revolution, the British parliamentarian and political theorist Edmund Burke received a vibrant reception in German-speaking Europe. Anxious to uncover the ideological roots of the anarchy that enveloped France – and worried that their own society might be vulnerable to a similar fate – a series of important German thinkers began studying his Reflections on the Revolution in France (1790). This dissertation brings into focus the diverse interpretations of Burke that were assembled in this turbulent era, and explains them vis-à-vis contemporary debates among German idealists (Kant and his heirs) about the philosophical nature of freedom. This dissertation centers on Burke’s three most perceptive and influential students: the civil servant and philosopher August Wilhelm Rehberg; the journalist, translator, and diplomat Friedrich Gentz; and the political economist and cultural critic Adam Müller. For many decades, both German- and English-speaking intellectual historians have shoehorned these thinkers into a rigid ideological box labeled ‘conservatism’. Inspired by Burke, they are said to have turned away from the ideals of Enlightenment, theorizing an illiberal form of politics that was traditionalistic, authoritarian, and reactionary. A careful, contextualized reconstruction of their engagements with Burke, however, renders this thesis untenable. Far from triggering a monolithic backlash against Enlightenment, Burke in fact inspired a series of divergent, and often incompatible, analyses of the Revolution’s origins, grounded in different readings of his Reflections. Rehberg, for instance, saw Burke as a principled skeptic: he admired the Reflections as an incisive critique of the revolutionaries’ philosophical dogmatism. Gentz, an erstwhile student of Kant, disagreed completely, arguing that Burke’s politics were entirely compatible with Kantian metaphysics. In his view, the Reflections’ central insight was that it takes political prudence to realize the rights of man in practice. Müller, finally, read the Reflections as a lament for the fall of Christendom, and as a diagnosis of the social alienation and moral confusion that had followed its demise. In other words, whereas Rehberg was a Humean skeptic and Gentz was a Kantian liberal, Müller was a Trinitarian Christian. Each of these men, moreover, claimed Burke as an ally. What this means is that Rehberg, Gentz, and Müller cannot have jointly invented a single thing called ‘conservatism’, and Burke cannot have inspired it. This becomes clear only after we recognize that at the turn of the nineteenth century, neither the meaning of Enlightenment nor the crux of Burke’s Reflections was clear: these were not fixed variables, but points of contemporary debate. By recapturing the diversity of Burke’s German reception, this thesis invites scholars to consider the ways that his students shepherded their differing visions of Enlightenment through the fires of the Revolution, down into the nineteenth century.

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Made available in DSpace on 2014-12-17T14:35:56Z (GMT). No. of bitstreams: 1 NivaldeteFC.pdf: 706112 bytes, checksum: 3b427d139075a4af71696ede4066fd51 (MD5) Previous issue date: 2005-08-29 / La investigaci?n parte de una visi?n hist?rica de la mu?eca Em?lia creaci?n del escritor Monteiro Lobato , relacion?ndola con la educaci?n en cuanto pedagog?a perform?tica. Utiliza aportes te?ricos de Renato Cohen, investigador brasile?o del lenguaje perform?tico, como tambi?n del pensador y pedagogo alem?n Nietzsche, aplic?ndolos a las obras Em?lia en el pa?s de la Gram?tica, Aritm?tica de Em?lia y La llave del tama?o. Muestra que lo perform?tico tiene sus or?genes m?s remotos en el mito de Dioniso y que, a semejanza del arte perform?tica, propuesta como arte de frontera, la pedagog?a perform?tica se constituye tambi?n como una pedagog?a de frontera, en vista de lo h?brido pedagog?a-y-arte en que es fundado, coloc?ndose igualmente en el espacio de las pedagog?as culturales o no formales. Dentro del concepto de pedagog?a perform?tica, llegamos a la construcci?n de un peque?o sistema pedag?gico que subraya tanto lo existencial cuanto lo cient?fico. La pedagog?a perform?tica representada por la mu?eca Em?lia contesta a la condici?n bidimensional del ser humano: raz?n y sensibilidad. Por hacer mediante una alianza con el arte en este caso, la literatura -, es m?s sugestiva que prescritiva; est? apta a colaborar para el surgimiento de un paradigma pedag?gico no-centrado en la hegemon?a de lo racional; tiene um car?cter atemporal y universal, pudiendo ser aplicada en todos los niveles de ense?anza, no se ha restringido, sin embargo, al espacio escolar / A pesquisa parte de uma vis?o hist?rica da boneca Em?lia cria??o do escritor Monteiro Lobato , relacionando-a com a educa??o, enquanto pedagogia perform?tica. Utiliza aportes te?ricos de Renato Cohen, pesquisador brasileiro da linguagem perform?tica, e do pensador e pedagogo alem?o Nietzsche, aplicando-os ?s obras Em?lia no pa?s da Gram?tica, Aritm?tica da Em?lia e A chave do tamanho. Mostra que o perform?tico tem suas origens mais remotas no mito de Dioniso e que, ? semelhan?a da arte perform?tica, tida como arte de fronteira, a pedagogia perform?tica constitui-se tamb?m como uma pedagogia de fronteira, em vista da hibridiza??o pedagogia-e-arte em que se funda, colocando-se igualmente no espa?o das pedagogias culturais ou n?o formais. Dentro do conceito de pedagogia perform?tica, chegamos ? constru??o de um pequeno sistema pedag?gico que abrange tanto o existencial quanto o cient?fico. A pedagogia perform?tica representada pela boneca Em?lia responde ? condi??o bidimensional do ser humano: raz?o e sensibilidade. Por se fazer mediante uma alian?a com a arte - no caso, a literatura -, ? mais sugestiva do que prescritiva; est? apta a colaborar para o surgimento de um paradigma pedag?gico n?o-centrado na hegemonia do racional; tem um car?ter atemporal e universal, podendo ser aplicada em todos os n?veis de ensino, n?o se restringindo, entretanto, ao espa?o escolar

Résumé (FR)Cette thèse s’articule autour de cinq études ayant pour objectif principal de tenter de mieux comprendre les processus de plasticité cérébrale prenant place après un apprentissage, ainsi que les modifications apparaissant au cours du vieillissement normal. La magnétoencéphalographie (MEG) et l’électroencéphalographie (EEG) ont été utilisées pour investiguer les mécanismes électrophysiologiques de la consolidation en mémoire procédurale et déclarative durant la veille et le sommeil, chez des personnes jeunes et âgées en bonne santé. L’ensemble de nos études indique un déclin de la plasticité cérébrale avec l’âge, ainsi qu’une réorganisation différenciée en fonction de l’âge des réseaux cérébraux impliqués dans les premières étapes de la consolidation en mémoire. L’acquisition de nouvelles habiletés motrices chez les personnes âgées dépend davantage de réseaux neuronaux sous-tendant des processus attentionnels et de contrôle cognitif. Le recrutement de ces réseaux plus diffus et non spécifiques à la tâche d’apprentissage chez les personnes âgées semble défavorable au développement d’une nouvelle habileté motrice. Cependant, le recrutement chez les personnes âgées d’un réseau cortico-striatal spécifique à l’apprentissage moteur pourrait être favorable à la consolidation en mémoire procédurale. Ces résultats soulignent l’existence d’une grande variabilité interindividuelle dans le vieillissement, qui ouvre des perspectives quant aux processus favorisant le maintien versus contribuant au déclin des capacités de consolidation en mémoire avec l’âge. / Abstract (EN)The 5 studies presented in this doctoral thesis aimed at better understanding post-learning cerebral plasticity process, and the cerebral changes that occur during normal ageing. Magnetoencephalography (MEG) and electroencephalography (EEG) techniques were used to investigate the electrophysiological mechanisms of procedural and declarative memory consolidation during awakening and sleep in young and old healthy adults. Altogether, our studies highlight reduced experience-dependent plasticity in the aging brain, and the age-dependent reorganization of large-scale functional networks involved in the early stages of memory consolidation. With aging, new motor skills acquisition depends more on neuronal networks subtending controlled and attentional processes. These networks are unspecific to the motor learning task, and their involvement in old adults is negative for the development of a new motor skill. However, the involvement of a learning-related cortico-striatal network in old adults promotes procedural memory consolidation. These results indicate high inter-subjects variability in ageing, and open new perspectives to understand the memory consolidation processes that contribute to the maintenance versus the decline of newly learned information. / Doctorat en Sciences psychologiques et de l'éducation / info:eu-repo/semantics/nonPublished

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