A síndrome do x-frágil (SXF) é a principal causa de deficiência mental herdada, sendo suplantada apenas pela síndrome de Down (SD). Alguns estudos sugerem que ela afeta 1 a cada 4000 homens e 1 a cada 6000 mulheres (Turner, Web, Wake & Robinson, 1996) e com incidência de pré-mutação em torno de 1 para cada 200 cromossomos X (Watson, 2005). A alta prevalência estatística torna claro que a SXF é uma das doenças genéticas mais comuns em seres humanos, mas ainda não corretamente diagnosticada. Caracteriza-se por ser hereditária, sendo a mulher a principal transmissora. Indivíduos com a SXF apresentam um conjunto de características físicas, clínicas, comportamentais e cognitivas, que podem causar um impacto no sistema familiar e, em especial, nas figuras parentais. Este estudo investiga o estresse e o autoconceito em pais e mães de meninos com a SXF, SD e desenvolvimento típico (DT), baseado no modelo biopsicossocial de Bradford (1997). A amostra total foi composta por pais e mães biológicos de meninos com a SXF (n=30), SD (n=30) e DT (n=30). As hipóteses são que pais e mães dos grupos SXF e SD apresentam níveis mais elevados de estresse do que os do grupo DT; que as mães do grupo SXF apresentam maior nível de estresse e maior prejuízo em seu autoconceito do que os pais desse mesmo grupo, tendo em conta o fato de serem as transmissoras; e que as mães do grupo SXF apresentam um autoconceito negativo se comparado às mães dos grupos SD e DT. Os resultados não revelaram diferença significativa na variável estresse, apesar de haver uma clara tendência das mães dos grupos SXF e SD em apresentar níveis mais altos de estresse. A presença de suporte encontrado (apoio e orientação) pode ter contribuído para a ausência de um estresse mais exacerbado. Os resultados também revelaram uma diferença significativa no autoconceito (self pessoal) entre as mães de crianças com a SXF e as mães de crianças com desenvolvimento típico, sugerindo que o fator da transmissão pode estar implicado no prejuízo no autoconceito. / The Fragile X Syndrome (FXS) is the main cause of hereditary mental retardation, being lower only by Down Syndrome (DS). Some studies suggest that it affects 1 in 4000 males and 1 in 6000 females (Turner, Web, Wake & Robinson 1996) and the pre-mutation incidence is around of the 1 in 200 X chromosomes (Watson, 2005). The high statistical prevalence make it clear that FXS is one of the most common genetic diseases in humans, but it is not yet correctly diagnosed. It is characterized by hereditary and the woman is the principal transmitter. People with the FXS have a cluster of physical, clinical, behavioral and mental characteristics. These impairments are likely to have an impact in the family, especially in the parents. This study investigates the stress and the self-concept in mothers and fathers of boys with FXS, DS and typical development (TD), based on the Bradford’s biopsicosocial model (1997). The total sample was comprised of biological mothers and fathers (married couple) of boys with FXS (n=30), DS (n=30) and TD (n=30). The hypothesis are that the SXF and DS parents show more stress than TD’s parents; the mothers of FXS show more stress and difficult in their self-concept than fathers, taking into account that mothers are the obligate carrier; and the FXS’s mothers have a negative self-concept when compared to DS and TD’s mothers. Although the results didn’t show significant differences in the stress variable, there was a clear tendency of mothers of FXS and DS in showing more stress than fathers and than TD’s parents. The occurrence of social support may have contributed to the absence of significant differences. The results also reveal a significant difference in the self-concept (self pessoal) between the mothers of FXS and of TD’children, suggesting that the transmission factor can play a part in the self-concept impairment.

As dificuldades de aprendizagem matemática constituem um campo bastante complexo e ainda relativamente pouco explorado. Pesquisas com síndromes associadas ao baixo desempenho matemático indicam que há diferentes perfis cognitivos subjacentes às dificuldades na matemática e nos mostram que nem toda dificuldade de aprendizagem matemática é originada da mesma maneira. Esta dissertação de mestrado apresenta dois estudos de caso: um realizado com estudante com Síndrome do X-Frágil e o outro com estudante com Síndrome de Prader-Willi. O objetivo foi investigar e compreender a aquisição dos princípios e procedimentos de contagem numérica e recuperação de fatos aditivos da memória em cada estudante. Os dados foram obtidos a partir de análise documental, observações em sala de aula e no espaço escolar e aplicação de tarefas para investigação do senso numérico, dos princípios e procedimentos de contagem e da recuperação de fatos aditivos da memória. Os resultados obtidos indicaram que os sujeitos pesquisados apresentam lentidão no processo de aprendizagem, especialmente na construção dos princípios da contagem numérica, falhas no desenvolvimento do senso numérico e não utilizaram recuperação dos fatos aditivos da memória. As implicações educacionais resultantes deste estudo, principalmente no que diz respeito à educação inclusiva, determinam a necessidade de um novo olhar para o processo de inclusão de estudantes com diferentes síndromes em salas de aulas regulares, pois suas características cognitivas e comportamentais indicam que a inclusão por si só não garante o sucesso escolar. / The difficulties in learning mathematics are a very complex field and still relatively unexplored. Researches of syndromes associated with low mathematical performance indicates that different cognitive profiles underlie math learning difficulties and show us that not all of these difficulties have the same origins. This dissertation presents two case studies: one with Fragile X Syndrome (FXS) and another with Prader-Willi Syndrome (PWS). The objective was to investigate and understand the acquisition of the principles and procedures of numerical count and recovery additive facts from memory in each student. The data obtained were from documental analysis, observations in the classroom and in the school playground and applying tasks to investigate the number sense, the principles and procedures of numerical count and recovery additive facts from memory. The results indicated that the subjects studied show slow learning process, especially in the construction of the principles of counting, flawed development of number sense and did not recovery additive facts from memory. The educational implications, particularly in inclusive educations, determine a new look at the process of students with different syndromes in regular classrooms because their cognitive behavioral characteristics indicate that the inclusion only does not guarantee school success.

A Síndrome do X frágil (SXF) é a forma mais comum de deficiência intelectual herdada. É causada por uma mutação no gene FMR1; (Fragile X Mental Retardation 1;), que resulta na deficiência da proteína FMRP (Fragile X Mental Retardation Protein;). O gene FMR1;, localizado no braço longo do cromossomo X, em Xq27.3, possui uma repetição de trinucleotídeos (CGG)n em sua região 5\' não traduzida (região reguladora). Na população geral, o tamanho dessa repetição varia entre 5 a 44 trincas de bases. Uma expansão superior a 200 trinucleotídeos leva à hipermetilação e consequente silenciamento da transcrição do gene. Quando isso ocorre, tem-se uma mutação completa, a causa da SXF. Se a repetição expandida tem de 55 a 200 trincas de bases, chamada de pré-mutação, não ocorre hipermetilação e a proteína FMRP é produzida; portanto, a pré-mutação não está associada à SXF, porém está relacionada a outros quadros clínicos, particularmente à síndrome de tremor/ataxia associada ao X frágil (FXTAS; Fragile-X associated Tremor Ataxia Syndrome;) e à insuficiência ovariana primária associada ao X frágil (FXPOI; Fragile-X associated Primary Ovarian Insufficiency;). O objetivo deste trabalho foi investigar duas famílias cujos casos-índice foram encaminhados para o Centro de Pesquisa sobre o Genoma Humano e Células-Tronco para investigar ataxia espinocerebelar e nos quais a avaliação clínica e a história familial sugeriram a possibilidade de FXTAS; em ambos os pacientes, pré-mutação do gene FMR1; foi detectada. Na Família 1, foi feito o diagnóstico de SXF em um neto da propósita e foi identificada a mutação completa em várias filhas e netas, todas com dificuldade de aprendizado. Na Família 2 não foram identificadas mutações completas e em um dos netos do propósito detectou-se mosaicismo de alelo intermediário e pré-mutação. Assim, diante da variada apresentação fenotípica, a possibilidade de condição associada ao gene FMR1; deve ser considerada frente aos fenótipos de deficiência intelectual, dificuldade de aprendizado, falência ovariana prematura e síndrome de tremor-ataxia. O diagnóstico de FXTAS em famílias em que não há registro de SXF não é frequente, provavelmente diante do desconhecimento dessa possibilidade, mas tem importância fundamental para o aconselhamento genético, particularmente quanto à ocorrência de deficiência intelectual / RIBEIRO, M. D. O. From top to bottom: genetic counseling in families ascertained through fragile X-associated tremor/ataxia syndrome (FXTAS) 2017. 64 f. Dissertação (Mestrado em Aconselhamento Genético e Genômica Humana) - Instituto de Biociências, Universidade de São Paulo, São Paulo, 2017. Fragile X syndrome (FXS) is the most common form of inherited intellectual disability. It is caused by a mutation in the Fragile X Mental Retardation 1 (FMR1;) gene located on the long arm of the X chromosome at Xq27.3 that results in FMRP (Fragile X Mental Retardation Protein) deficiency. The FMR1; gene has a trinucleotide repeat (CGG)n at the 5\' untranslated region (regulatory region); in the general population, this repeat varies in size from 5 to 44 CGG triplets. An expanded repeat of more than 200 trinucleotides leads to hypermethylation and consequent silencing of the gene transcription - the full mutation that causes FXS. The repeat containing 55 to 200 triplets characterizes a premutation; there is no hypermethylation, the gene is transcribed, and the FMRP is produced; then premutations are not associated with FXS, but are related to other clinical conditions: Fragile X-associated Tremor/Ataxia Syndrome (FXTAS) and Fragile X-associated Primary Ovarian Insufficiency (FXPOI). The objective of this study was to investigate two families whose index cases were referred to the Centro de Pesquisa sobre o Genoma Humano e Células-Tronco to investigate spinocerebellar ataxia, whose clinical evaluation and family history suggested the possibility of FXTAS. Both probands were found to carry FMR1; premutations. In Family 1, the diagnosis of FXS was established in a grandson of the proband, and the full mutation was also identified in several of her daughters and granddaughters, all presenting with learning difficulties. In Family 2, no full mutations were detected; a proband\'s grandson had size mosaicism for FMR1; ; alleles, carrying an intermediate allele and a premutation. Although uncommon, possibly due to lack of knowledge about the syndrome, the diagnosis of FXTAS in families without FXS is important for genetic counseling, particularly regarding the occurrence of intellectual disability

Orientador: Paulo Dalgalarrondo / Dissertação (mestrado) - Universidade Estadual de Campinas, Faculdade de Ciências Médicas / Made available in DSpace on 2018-08-19T03:00:44Z (GMT). No. of bitstreams: 1 Pegoraro_LuizFernandoLonguim_M.pdf: 2266541 bytes, checksum: 79f7b25b4b175b872cd3d424776438f6 (MD5) Previous issue date: 2011 / Resumo: As síndromes genéticas de Williams (SW), do X-Frágil (SXF) e de Prader-Willi (SPW) apresentam déficit cognitivo geral que varia do grau leve ao moderado. Apesar de compartilharem rebaixamento da inteligência como um todo, prejuízos e potencialidades em habilidades cognitivas específicas dessas síndromes são amplamente descritos na literatura internacional, mas não tão enfaticamente no Brasil. Este estudo teve por objetivo investigar, descrever e comparar o perfil cognitivo de crianças e adolescentes com SW, SXF e SPW. Trinta e quatro crianças e adolescentes de seis a 16 anos, de ambos os sexos, com diagnóstico confirmado para a SW (n = 10), a SXF (n = 13) e a SPW (n = 11), pacientes dos ambulatórios de Psiquiatria da Criança ou Adolescente e/ou Genética Geral II do Hospital de Clínicas (HC) da Unicamp participaram deste estudo. Os sujeitos foram avaliados em suas funções cognitivas por meio da Escala de Inteligência Wechsler para Crianças (WISC-III). Dados sócio-culturais, exames citogenéticos e os sintomas e diagnósticos psiquiátricos associados aos participantes foram coletados nos prontuários médicos e também por meio de entrevistas com os responsáveis por cada criança ou adolescente. O QI total (QIT), o QI verbal (QIV), o QI de execução (QIE) e os escores ponderados de cada subteste da escala WISC-III, assim como os dados pessoais dos sujeitos de pesquisa, foram transpostos para o software estatístico SPSS, versão 17 para Windows. Não foram encontradas diferenças significativas em relação à idade, à classe social e ao tipo de escola que cada participante freqüenta entre as três síndromes. Por outro lado, houve diferença significativa quanto ao gênero dos participantes (p < 0,05). Foram encontradas diferenças significativas em relação ao QIV, aos subtestes verbais Informação, Vocabulário, Compreensão e em relação aos subtestes de execução Cubos e Armar Objetos. O teste post hoc de comparações múltiplas de Dunn (? = 0,05) apontou um escore significativamente superior nos subtestes de linguagem verbal e no QIV para o grupo com SW e um escore significativamente superior nos subtestes visuo-espaciais para o grupo com SPW. Estes resultados dão suporte à noção do perfil cognitivo específico para estas síndromes genéticas, constituído por "picos e vales" de rendimento, apesar do déficit intelectual geral destas condições, contrariando a concepção do fator g em crianças e adolescentes com SW, SXF e SPW / Abstract: Genetic syndromes such as Williams (WS), Fragile X (FXS) and Prader-Willi syndrome (PWS) present general cognitive impairment ranging from mild to moderate. Despite sharing a diminishment of intelligence as a whole, strengths and weakness in specific cognitive abilities of each syndrome are well described in international literature, but not so emphatically in Brazil. This study aimed to investigate, describe and compare the cognitive profile of children and adolescents with WS, FXS and PWS. Thirty-four children and adolescents, aged between 6 and 16, of both genders, with a confirmed diagnosis of either WS (n = 10), FXS (n = 13) or PWS (n = 11), from the outpatient clinics of Child and Adolescent Psychiatry or from the General Genetics II clinic, located at the Hospital das Clinicas (HC), participated in this study. The subjects cognitive functions were evaluated using the Wechsler Intelligence Scale for Children (WISC-III). Socio-cultural, cytogenetic tests and associated psychiatric symptoms and diagnoses were collected from the participants medical records and through interviews with those responsible for each child or adolescent. The Full-Scale IQ (FSIQ), Verbal IQ (VIQ), Performance IQ of (PIQ) and the standard scores of each subtest in the WISC-III scale, as well as the personal data of research subjects, were entered in version 17 of the SPSS statistical software for Windows. No significant differences were found between the three syndromes regarding age, social class or the type of school (private or public) each participant attends. On the other hand, there were significant differences in gender of the participants (p <0.05). Significant differences were found with respect to VIQ, and the verbal subtests Information, Vocabulary and Comprehension, and also in relation to the performance subtests Block Design and Object Assembly. The Dunn's multiple comparison test showed a significantly higher score on the verbal subtests and VIQ for the group with WS and a significantly higher score on the visuospatial subtests for the group with PWS. These results support the notion that there are specific cognitive profiles for these genetic syndromes, consisting of "peaks and valleys" in performance, despite the general intellectual deficit of these conditions, contrary to the g factor concept in children and adolescents with WS, FXS and PWS / Mestrado / Saude da Criança e do Adolescente / Mestre em Ciências

Le syndrome de l’X fragile représente la première cause de déficience intellectuelle héréditaire. Ce syndrome résulte de l’absence de la protéine FMRP. FMRP est proposée réguler, sous contrôles des mGluR-I et d’autres récepteurs, l’expression de protéines importantes pour la plasticité synaptique en se fixant spécifiquement sur leur ARNm et en modulant leur traduction. Des milliers d’ARNm cibles ont déjà été proposées dans la littérature, mais très peu ont pu être validées. Par approche de pontage covalent aux UV et immunoprecipitation (CLIP) couplé à une analyse microarray, nous avons identifié un ARNm comme cible unique de FMRP dans les neurones corticaux. Cet ARNm code pour une kinase contrôlant le niveau de deux seconds messagers lipidiques importants pour le remodelage des épines dendritiques. De plus, nous avons montré que l’activation mGluR-I dépendante de la kinase est absente dans les neurones Fmr1 KO, avec pour conséquence une altération de plusieurs espèces lipidiques du neurone. Ces défauts peuvent expliquer les altérations morphologiques et fonctionnelles des épines dendritiques, cause principale proposée du syndrome de l’X fragile. / Fragile X syndrome is the leading cause of inherited intellectual disability and is due to the absence of the RNA binding protein FMRP (Fragile X Mental Retardation Protein). FMRP is proposed to bind and regulate synaptic expression of mRNA targets upon mGluR-I activation. Thousands of mRNA targets have already been proposed in the literature, but only a few have been validated leaving unsolved the question of the genes mostly affected by the absence of FMRP in the brain of fragile Xpatients. The main project of the thesis was to identify the mRNAs associated with FMRP in cortical neurons by performing cross-linking immunoprecipitation approach (CLIP). We found that FMRP principally targets one unique mRNA which encodes an important synaptic kinase. This enzyme controls the level of two second lipid messengers important for remodeling of dendritic spines. Consequently, the mGluR-I-dependant activation of the enzyme is lost in absence of FMRP, leading to several lipid species alterations in the neuron. These defects may explain the morphological and functional alterations of dendritic spines, the hallmark of fragile X syndrome.

Le syndrome du X fragile (SXF) est la première cause héréditaire de déficience intellectuelle et également la première cause monogénique d’autisme. Le SXF est causé par l'expansion de la répétition du nucléotide CGG sur le gène FMR1, ce qui empêche l’expression de la protéine FMRP. L’absence du FMRP mène à une altération du développement structurel et fonctionnel de la synapse, ce qui empêche la maturation des synapses induite par l’activité et l’élagage synaptique, qui sont essentiels pour le développement cérébral et cognitif. Nous avons investigué les potentiels reliés aux événements (PRE) évoqués par des stimulations fondamentales auditives et visuelles dans douze adolescents et jeunes adultes (10-22) atteints du SXF, ainsi que des participants contrôles appariés en âge chronologique et développemental. Les résultats indiquent un profil des PRE altéré, notamment l’augmentation de l’amplitude de N1 auditive, par rapport aux deux groupes contrôle, ainsi que l’augmentation des amplitudes de P2 et N2 auditifs et de la latence de N2 auditif. Chez les patients SXF, le traitement sensoriel semble être davantage perturbé qu’immature. En outre, la modalité auditive semble être plus perturbée que la modalité visuelle. En combinaison avec des résultats anatomique du cerveau, des mécanismes biochimiques et du comportement, nos résultats suggèrent une hyperexcitabilité du système nerveux dans le SXF. / We investigated early auditory and visual information processing in Fragile X Syndrome (FXS), the most common form of X-linked Intellectual Disability (ID) and the only known monogenetic cause of autism. FXS is caused by a trinucleotide repeat expansion in the FMR1 (‘Fragile X mental retardation 1’) gene, which prevents expression of the ‘fragile X mental retardation protein’ (FMRP). FMRP absence leads to altered structural and functional development of the synapse, while also preventing activity-based synapse maturation and synaptic pruning, which are essential for cerebral and cognitive development. We review the contribution of electrophysiological signal studies for the understanding of information processing in FXS and compare event-related potential (ERP) findings to those concerning other clinical populations that share symptoms with FXS. In our research project, we investigated ERPs evoked by basic auditory and visual stimulation in twelve adolescents and young adults (10-22) with FXS, as well as healthy chronological- and developmental- age matched controls. We found an altered ERP profile in FXS, including increased auditory N1 amplitude, relative to both control groups, as well as increased auditory P2 and N2 amplitudes and increased auditory N2 latencies. Rather than being immature, sensory processing appears to be specifically disrupted in FXS. Furthermore, the auditory modality seems to be more affected than the visual modality. In combination with brain anatomical, biochemical and behavioural findings, our results suggest a hyperexcitable nervous system in FXS.

Le syndrome du X fragile (SXF) est la première cause héréditaire de déficience intellectuelle et également la première cause monogénique d’autisme. Le SXF est causé par l'expansion de la répétition du nucléotide CGG sur le gène FMR1, ce qui empêche l’expression de la protéine FMRP. L’absence du FMRP mène à une altération du développement structurel et fonctionnel de la synapse, ce qui empêche la maturation des synapses induite par l’activité et l’élagage synaptique, qui sont essentiels pour le développement cérébral et cognitif. Nous avons investigué les potentiels reliés aux événements (PRE) évoqués par des stimulations fondamentales auditives et visuelles dans douze adolescents et jeunes adultes (10-22) atteints du SXF, ainsi que des participants contrôles appariés en âge chronologique et développemental. Les résultats indiquent un profil des PRE altéré, notamment l’augmentation de l’amplitude de N1 auditive, par rapport aux deux groupes contrôle, ainsi que l’augmentation des amplitudes de P2 et N2 auditifs et de la latence de N2 auditif. Chez les patients SXF, le traitement sensoriel semble être davantage perturbé qu’immature. En outre, la modalité auditive semble être plus perturbée que la modalité visuelle. En combinaison avec des résultats anatomique du cerveau, des mécanismes biochimiques et du comportement, nos résultats suggèrent une hyperexcitabilité du système nerveux dans le SXF. / We investigated early auditory and visual information processing in Fragile X Syndrome (FXS), the most common form of X-linked Intellectual Disability (ID) and the only known monogenetic cause of autism. FXS is caused by a trinucleotide repeat expansion in the FMR1 (‘Fragile X mental retardation 1’) gene, which prevents expression of the ‘fragile X mental retardation protein’ (FMRP). FMRP absence leads to altered structural and functional development of the synapse, while also preventing activity-based synapse maturation and synaptic pruning, which are essential for cerebral and cognitive development. We review the contribution of electrophysiological signal studies for the understanding of information processing in FXS and compare event-related potential (ERP) findings to those concerning other clinical populations that share symptoms with FXS. In our research project, we investigated ERPs evoked by basic auditory and visual stimulation in twelve adolescents and young adults (10-22) with FXS, as well as healthy chronological- and developmental- age matched controls. We found an altered ERP profile in FXS, including increased auditory N1 amplitude, relative to both control groups, as well as increased auditory P2 and N2 amplitudes and increased auditory N2 latencies. Rather than being immature, sensory processing appears to be specifically disrupted in FXS. Furthermore, the auditory modality seems to be more affected than the visual modality. In combination with brain anatomical, biochemical and behavioural findings, our results suggest a hyperexcitable nervous system in FXS.

Diese qualitative Studie untersucht den schulischen Alltag von drei Jungen mit Fragilem-X- Syndrom. Das Fragile-X-Syndrom ist die häufigste bekannte erbliche Ursache von geistiger Behinderung und wird mit einer Reihe von charakteristischen Eigenschaften assoziiert. Dazu zählen vor allem physische, kognitive und psychosoziale Merkmale. Mithilfe der Ethnografie mit teilnehmender Beobachtung im schulischen Umfeld der Schüler werden die Bedingungen herausgearbeitet, die das Fragile-X-Syndrom der Schüler „sichtbar“ machen. Diese Bedingungen sind vor allem durch den jeweiligen Kontext geprägt, welcher sich aus dem Ausmaß der Hilfestellungen, der Struktur der Anforderungen und der räumlichen und organisatorischen Gestaltung der Umgebung zusammensetzt. Menschen mit Fragilem-X-Syndrom dürfen nicht nur als Träger eines genetischen Syndroms angesehen werden, sondern auch als Mitglieder sozialer Gruppen und Gemeinschaften, an deren immanenten Regeln sie ihr Handeln ausrichten. Die institutionellen und sozialen Bedingungen auf der Ebene des Klassenraums mit seinen jeweiligen Teilnehmerinnen und Teilnehmern bilden die Grundlage für eine soziale Konstruktion des Fragilen-X- Syndroms in der Schule. Diese Annahme ist die Voraussetzung für einen Verstehensprozess, der das Syndrom nicht nur als Ursache einer Behinderung ansieht, sondern vielmehr die Handlungen und performativen Äußerungen der Schüler als individuellen, kompetenten Teil ihrer Kommunikation deutet. Das gegenseitige Verstehen führt dazu, dass die Bedingungen des Fragilen-X-Syndroms, der Verhaltensphänotyp des Schülers sowie die jeweilige soziale Umgebung, in einen angemessenen Kontext gesetzt werden können. Erst dadurch kann der Schulalltag erfolgreich gestaltet und ein Scheitern des Schülers minimiert werden. / This qualitative research project examines the everyday life of three boys with Fragile X syndrome in their special education classrooms. Fragile X syndrome is the leading inherited cause of intellectual disability and is associated with a specific behavioral phenotype and cognitive and physical characteristics. Utilizing ethnographic participant observation, the specific context in which the Fragile X syndrome becomes “visible” will be analyzed. This context is mainly shaped by the institutional and social conditions on the level of the classroom with its participants (peers and educators). Individuals with Fragile X syndrome need to be viewed not only as living under a genetic condition, but as members of social groups and communities who act in relation to socially and culturally ordered expectations. The understanding of the students’ performative acts as part of their communication abilities can initiate the understanding of the behavioral phenotype within its context. This understanding of Fragile X syndrome as a social category may lead to a successful organization of everyday school life.

L'objectif de ce projet est l’étude de la plasticité des circuits corticaux dans le contexte de l'apprentissage des souris « sauvages » et modèles du syndrome de l’X fragile. Des études sur l'efficacité de la combinaison d'enregistrement des potentiels de champ locaux extracellulaires avec la stimulation laser UV (LSPS) pour cartographier les réseaux ont été réalisées. Nous avons trouvé des enregistrements de champs extracellulaires qui pourraient être utilisés pour détecter les réponses synaptiques évoquées par LSPS. Nos résultats indiquent une méthode alternative pour obtenir des cartes complètes de réseaux intracorticaux excitateurs. Ensuite, nous avons développé un paradigme d'apprentissage associatif sensoriel et étudié ses effets sur les réseaux intracorticaux excitateurs du cortex baril. Ex vivo un affaiblissement des projections excitatrices entre les couches 4 et 2/3 qui dans les colonnes de vibrisses C a été observée. Enfin, nous avons utilisé ces mêmes approches dans une souris modèle du syndrome de l'X fragile (FXS). Pour étudier les liens entre les déficits sensoriels, l'apprentissage associatif et les altérations fonctionnelles des réseaux sensoriels, nous avons utilisé un modèle de souris mutantes dans lequel la pathologie FXS était ciblée sur la couche 4 du cortex somatosensoriel. Il a été constaté que les souris WT présentaient une dépression similaire, alors qu'elle était absente FXS. En conclusion, les études sur les mutants sensoriels de type sauvage ont mis en lumière les conséquences de l'apprentissage sur les réseaux corticaux sensoriels et les liens entre la plasticité des réseaux corticaux sensoriels et les capacités cognitives. / The aim of this project is to study the plasticity of the cortical circuits in the context of the learning of wild type mice and models of Fragile X Syndrome. First, investigations into the efficacy of recording combination of extracellular local field potentials with UV laser stimulation (LSPS) to map networks were performed. We found extracellular field records could be used to detect the synaptic responses evoked by LSPS. Our results indicate an alternative method for obtaining complete maps of excitatory intracortical networks. Next, we developed a sensory associative learning paradigm and studied its effects on excitatory intracortical networks the barrel cortex. Ex vivo a weakening of the excitatory projections between layers 4 and 2/3 which in the columns of vibrissae C was observed and declined function of the speed of the behavioural response. Finally, we used these same approaches in a Fragile X Syndrome (FXS) model mouse. To study the links between sensory deficits, associative learning, and functional alterations of sensory networks, we used a model of mutant mice in which the FXS pathology was targeted to the layer 4 of the somatosensory cortex. Our hypotheses were that behavioural conditioning would change the cortical sensory circuits of the FXS sensory mutant and that the abnormal plasticity of these circuits would in turn affect the performance. It was found the WT mice exhibited a similar depression, whereas it was absent FXS. In conclusion, wild type mouse and FXS sensory mutant studies shed light on the consequences of learning on sensory cortical networks and on the links between plasticity of sensory cortical networks and cognitive abilities.

<p><a></a><a>The visual system is capable of interpreting immense sensory complexity, allowing us to quickly identify behaviorally relevant stimuli in the environment. It performs this task with a hierarchical organization that works to detect, relay, and integrate visual stimulus features into an interpretable form. To understand the complexities of this system, visual neuroscientists have benefited from the many advantages of using mice as visual models. Despite their poor visual acuity, these animals possess surprisingly complex visual systems, and have been instrumental in understanding how visual features are processed in the primary visual cortex (V1). However, a growing body of literature has shown that primary sensory areas like V1 are capable of more than basic feature detection, but can express neural activity patterns related to learning, memory, categorization, and prediction. </a></p> <p>Visual experience fundamentally changes the encoding and perception of visual stimuli at many scales, and allows us to become familiar with environmental cues. However, the neural processes that govern visual familiarity are poorly understood. By exposing awake mice to repetitively presented visual stimuli over several days, we observed the emergence of low frequency oscillations in the primary visual cortex (V1). The oscillations emerged in population level responses known as visually evoked potentials (VEPs), as well as single-unit responses, and were not observed before the perceptual experience had occurred. They were also not evoked by novel visual stimuli, suggesting that they represent a new form of visual familiarity in the form of low frequency oscillations. The oscillations also required the muscarinic acetylcholine receptors (mAChRs) for their induction and expression, highlighting the importance of the cholinergic system in this learning and memory-based phenomenon. Ongoing visually evoked oscillations were also shown to increase the VEP amplitude of incoming visual stimuli if the stimuli were presented at the high excitability phase of the oscillations, demonstrating how neural activity with unique temporal dynamics can be used to influence visual processing.</p> <p>Given the necessity of perceptual experience for the strong expression of these oscillations and their dependence on the cholinergic system, it was clear we had discovered a phenomenon grounded in visual learning or memory. To further validate this, we characterized this response in a mouse model of Fragile X syndrome (FX), the most common inherited form of autism and a condition with known visual perceptual learning deficits. Using a multifaceted experimental approach, a number of neurophysiological differences were found in the oscillations displayed in FX mice. Extracellular recordings revealed shorter durations and lower power oscillatory activity in FX mice. Furthermore, we found that the frequency of peak oscillatory activity was significantly decreased in FX mice, demonstrating a unique temporal neural impairment not previously reported in FX. In collaboration with Dr. Christopher J. Quinn at Purdue, we performed functional connectivity analysis on the extracellularly recorded spikes from WT and FX mice. This analysis revealed significant impairments in functional connections from multiple layers in FX mice after the perceptual experience; some of which were validated by another graduate student (Qiuyu Wu) using Channelrhodopsin-2 assisted circuit mapping (CRACM). Together, these results shed new light on how visual stimulus familiarity is differentially encoded in FX via persistent oscillations, and allowed us to identify impairments in cross layer connectivity that may underlie these differences. </p> <p>Finally, we asked whether these oscillations are observable in other brain areas or are intrinsic to V1. Furthermore, we sought to determine if the oscillating unit populations in V1 possess uniform firing dynamics, or contribute differentially to the population level response. By performing paired recordings, we did not find prominent oscillatory activity in two visual thalamic nuclei (dLGN and LP) or a nonvisual area (RSC) connected to V1, suggesting the oscillations may not propagate with similar dynamics via cortico-thalamic connections or retrosplenial connections, <a>but may either be uniquely distributed across the visual hierarchy or predominantly</a> restricted to V1. Using K-means clustering on a large population of oscillating units in V1, we found unique temporal profiles of visually evoked responses, demonstrating distinct contributions of different unit sub-populations to the oscillation response dynamics.</p>