Cognitive deficits are the single strongest predictor of the functional outcome in patients with schizophrenia. Current treatments are largely ineffective in improving cognitive impairments and promising pre-clinical research has mostly failed to translate clinically. Despite the advances provided by rodent models, the neurobiological basis of cognitive deficits in schizophrenia is poorly understood. Therefore, this thesis proposes a zebrafish model for studying cognitive impairments of schizophrenia. Although more evolutionarily distant to humans compared to the rat, the zebrafish has emerged as a popular vertebrate model of human disorders due to its genetic tractability, complex nervous system and elaborate behavioural repertoire. We investigated the effects of genetic alterations and neurodevelopmental disruption on behaviour and learning in zebrafish. Using both disc1 mutant lines and sub-chronic phencyclidine (PCP) on larvae from 6-10 dpf, we were able to assess behavioural changes as a function of developmental age. In particular, this thesis aimed to develop appropriate behavioural assays to assess zebrafish learning and executive function relevant to disorders seen in human patients with schizophrenia. It was possible to demonstrate robust learning across several domains, namely, reversal, classical avoidance and non-associative learning, alongside locomotor and anxiety-related behaviours. There were varied deficits associated with each of the two – genetic (disc1 gene mutation) and environmental (sub-chronic PCP) – manipulations, consistent with observations in rat research. Together, the research in this thesis demonstrates that a zebrafish model exhibits behaviour resembling that of mammalian models of schizophrenia and provides a foundation for the utility of zebrafish in examining cognitive impairments associated with schizophrenia.

Le présent manuscrit développe une problématique liée à l’implication des capacités de gestion de buts et d’engagement des fonctions exécutives dans le raisonnement par analogie et son développement. Les trois premières expériences étudient cette problématique dans deux tâches de raisonnement par analogie différentes à travers l’étude des stratégies visuelles employées par des adultes et des enfants de 6-7 ans. Les résultats montrent des différences de stratégies visuelles entre les tâches, liées aux buts différents de celles-ci, ainsi que, entre enfants et adultes, des différences de patterns visuels liés à l’inhibition de l'information non pertinente pour la résolution des problèmes. Les deux expériences suivantes étudient les stratégies visuelles, toujours en lien avec le fonctionnement exécutif et le maintien du but, dans une tâche A:B::C:? dont la difficulté est manipulée afin de mettre en évidence des différences d’engagement de processus de contrôle et d’évaluation. Les résultats montrent un effet de la difficulté des essais, ainsi que du type de distracteur, dans les stratégies visuelles. Enfin les trois dernières expériences étudient l’implication de la flexibilité cognitive, une des fonctions exécutives, dans le raisonnement par analogie, chez l’enfant (5-6 ans), limité dans sa flexibilité. Les résultats montrent que l’ancrage dans un type de représentation, pertinent ou non pour la solution du problème, est lié à leur capacité à résoudre le problème, et suggèrent une difficulté à changer de représentation au cours de la résolution. Ces résultats sont finalement discutés en rapport aux modèles de raisonnement par analogie et de développement de cette capacité. / This manuscript develops an issue related to the involvement of goal management capabilities and executive functions in this type of reasoning and its development. The first three experiments examine this issue in two tasks of analogical reasoning, the scene analogy task and the A:B::C:? task, through the study of visual strategies used by adults, and children aged 6-to-7. The results show differences in visual patterns related to goals, and to the inhibition of irrelevant information for the solution of the problems, between the different tasks, and between children and adults. The following two experiments study the visual strategies, always in relation to executive functioning and goal management, in an A:B::C:? task whose difficulty is manipulated to highlight the difference in involvement of monitoring and evaluation processes. The results do show an effect of the difficulty of the test and the type of distractor in the visual strategies employed. Finally, the last three experiments investigate the involvement of cognitive flexibility, one of the executive functions, in the analogical reasoning of preschool children (5-6-year-olds), limited in their flexibility. The results show that their early anchoring in a type of representation, relevant or not to the solution of the problem, is related to their ability to solve the problem later, and thus suggest a difficulty in shifting their representation during the resolution of the problems. These results are finally discussed in relation to models of analogical reasoning and of the development of this ability, especially those integrating goal management and executive functions.

Esta tese tem como objetivo central investigar como a flexibilidade cognitiva se opera no processo de elaboração de modelos matemáticos de relações jurídicas em domínios complexos ou mal estruturados com enfoque transdisciplinar e que conhecimentos matemáticos podem ser mobilizados. Para tanto, uma pesquisa qualitativa foi realizada com bacharelandos do 1º semestre do Curso de Engenharia Ambiental de uma Instituição Particular de Ensino Superior, localizada no município de São Paulo (SP), durante um Curso de Formação Acadêmica e Profissional. A fundamentação teórica está embasada na Teoria da Flexibilidade Cognitiva de Spiro e colaboradores (1988, 1992, 2003) e nas ideias de Robert (1987) sobre níveis de funcionamento de conhecimentos matemáticos. Em relação à Modelagem Matemática, primordialmente nos embasamos nas concepções de D´Ambrosio (1986, 1996, 2009, 2013) sustentadas pelas ideias de Barbosa (2001, 2002, 2003, 2004) e Bassanezi (1994, 2002), entre outros. Para análise da flexibilidade cognitiva foram elaborados indicadores com base nos trabalhos de Sternberg (1985, 1988, 1993, 2000, 2005) sobre a Teoria Triárquica da Inteligência e de Ennis (1991, 1993, 1996, 2011) sobre pensamento crítico. Os resultados demonstram que o grupo de alunos pesquisado apresenta dificuldades em mobilizar os conhecimentos intramatemáticos na modelagem matemática de relações jurídicas, provavelmente decorrente de falhas na assimilação de conteúdos matemáticos ao longo de sua formação escolar. Identificamos ainda dificuldades em relacionar a linguagem materna com a linguagem algébrica na elaboração dos modelos matemáticos, bem como na validação dos modelos matemáticos. No entanto, apresentaram indícios favoráveis ao pensamento criativo, prático e crítico, o que favorece consideravelmente a flexibilidade cognitiva e o desenvolvimento de habilidades para se lidar com situações novas em domínios complexos ou mal estruturados. Assim, consideramos o resultado dessa pesquisa satisfatório com relação ao nível introdutório, pois o grupo de alunos pesquisado apresentou indícios de flexibilidade cognitiva durante o processo de modelagem, sendo necessário favorecer a promoção de outras atividades com enfoque transdisciplinar que possibilitem o avanço no desenvolvimento da flexibilidade cognitiva, sobretudo em relação ao pensamento analítico que se refere à abstração. / This thesis main objective is to investigate how cognitive flexibility operates in the elaboration process of legal relationships mathematical models in complex or ill-structured domains with a transdisciplinary view and which kind of mathematical knowledge can be mobilized. Therefore, during a course of Academic and Vocational training, a study was conducted with 1st semester students of Environmental Engineering of a private higher education institution, located in the São Paulo City SP). The theoretical foundation is based in Spiro and Colleagues Cognitive Flexibility Theory (1988, 1992, 2003) and in the ideas of Robert (1987 ) on the working levels of mathematical knowledge. Regarding Mathematical Modelling we have initially based ourselves in conceptions of D\' Ambrosio (1986, 1996, 2009, 2013) supported by the ideas of Barbosa (2001, 2002, 2003, 2004) and Bassanezi (1994, 2002 ), among others. Indicators have been developed, to analyze Cognitive Flexibility, based on Sternberg works (1985, 1988, 1993, 2000, 2005) of the Triarchic Theory of Intelligence and of Ennis (1991, 1993, 1996, 2011) on critical thinking. The results have demonstrated that the researched group of students presented difficulties on mobilizing the intra-mathematical knowledge in the mathematical modeling of legal relationships , probably due to fails in the assimilation of mathematical content during their education. We could also identify students difficulties in relating their mother language with the algebraic language in the elaboration of mathematical models as well as in their validation. However, the students have presented favorable signs to creative, practical and critical thought which considerably favours cognitive flexibility and the development of skills to deal with new situations in complex or ill-structured domains. Thus, we consider the results of this research satisfactory regarding the introductory level, as the researched group of students have shown signs of cognitive flexibility during the modeling process. So we have found that promotion of other activities with a transdisciplinary approach should be favoured to enable to students an advancement to develop cognitive flexibility, particularly with relation to analytical thinking which refers to the abstraction.

La prise de perspective (PP) renvoie à la capacité de comprendre le point de vue psychologique d’autrui. Elle constitue une notion complexe, impliquant différents processus, comme la capacité de prendre conscience de soi et d’autrui, d’inhiber son point de vue, de passer d’un point de vue à un autre ou d’endosser la perspective d’autrui. Ces étapes mobilisent la conscience de soi (CS), la distinction soi-autrui (DSA) et la flexibilité cognitive (FC).Notre recherche vise à évaluer comment des déficits dans chacune de ces sphères pourraient sous-tendre une altération des capacités de PP. Pour ce faire, trois protocoles originaux sont utilisés : ils s’attachent à clarifier les liens entre la PP et les autres composantes empathiques à l’aide de mesures physiologiques, à évaluer les déficits des composantes évoquées dans la dépression sous-clinique et à tester l’effet de deux programmes d’entraînements (CF, PP) sur la symptomatologie dépressive.Les résultats montrent une implication de la PP comme processus transversal des réponses empathiques et son lien avec les composantes automatiques de l’empathie. Ils soutiennent l’existence d’un pattern de déficits en CS, DSA, FC et PP semblables à ceux mis en évidence dans les niveaux cliniques de dépression. Enfin, l’efficacité d’un entraînement à la CF sur les capacités de PP ajoute un argument au lien causal unissant les deux concepts. Nos résultats contribuent à mieux comprendre la dynamique commandant à une chaîne de déficits inter-reliés pour mieux prévenir la maladie chez les personnes à risques. / Perspective-taking (PT) refers to the ability to understand the psychological point of view of others. It is a complex notion involving the ability to become aware of oneself and others, to inhibit one's point of view, to move from one point of view to another and to adopt the perspective of others. These various stages mobilize self-consciousness (CS), self-other distinction (SOD) and cognitive flexibility (CF).Our research aims to evaluate how deficits in each of these spheres could underlie an alteration of perspective-taking abilities. To do so, it uses three original protocols aimed at clarifying the links between PT and the other empathic components by using physiological measures, evaluating the deficits of the processes mentioned in subclinical depression and to test the effect of two training programs (CF, PT) on depressive symptomatology.The results show PT involvement as a transversal process of empathic responses and its connection to the automatic components of empathy. They also support the existence of a pattern of deficits in CS, SOD, FC and PT similar to those found in clinical depression levels. Finally, the effectiveness of PT training on PT capabilities adds an argument to the causal link between these two concepts. Our results contribute to a better understanding of the dynamics driving a chain of interrelated deficits to better prevent the emergence of depression among people at risk.

5 Abstract Cognitive flexibility is an ability to adapt a behavior according to a dynamic changes in an environment. It belongs to executive functions, along with the processes of working memory, attention, motivation and others. Flexibility is important in the process of changing "stimulus-response" contingency at the time when the initial stimulus no longer leads to reward. According to the nature of the changes we can distinguish three types of cognitive flexibility: reversal learning, intradimensional set shifting and extradimensional set shifting. The processes of cognitive flexibility take place in fronto-striato-thalamic circuit with numerous connections to other brain regions, especially the limbic system. Deficit in cognitive flexibility belongs among cognitive symptoms of schizophrenia, a psychiatric illness we studied in the experimental part of this work using its analogue in rat. The aim of the experimental work was to test cognitive flexibility deficit in the rat model of schizophrenia-like behavior in the Carousel maze in four versions of task with different cognitive load. Animal model of schizophrenia was induced by acute administration of non-competitive NMDA receptor antagonist MK-801 at doses of 0.05 and 0.10 mg/kg i.p. Reversal learning was not damaged in this type of task following the...

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[pt] O Transtorno do Espectro Autista (TEA) é um distúrbio do neurodesenvolvimento caracterizado por prejuízos sociais, comportamentais e de comunicação. Um dos modelos que tentam explicar tais sintomas é o da neuropsicologia, que propõe déficit em Funções Executivas (FEs), destacando o componente de flexibilidade cognitiva. O constructo de flexibilidade cognitiva é amplo, porém é comum estar relacionado à capacidade de alternar foco atencional e pensamento, e a capacidade de adaptação às mudanças no ambiente, estando, dessa forma, na base dos sintomas de comportamento repetitivo e estereotipado no TEA. A flexibilidade cognitiva também aparece correlacionada com Teoria de Mente (ToM) e atenção compartilhada, estando, também, em algum nível associada ao funcionamento social. A literatura afirma que FEs podem melhorar com treinamento. Existem diversos modelos de intervenção para o TEA e, entre eles, a reabilitação neuropsicológica tem sido foco de estudo. A reabilitação neuropsicológica é um modelo potente para remediar e desenvolver habilidades cognitivas que se mostram prejudicadas em alguns diagnósticos infantis como TEA. Existe uma escassez de ferramentas que atuem no campo da reabilitação neuropsicológica que atenda tanto à necessidade de desenvolvimento de flexibilidade cognitiva quanto a de promover mudanças ecológicas, ou seja, instrumento que potencialize a generalização da aprendizagem para situações de vida diária. No entanto, existem tentativas nessa área e uma ferramenta comum utilizada na reabilitação infantil envolve atividade lúdica. Para atender a estas necessidades o objetivo deste trabalho foi desenvolver uma ferramenta para estimulação de flexibilidade cognitiva em crianças com TEA leve e verbais, entre 9 e 12 anos. A ferramenta desenvolvida foi um jogo de Role- Playing Game (RPG). O jogo de RPG envolve a encenação de uma história, onde os participantes devem encenar papéis, considerando as características de seus personagens. Ao longo do jogo eles se deparam com desafios, que são situações problemas que devem resolver de forma compartilhada. A dinâmica deste jogo oferece um contexto favorável a prática e experiência de comportamentos flexíveis e atende ao constructo de flexibilidade cognitiva. Para o desenvolvimento do jogo foram realizadas diversas etapas para chegar ao modelo final que foi testado em um grupo piloto para posterior revisão e adequação. O modelo final passou por uma avaliação de concordância por juízes especialista que apresentou resultado de 100 por cento para todos os itens avaliados. Este resultado confirmou a hipótese que o jogo de RPG, chamado, Fábulas e Fantasias estimula flexibilidade cognitiva, estando apto a ser usado no grupo proposto. O jogo de RPG Fábulas e Fantasias estimula flexibilidade cognitiva por meio do treino cognitivo, oferecendo oportunidade e suporte adequado para que esta habilidade seja experimentada e praticada, com a integração de estratégias metacognitivas e de instrução. Uma limitação do presente trabalho foi à ausência da realização do estudo de eficácia da ferramenta, e este objetivo compõe as perspectivas futuras. / [en] Autistic Spectrum Disorder (ASD) is a neurodevelopmental disorder mitigated by social, behavioral and communication impairments. One of the models that try to explain such symptoms is that of neuropsychology, which offers deficits in Executive Functions (EFs), highlighting the component of cognitive flexibility. The cognitive flexibility construct is broad, however it is common to be related to the ability to alternate attentional focus and thinking, and the ability to adapt to changes in the environment. Thus, linking on the basis of symptoms of repetitive and stereotyped behavior in the ASD. Cognitive flexibility also appears to be correlated with Theory of Mind (ToM) and shared attention, too, at a level associated with social functioning. Literature states that FEs can improve with training. There are several intervention models for ASD, among them neuropsychological rehabilitation has been the focus of the study. Neuropsychological rehabilitation is a powerful model to remedy and develop cognitive skills that are impaired in some childhood diagnoses such as ASD. There is a scarcity of tools that work in the field of neuropsychological rehabilitation that meet both the need to develop cognitive flexibility and ecological changes, that is, an instrument that enhances the generalization of learning to situations of daily life. However, in this area there are and a common tool used in child rehabilitation involves playful activity. To meet these needs, the objective of this work is to develop a tool for stimulating cognitive flexibility in children with mild and verbal ASD, between 9 and 12 years old. The tool developed was a Role-Playing Game (RPG). The role-playing game involves a re-enactment of a story, where participants must enact roles, considering the characteristics of their characters. Throughout the game, they are faced with challenges, which are problem situations that they must solve in a shared way. The dynamic game offers a favorable context for this flexible behavior practice and experience and meets the cognitive flexibility construct. For the development of the game, several steps were taken to reach the final model, which was tested in a pilot group for later review and adaptation. The final model underwent an agreement assessment by expert judges who presented a 100 percent result for all items obtained. This result confirmed the hypothesis that the role-playing game, called Fables and Fantasies, estimated cognitive flexibility, fit to be used in the proposed group. The Fables and Fantasies RPG game stimulates cognitive flexibility through cognitive training, offering the opportunity and adequate support for this skill to be tried and practiced, with the integration of metacognitive and instructional. of the tool, and this objective composes the future perspectives.

Research conducted with youth with type 1 diabetes (T1D) has shown that glycemic extremes and poorer T1D management are associated with poorer performance on measures of executive functioning (EF) compared to non-T1D counterparts. Deficits in EF may negatively impact the development of healthy T1D management skills. Our primary aim was to conduct a meta-analytic review of previous studies investigating the associations between glycemic control and EF in children with T1D across the developmental span. Comprehensive literature searches were conducted using PubMed, MedLine, PsycInfo, Google Scholar, and EBSCO for articles that met eligibility criteria. Eligibility criteria included correlational, randomized, and non-randomized studies published after 1985 involving participants ages 0-26 with a diagnosis of T1D. Studies evaluated EF using the Behavior Rating Inventory of Executive Functioning (BRIEF) or fMRI and evaluated glycemic control using Hemoglobin A1c. Across twelve studies examining the effect of glycemic control on EF in patients with T1D, 2,204 children, adolescents, and emerging adults were included in the study. Effect sizes (Hedges' g) were calculated between the T1D group and either control participants or a normative sample. Participant age was included as a moderator to determine whether the hypothesized association varied in magnitude across development. Participant A1c was used as a moderator to determine whether the hypothesized variation varied with diabetic management. A trend towards poorer performance on measures of executive functioning was observed in the T1D group compared to the normative sample (g = -0.22). In comparing age cohorts to the normative sample, a significantly poorer performance on measures of EF was observed in the 9-11, 15-17, and 18-26 age cohorts (g = -0.201, -0.258, and -0.452, respectively) compared to other age cohorts. Overall, research indicates that poor diabetic management may result in poorer performance on measures of EF compared to non-diabetic participants. These findings imply that this trend of poorer EF in children and adolescents with type 1 diabetes may lead to suboptimal diabetic management. Research suggests that suboptimal diabetic management often persists across the lifespan. Examining this association across critical periods where diabetes management may exert the most influence on the developing brain may provide guidance about when youth may benefit most from T1D management interventions.

Dietary N-3 PUFA plays a key role in brain maturation, development, stress response and cognitive abilities (Weiser et al., 2016; Devarshi et al., 2019). As adolescent’s prefrontal cortex is maturating, the period becomes sensitive to external factors such as environment, nutrition, and stress (Petrovich et al., 2001; Calabro et al., 2020). In this thesis, we aim to expand our knowledge of the influence of external factors, such as dietary omega-3 supplementation and enriched environment, during this critical maturation period. By designing four distinct studies, we tested the hypothesis that visible sex-specific alterations would arise from adolescence targeted diet n-3 PUFA supplementation and enriched environment, which would act to modify physiological and stress responses, as well as socio-emotional and cognitive performance. Our first study characterized the impact n-3 PUFA and n-6 PUFA regimen on corticosterone secretion and behavioural responses in adolescent male rodents. Additionally, it assessed the effects of delivery method (gavage versus restricted feeding) during this sensitive maturation period to ensure using a method with limited stress-mediated outcomes. This study highlighted gavage to induce reduced effects on corticosterone (CORT) secretion, regardless of the provided supplementation. On the last day of feeding, CORT secretion was diminished in fish oil (FO) fed rats exposed to restricted feeding, suggesting FO diet to promote physiological adjustments. Data also demonstrated that FO and soybean (CSO) rich diets were able to reduce anxiety-like behaviour compared to a high-fat diet intake (Hydrogenated Vegetal Fat - HVF), highlighting the role of n-3 PUFA dietary supplementation during adolescence on stress regulation. Our second study assessed sex-specific impact of adolescence targeted dietary supplementation on brain Docosahexaenoic Acid (DHA), Arachidonic Acid (AA) and Linolenic acid (LA) concentrations immediately following supplementation and during adulthood. Our findings demonstrated overall elevated DHA, AA and LA brain tissue concentrations in female compared to male rats, regardless of dietary supplementation. Benefit of supplementation were most apparent in adolescent males, where FO led to higher DHA concentrations compared to soybean oil supplementation, supporting a positive influence of FO dietary supplementation in males during intensive hormonal fluctuation and brain maturation. However, adolescent male rats showed reduced ability to extract nutrient essential fatty acids compared to female counterparts. Our third study characterized sex-specific coping strategies, socioemotional responses, and glucocorticoid regulation following an n-3 PUFA rich diet and enriched environment (EE) during the adolescent period. While basal CORT secretions were not significantly altered by supplementation in males, a gradual increase in CORT was observed during supplementation, peaking at DAY21. Passive coping strategies was preferred in the FST in RC (Regular Cage)- housed females exposed to FO while RC-housed CSO-fed males opted for an active climbing coping strategy. Increase locomotion and anxiolytic behaviour were observed in CSO-supplemented males (exposed to EE), while CSO by itself promoted social recognition in males. In contrast, sociability was improved in FO EE exposed females, indicating possible synergic effects. Adulthood hippocampal GR-ir expression was reduced at the hippocampal CA3 region in FO/RC and CSO/EE rat groups, which could have influenced memory consolidation and stress resilience. Overall, results from this study provided insights on positive effects associated with short-term adolescent n-3 PUFA supplementation in females, while male appeared to most benefited from soybean diet supplementation. Our fourth and last study assessed age- and sex-dependent influences of dietary supplementation on cognitive performance in the Barnes Maze Test. Our results showcase a gradual decrease in latencies to the escape box, as well as progressive decrease in working memory errors (WME) in adult compared to adolescent rats. Over the testing period, the FO females and CSO males showed improved performance through reduction of WMEs on specific days, which could subtend sex-related effects of dietary supplementations. However, while discrete effects of n-3 PUFA were more apparent in female rats, short-term supplementation appeared insufficient to promote consistent enhancement of visuospatial performance or cognitive flexibility that could be observed throughout the testing period. In conclusion, our findings support the importance of studying single and combined factors to understand overall impact. We were able to consistently demonstrate beneficial effects on coping strategies, stress reactivity, sociability, and cognitive performance of adolescence-targeted fish oil supplementation, especially in female rodents.