The dissertation is divided into two separate experiments that explore the effects of visual-spatial learning on PSD-95 dorsal hippocampal expression. Specifically, the aim of these studies was to explore the effect of learning an assay, the Hebb-Williams mazes, on the protein expression of PSD-95 in Fmr1 KO mice. PSD-95 is an important scaffolding protein hypothesized to be involved in learning and memory. In cellular models of Fragile X Syndrome it has been shown to be dysregulated but it has never been measured following behavioural learning. Establishment of a deficit using an ecologically valid behavioural assay could lead to the development of novel interventions. Study one employed a subset of the Hebb-Williams mazes of various levels of difficulty to evaluate PSD-95 protein expression in Fmrp intact and Fmr1 KO mice following learning. The results revealed significant increases in PSD-95 protein expression in control runners when compared to Fmr1 KO mice. There was a negative correlation between PSD-95 protein levels and mean total errors on the mazes meaning that as expression was increased, errors were decreased. The goals of study two were to reverse the molecular and behavioural deficits using pharmacological antagonist treatment shown to be effective in cellular models of Fragile X Syndrome. Fmr1 KO mice were treated with either saline or 20 mg/kg of a metabotropic glutamate receptor antagonist, 2-Methyl-6-(phenylethynyl) pyridine (MPEP). Relative to saline treated controls, drug treated Fmr1 KO mice made fewer errors on the same subset of Hebb-Williams mazes used in study one. Latency to complete these mazes did not differ between groups, indicating that MPEP treatment does not adversely affect motor functioning. Protein assessment revealed that PSD-95 was selectively rescued in MPEP treated mice and not saline controls. Similar to study one, a negative correlation between PSD-95 protein levels and mean total errors was observed. When taken together, these studies indicate that protein deficits are associated with a deficit of learning that can be reversed with a selective glutamate receptor antagonist. One of the strengths of the Hebb-Williams mazes is that performance is measurable without floor or ceiling effects, which plague other common behavioural assays. These data further suggest that pharmacological antagonist treatments may be promising in correcting the learning deficits in human Fragile X Syndrome patients.

Qu'elle soit naturelle ou artificielle, la sériation des informations est omniprésente. Aussi, l'ordre sériel est une problématique fondamentale chez l'humain (Lashley, 1951). Nos activités sérielles des plus basiques aux plus spécifiques reposent sur notre faculté de maintien permanent de suites ordonnées d'informations en mémoire ou apprentissage de séquences, un thème central en psychologie qui reste toutefois abordé de façon cloisonnée au travers des paradigmes expérimentaux de Hebb (Hebb, 1961) et de temps de réaction sériel (TRS) (Nissen & Bullemer, 1987). Jusque-là, les études ont montré que le traitement répété de l'ordre, en mémoire sérielle dans le premier cas et perceptivo-moteur dans le deuxième, bénéficie à son apprentissage. La présente étude questionne la similitude du mécanisme sous-tendant l'apprentissage de séquences observé dans les deux paradigmes. Les deux pans de la littérature sont rapprochés afin de savoir si l'apprentissage de séquences résulte d'un processus de mémorisation sollicitant à la fois l'encodage et la récupération de l'ordre sériel. Les résultats montrent que les performances perceptivo-motrices et de reconstruction spatiale s'améliorent au cours des répétitions dans une tâche hybride originale combinant les tâches de TRS et de reconstruction sérielle et où la procédure de répétition de Hebb est appliquée. Pour la première fois il est montré que les modes procéduraux et hebbien opèrent durant l'apprentissage de séquences lequel semble émerger d'un processus hybride de mémorisation à long terme selon lequel l'encodage sensorimoteur de l'ordre spatial pourrait bénéficier à sa récupération en mémoire. L'apport de la méthodologie hybride est majeur puisqu'il permet de réunir deux domaines d'étude de l'apprentissage de séquences aux apparences distinctes tout en approfondissant sa compréhension. Les résultats sont discutés au regard des théories sur la mémoire de l'ordre et des modèles de l'apprentissage de séquences. Mots clés: Mémoire de l'ordre, apprentissage de séquences, TRS, effet de Hebb, hybridité

L'apprentissage de séquence d'informations est une habileté fondamentale, qui sous-tend une foule de comportements quotidiens (p. ex. la lecture). Plusieurs techniques sont utilisées pour étudier le phénomène, dont l'effet de répétition de Hebb : un apprentissage est observé par l'amélioration du rappel d'une séquence d'informations qui est répétée au cours d'une tâche de rappel ordonné. Son examen est cependant restreint aux mesures de performance, qui n'offrent qu'une lecture du phénomène au terme de la chaine de processus permettant l'apprentissage. Ainsi, certains suggèrent l'emploi de mesures physiologiques pour pallier ces limites et offrir une lecture des mécanismes déployés durant l'apprentissage du matériel. Ainsi, la thèse s'intéresse à l'exploration d'une mesure physiologique candidate à l'examen de l'effet de Hebb. La pupillométrie propose deux avenues plausibles pour refléter les manifestations associées à l'apprentissage d'une séquence. D'une part, la dilatation pupillaire est liée à l'effort mental déployé dans la tâche : une baisse de l'effort mental face au traitement d'une séquence répétée impliquerait une meilleure maitrise de son contenu, et donc son apprentissage. D'autre part, une réponse pupillaire est observée lorsqu'une transgression du patron de régularités de l'environnement est décelée : une telle réponse pupillaire face à une irrégularité insérée dans une séquence répétée suggérait alors l'apprentissage de ce patron d'informations. Ce faisant, les présents travaux ont pour objectifs de tester l'aptitude de ces deux mesures pupillaires à refléter les manifestations associées à l'effet de Hebb. À travers deux expériences, le premier chapitre de thèse suggère que la réponse pupillaire à l'effort mental reflète le bénéfice engendré par l'effet de Hebb. En effet, l'avantage au rappel induit par l'apprentissage s'illustre sur l'indice pupillaire de l'effort mental via une baisse du diamètre pupillaire à partir de la fin de l'encodage jusqu'à la rétention du matériel, indiquant un relâchement des ressources cognitives avant le rappel. Au second chapitre de thèse, une expérience teste les répercussions pupillaires de l'insertion d'une irrégularité dans la séquence apprise. En fin d'apprentissage, une réponse pupillaire signalant le bris du patron de la séquence répétée est observée, suggérant son apprentissage. Les résultats de la thèse appuient l'aptitude de la pupillométrie à offrir deux nouvelles avenues pour mesurer l'apprentissage d'une séquence répétée. L'examen du potentiel de ces deux indices pave la voie à de nouvelles manières d'étudier le phénomène d'apprentissage de séquence, et d'approfondir les modélisations contemporaines de la mémoire de l'ordre. / Sequence learning is a fundamental ability that underpins numerous daily tasks (e.g., reading). This phenomenon can be studied in a serial recall task, in which the learning of a repeated sequence of information can be observed from the improvement of its recall over repetitions. The investigation of this Hebb repetition effect is, however, restricted to performance measures, that only reflect the cumulative influence of all processes allowing learning. Many researchers suggest that physiological measures could provide an in-depth look at these mechanisms engaged during learning. In this view, the thesis seeks to investigate a physiological measure capable of reflecting sequence learning occurring in the Hebb repetition effect. Pupillometry aspires to provide two ways of indexing the processes associated with sequence learning. First, task-evoked pupil dilatation is a valid index of cognitive load: a decrease in cognitive effort associated with the processing of the repeated sequence would imply that the sequence has been learned. Second, a rapid pupillary response is observed when a violation in the environmental regularity pattern is detected: this pupillary response in the face of an irregularity inserted in the repeated sequence would denote learning of the information pattern. Thus, the present work aims to test the ability of these two pupillary responses of reflecting processing linked to the Hebb repetition effect. In two experiments, the first chapter suggests that the beneficial effect of learning can be observed through task-evoked pupil response: the recall advantage induced by learning is echoed to the pupillary index of mental load, by a decrease in pupil size following the end of encoding until retention, suggesting a gradual release of cognitive resources before recall. In the second chapter, a third experiment tests the pupillary response to a pattern transgression in the repeated sequence. Towards the end of the task, a rapid pupillary response following the violation of the sequence pattern suggests that the structure of the sequence was indeed learned. Taken together, these results support pupillometry's potential to offering two novel ways to assess learning associated with the Hebb repetition effect. This thesis provides a new playground for studying this sequence learning phenomenon, hence offering opportunities of deepening contemporary modelling of memory for serial order.

Made available in DSpace on 2016-03-15T19:37:31Z (GMT). No. of bitstreams: 1 Ricardo Fabio Sato.pdf: 2268590 bytes, checksum: 40455266ba2f27af16965ee2b98d813a (MD5) Previous issue date: 2010-08-04 / Algorithms for solving the classical optimization problem called traveling salesman problem are proposed. These algorithms are inspired on the fact that synapses connecting biological neurons can be altered as the time passes in function of the neuronal activity. Thus, analogies between neurons and cities to be visited by the salesman and between roads and synapses coupling neurons are made. The performances of the proposed algorithms are evaluated by comparing the lengths of the paths produced by them with the length of the optimal solution. The results obtained in experiments performed by using randomly-generated instances and ten instances from a public database suggest that this is a promising approach. / Propõem-se algoritmos para solucionar o clássico problema de otimização chamado de o problema do caixeiro viajante. Esses algoritmos são inspirados no fato de que sinapses que conectam neurônios biológicos podem se alterar com o passar do tempo em função da atividade desses neurônios. Assim, fazem-se analogias entre neurônios e cidades a serem visitadas pelo caixeiro, e entre estradas e sinapses que conectam os neurônios. Os desempenhos dos algoritmos propostos são avaliados comparando-se os comprimentos dos caminhos gerados por eles com o comprimento do caminho ótimo. Os resultados obtidos em testes realizados em instâncias geradas aleatoriamente e em dez instâncias de base de dados pública indicam que essa é uma abordagem promissora.

This dissertation describes separate but related studies that explore visual spatial learning and memory in Fragile X Syndrome. Across all studies, either the performance of individuals affected by FXS and/or fmr1 KO mice was compared to comparison controls on seven H-W mazes of increasing difficulty levels. Study one employed the traditional configuration of the H-W mazes to evaluate performance variables that include latency to complete the maze and number of the errors. The results of study 1 revealed significant differences in performance for both FXS groups as compared to mental age-matched comparison individuals and wild type mice, respectively. In contrast to the FXS group, performance of the comparison group improved as indicated by significantly fewer errors across trials. A similar pattern of results was observed when latency across trials was analyzed. Taken together, the results of study one support the hypothesis that a selective deficit in spatial learning and memory characteristic of the FXS phenotype can be observed in the murine model of FXS, if equivalent tasks are employed in testing humans and mice. Study two expanded on these findings by adding landmarks to the maze environment to evaluate how these may impact spatial learning and memory in fmr1 KO mice. Contrary to our hypotheses, landmarks significantly impaired wild type control performance. In addition, results revealed that the performance of the fmr1 KO mice generally did not differ between landmark and non-landmark tasks, indicating that the presence of landmarks neither enhanced nor hindered mouse performance. Lastly, study three entailed a more in-depth behavior analysis of maze navigation performance for FXS individuals from study 1. Consistent with the hypotheses and findings from study 1, results revealed significant differences in performance variables between individuals, with FXS participants generally performing worse than the comparison group participants. Taken together, the results of study 3 generally supported the hypothesis that there was greater impairment in performance for individuals affected by FXS as compared to controls. This impairment was evident in the pattern of pathways taken to solve H-W mazes, consistent with the notion that affected individuals employed different behavioral strategies.

京都大学 / 新制・課程博士 / 博士(教育学) / 甲第24988号 / 教博第297号 / 新制||教||221(附属図書館) / 京都大学大学院教育学研究科教育学環専攻 / (主査)教授 齊藤 智, 教授 MANALO Emmanuel, 准教授 高橋 雄介 / 学位規則第4条第1項該当 / Doctor of Philosophy (Education) / Kyoto University / DGAM

The present study had as an objective the analysis of the role of attention in the encoding of sentences and stories based on the working memory model and the Hebb Effect paradigm. The study tried to determine whether there were significant differences between of immediate serial recall in the presence or absence of an attentional concurrent task. The work hypothesis was that attention would act differently in the processing of sentences and stories. 40 students, 18 years or older, participated on the study. The results indicate that attention is primordial for the processing of sentences, but as far as stories go, the processing is done in a relatively automatic way, with little use of attention. The best support for long-term memory for the processing of the stories occurs in an automatic way. The study of the Hebb effect showed that learning occurred in a more efficient way with the stories. As far as the theoretical models, the data match the concept of the Episodic Buffer proposed by Baddeley (2000) and to the Embedded-Processes Model proposed by Cowan (1999). / O presente estudo teve como objetivo analisar o papel da atenção no processamento de frases à luz do conceito de Memória de Trabalho e do paradigma do Efeito Hebb. Buscouse verificar se existiam diferenças significativas entre provas de recordação imediata serial quando da presença ou não de uma tarefa concorrente atencional. A hipótese de trabalho foi que a atenção atuaria de maneira diferenciada no processamento das frases quando estas possuíam ou não relação de significado entre si. Participaram do estudo 40 estudantes, todos com idade acima de 18 anos. Os resultados apontam que a atenção é primordial ao processamento das seqüências de frases sem relação de significado entre si, mas que para aquelas com relação de significado, o processamento é feito de forma relativamente automática, com pouco uso da atenção. O maior suporte da memória de longo prazo ao processamento das seqüências de frases com relação de significado entre si ocorre de forma automática. O estudo do Efeito Hebb mostrou que o aprendizado ocorre de maneira mais eficiente nas seqüências de frases com significado. No que tange aos modelos teóricos, os dados vão de encontro ao conceito de funcionamento do buffer episódico proposto por Baddeley (2000) e ao processamento de informações proposto por Cowan (1999). / Mestre em Psicologia Aplicada

L'homme est capable d'utiliser des stratégies ou règles concurrentes selon les contraintes environnementales. Nous étudions un modèle plausible pour une tâche nécessitant l'apprentissage de plusieurs règles associant des stimuli visuels à des réponses motrices. Deux réseaux de populations neurales à sélectivité mixte interagissent. Le réseau décisionnel apprend les associations stimulus-réponse une à une, mais ne peut gérer qu'une règle à la fois. Son activité modifie la plasticité synaptique du second réseau qui apprend les statistiques d'évènements sur une échelle de temps plus longue. Lorsque des motifs entre les associations stimulus-réponse sont détectés, un biais d'inférence vers le réseau décisionnel guide le comportement futur. Nous montrons que le mécanisme de Hebb non-supervisé dans le second réseau est suffisant pour l'implémentation des règles. Leur récupération dans le réseau de décision améliore la performance. Le modèle prédit des changements comportementaux en fonction de la séquence des réponses précédentes, dont les effets sur la performance peuvent être positifs ou négatifs. Les prédictions sont confirmées par les données, et permettent d'identifier les sujets ayant appris la structure de la tâche. Le signal d'inférence corrèle avec l'activité BOLD dans le réseau fronto-pariétal. Au sein de ce réseau, les n¿uds préfrontaux dorsomédial et dorsolatéral sont préférentiellement recrutés lorsque les règles sont récurrentes: l'activité dans ces régions pourrait biaiser les circuits de décision lorsqu'une règle est récupérée. Ces résultats montrent que le mécanisme de Hebb peut expliquer l'apprentissage de comportements complexes en contrôle cognitif. / Depending on environmental demands, humans performing in a given task are able to exploit multiple concurrent strategies, for which the mental representations are called task-sets. We examine a candidate model for a specific human experiment, where several stimulus-response mappings, or task-sets, need to be learned and monitored. The model is composed of two interacting networks of mixed-selective neural populations. The decision network learns stimulus-response associations, but cannot learn more than one task-set. Its activity drives synaptic plasticity in a second network that learns event statistics on a longer timescale. When patterns in stimulus-response associations are detected, an inference bias to the decision network guides successive behavior. We show that a simple unsupervised Hebbian mechanism in the second network is sufficient to learn an implementation of task-sets. Their retrieval in the decision network improves performance. The model predicts abrupt changes in behavior depending on the precise statistics of previous responses, corresponding to positive (task-set retrieval) or negative effects on performance. The predictions are borne out by the data, and enable to identify subjects who have learned the task structure. The inference signal correlates with BOLD activity in the fronto-parietal network. Within this network, dorsomedial and dorsolateral prefrontal nodes are preferentially recruited when task-sets are recurrent: activity in these regions may provide a bias to decision circuits when a task-set is retrieved. These results show that Hebbian mechanisms and temporal contiguity may parsimoniously explain the learning of rule-guided behavior.

Les effets du vieillissement normal sur l’apprentissage de séquences sont examinés dans un contexte où l’intervention de la mémoire à court terme est requise (tâche d’apprentissage supra-empan de Hebb). Le paradigme consiste en une tâche de rappel sériel immédiat où, à l’insu du participant une séquence répétée survient en alternance avec des séquences aléatoires. L'apprentissage s'observe par une différence entre le rappel de la séquence répétée et des séquences aléatoires. Dans la première étude, la longueur des séquences correspond à l’empan de chaque participant plus un item (empan +1). Les résultats obtenus à cette étude montrent que l’apprentissage de séquences verbales est préservé chez les personnes âgées, tant avec des stimuli familiers (mots) que des stimuli moins familiers (pseudo-mots). Par contre, les résultats obtenus dans la seconde série d'études montrent un effet de l’âge en apprentissage de séquences spatiales, que les séquences comportent un nombre fixe d'items (9) ou que leur longueur soit ajustée en fonction de l'empan (empan +1) de chaque participant. Les résultats montrent également que l’effet d’âge observé ne relèverait pas de l'utilisation de stratégies explicites de rappel. L’ensemble de ces résultats suggèrent que certains processus associés à l'apprentissage de séquences visuo-spatiales subiraient des altérations significatives lors du vieillissement.

Using Hebb’s (1961) paradigm, it has been shown that older adults (OAs) fail to learn recurrent visuospatial supra-span sequence information (Turcotte, Gagnon, & Poirier, 2005); a deficit which has not been demonstrated on verbal versions of the same task or in younger adults (YAs). Since the Hebb paradigm is thought to rely on working memory and thus attention (Conway & Engle, 1996), one interpretation concerns an OA’s capacity to allocate the necessary attentional resources to carry out the various components of the task. Five studies investigated this proposal. The first three (Article 1) examined attention in a general manner by reducing the amount of attentional resources that a YA could devote to carrying out the visuospatial Hebb supra-span sequence learning task through the implementation of a verbal dual task (DT) procedure. The fourth (Article 2) further investigated the role of attention by using a DT induced at retrieval that overlapped extensively with the requirements (spatial and response features) of the visuospatial Hebb task. The final study (Article 3) aimed to use our previous findings to demonstrate learning among OAs in a visuospatial Hebb learning paradigm in which the motor response was replaced by a verbal response. Our findings confirm that attentional resources employed at the retrieval phase of the task appear to be particularly important for the demonstration of visuospatial sequence learning. The inclusion of a spatial and motor based DT at recall eliminated learning of the repeated sequence in YAs. Interestingly, the learning deficit of OAs was partially eliminated when the motor and spatial requirements at retrieval were reduced. Our findings offer strong support to the contention that supra-span learning of the Hebb type is not altered by the effect of age. However, learning deficits can be observed among OAs when the retrieval component of the task overly taxes attention-related processes. In the case of the visuospatial sequences, the basis of the deficit likely concerns an individual’s capacity to discriminate between responses made to previously presented sequences versus those that need to be made in reaction to the just seen sequence.