Les troubles du spectre autistique (TSA) sont des troubles neurodéveloppementaux fortement héritables. En parallèle, la théorie de l'hypoconnectivité fronto – postérieure semble être au coeur de la physiopathologie des TSA. Afin de comprendre la contribution des facteurs de risque familiaux de ce trouble, nous avons conduit conjointement une étude de connectivité anatomique et fonctionnelle chez des parents non atteints de sujets atteints de TSA. Nous avons réalisé une étude de tractographie en cerveau entier afin de comparer les valeurs de l'anisotropie fractionnelle généralisée le long des principaux faisceaux de substance blanche chez 85 sujets adultes : 39 parents non atteints, 18 sujets atteints de TSA comparés à 28 sujets contrôles. Après avoir corrigé pour les tests multiples, nous avons mis en évidence une diminution significative de l'anisotropie fractionnelle généralisée le long du faisceau fronto- occipital inférieur bilatéral chez les parents non atteints, les sujets atteints de TSA en comparaison aux sujets contrôles. Afin de comprendre l'implication fonctionnelle de la dysconnectivité anatomique fronto – occipitale retrouvée en tractographie, nous avons calculé la connectivité fonctionnelle entre les régions fronto – occipitales selon les extrémités du faisceau frontal - occipital inférieur bilatéral. En comparaison à 28 sujets contrôles, nous avons ainsi observé une augmentation significative de la connectivité fonctionnelle fronto - occipitale chez 38 parents non atteints et chez 13 sujets atteints de TSA. Une étude de connectivité fonctionnelle en cerveau entier serait une perspective prometteuse quant à l'interprétation de l'augmentation de la connectivité fronto – occipitale observée. Les anomalies fronto – occipitales montrées chez les parents non atteints, les sujets atteints de TSA pourraient correspondre à la mise en évidence d'un endophénotype dans les TSA. / Autism Spectrum Disorder (ASD) are neurodevelopmental disorders highly heritable.In parallel, the underconnectivity theory of ASD assumes that fronto-posterior brain disconnectivity is at the core of its pathophysiology. Our goal was to assess long-range structural and functional connectivity in unaffected parents of subjects with ASD to better understand the contributions of familial factors to heightened risk of ASD. We performed a diffusion weighted imaging (DWI) based whole brain tractography to compare generalized fractional anisotropy (gFA) in the main deep long white matter tracts in 85 adults: 39 unaffected parents, 18 probands compared to 28 controls. After corrections for multiple comparisons, we identified a significant decrease in gFA in the bilateral inferior frontal occipital fasciculus (IFOF) in both probands with ASD and unaffected parents when compared to controls. To understand the functional implication of fronto – occipital anatomical disconnectivity, we assessed the functional connectivity between the regions linked by IFOF exhibiting significant alterations in gFA. We also showed that both probands and unaffected parents exhibited a significantly increased functional connectivity between the frontal and occipital regions linked by the IFOF. In order to better understand and extend this interesting results, to evaluate the global functional connectivity of our sample in order to be able to interpret the increase of fronto-occipital functional connectivity would be an important perspective. These findings highlight an altered fronto-occipital connectivity in subjects with ASD and unaffected parents suggesting that fronto-occipital disconnectivity may be an endophenotype of ASD.

O transtorno bipolar (TB) é um transtorno grave, crônico e recorrente, e com um alto grau de prejuízo social e ocupacional. Pacientes com TB apresentam déficits em funções cognitivas como atenção, memória de trabalho verbal, funcionamento executivo. Estudos recentes têm sugerido que algumas dessas funções cognitivas podem ser candidatas a endofenótipos para o TB. Pacientes com TB também apresentam déficits na função cognitiva de reconhecimento de emoções faciais, mas o papel dessa função cognitiva como candidata a endofenótipo para o TB tem sido pouco estudado. O objetivo deste estudo foi avaliar a existência de déficits no reconhecimento de emoções em pacientes com TB e em seus parentes de primeiro grau quando comparados a um grupo de controles saudáveis. Foram estudados 23 pacientes com TB tipo I, 22 parentes de primeiro grau desses pacientes, e 27 controles saudáveis. Os instrumentos utilizados nas avaliações neuropsicológicas foram: Bateria de Reconhecimento de Emoções da Pennsylvannia (PENNCNP), e os subtestes de Vocabulário e Raciocínio Matricial da Escala Wechsler de Inteligência Abreviada (WASI). A partir dos dados obtidos, realizaram-se análise de variância (ANOVA) para variáveis que seguiam distribuição normal ou teste de Kruskal-Wallis para as demais. Os resultados mostraram que houve diferença estatisticamente significativa no número de respostas corretas para o reconhecimento de emoção tipo medo (p = 0,01) entre os três grupos. Pacientes com TB apresentaram menor número de respostas corretas para a emoção medo quando comparados a seus parentes e a controles saudáveis. Não houve diferença no reconhecimento de emoções faciais para tristeza, felicidade, raiva e neutra. Houve também uma diferença estatisticamente significativa entre os três grupos no tempo médio de resposta para a emoção do tipo felicidade (p = 0,00). Conclui-se assim que distúrbios no reconhecimento de emoções em faces podem não ser candidatos a endofenótipos para o TB tipo I / Bipolar disorder (BD) is a severe, chronic and recurrent disorder, and with a high degree of social and occupational impairment. TB patients have deficits in cognitive functions such as attention, verbal working memory, executive functioning. Recent studies have suggested that some of these cognitive functions may be candidate endophenotypes for TB. TB patients also have deficits in cognitive function of recognition of facial emotions, but the role that cognitive function as a candidate endophenotype for TB has been little studied. The aim of this study was to evaluate the existence of deficits in emotion recognition in patients with TB and their first-degree relatives when compared to a group of healthy controls. 23 patients with BD type I, 22 firstdegree relatives of these patients, and 27 healthy controls were studied. The instruments used in neuropsychological evaluations were: Battery Recognition of Emotions Pennsylvannia (PENNCNP), and subtests Vocabulary and Matrix Reasoning Scale of the Wechsler Abbreviated Intelligence (WAS ). From the data obtained, performed analysis of variance (ANOVA) for variables that followed a normal distribution or the Kruskal - Wallis test to the other. The results showed a statistically significant difference in the number of correct answers for the recognition of emotion fear (p = 0.01) between the three groups type. TB patients had a lower number of correct responses to the emotion fear when compared to their relatives and healthy controls. There was no difference in the recognition of facial emotions sadness, happiness, anger and neutral. There was also a statistically significant difference between groups in the average response time for the emotion of happiness type (p = 0.00). It follows therefore that disturbances in recognizing emotions in faces may not be Candidates for endophenotypes for BD type I

Os fatores genéticos e hereditários têm ganhado um foco especial como causa da dislexia, entretanto, há muito a ser estudado na busca de sua etiologia. Há vasta literatura associando o processamento fonológico ao aprendizado da leitura e escrita, porém pouco é investigado sobre a participação do processamento visual nas habilidades de leitura. Atualmente, a relação entre processamento fonológico e matemática tem sido apontada nas publicações científicas, sendo ainda pouco estudada, havendo necessidade de melhor compreensão entre a relação dessas habilidades, bem como as comorbidades entre dislexia e problemas na matemática. Este estudo teve como objetivo geral descrever o perfil endofenótipo dos sujeitos com dislexia referente à hereditariedade e influência do processamento fonológico e memória sequencial visual nas dificuldades da linguagem escrita e na matemática, no intuito de identificar semelhanças e diferenças no processamento da informação escrita entre indivíduos com dislexia e bons leitores. Participaram 35 indivíduos com o diagnóstico de dislexia e 46 bons leitores, de 8 a 13 anos e ambos os sexos. Nos dois grupos foram avaliadas as habilidades do processamento fonológico (consciência fonológica, acesso ao léxico e memória de trabalho fonológica), leitura de palavras, pseudopalavras, compreensão de texto, escrita e habilidades matemáticas. As habilidades do processamento fonológico e memória visual foram correlacionadas com a leitura, escrita e matemática nos dois grupos. Foi utilizado o Teste de Correlação de Pearson para correlacionar tais habilidades, e o Teste Qui-Quadrado e Teste U de Mann-Whitney para comparar o desempenho entre os grupos, adotando-se nível de significância de 5%. Encontrou-se que o histórico familial de problemas de aprendizagem esteve presente em mais da metade do grupo com dislexia, demonstrando que este é um importante fator de risco. Os indivíduos com dislexia apresentam pior desempenho no processamento fonológico, porém houve um pequeno número de disléxicos que não apresentou alterações na consciência fonológica e no acesso ao léxico. Em relação à memória de trabalho fonológica, os indivíduos com dislexia apresentaram pior desempenho, no entanto, quase metade dos bons leitores também apresentaram esta habilidade alterada. A maioria dos disléxicos apresentou o perfil de alteração nas três habilidades do processamento fonológico e um pequeno grupo apresentou a consciência fonológica e o acesso ao léxico preservado. Não houve diferenças significantes entre os grupos quanto à memória visual. Grande parte dos disléxicos apresentou dificuldades em habilidades matemáticas, o que foi encontrado em um pequeno grupo de bons leitores. Este estudo encontrou comorbidade entre dislexia e dificuldades matemáticas em 83% dos casos, sendo esta uma prevalência acima do que é descrito na literatura. As trocas ortográficas do tipo substituição de letras que representam fonemas surdos e sonoros e inversões parece ser um perfil da ortografia dos disléxicos. As habilidades de consciência fonológica, acesso ao léxico e memória de trabalho fonológica mostraram maior correlação na leitura e na escrita no grupo com dislexia, sugerindo que o processamento fonológico passa a ter menor participação na leitura e na escrita na medida em que os indivíduos se tornam leitores fluentes. A memória visual correlaciona-se com a matemática nos dois grupos. / Genetic and hereditarity factors have gained a special focus as the cause of dyslexia, however, there is much to be studied in the search for its etiology. There is extensive literature linking phonological processing to reading and writing learning, but the participation of visual processing in reading skills is little investigated. Currently, the relationship between phonological processing and mathematics has been identified in scientific publications, but still scarcely studied, there is need for better understanding the relationship between these skills as well as the comorbidities between dyslexia and problems in mathematics. This study aimed to describe the endophenotype profile of the subjects with dyslexia related to hereditarity and influence of phonological processing and visual sequential memory difficulties in written language and mathematics, in order to identify similarities and differences in written information processing between individuals with dyslexia and good readers. Participated in the study 35 diagnosed with dyslexia and 46 good readers, from 8 to 13 years old, both genders. Both groups were assessed the phonological processing skills (phonological awareness, lexical access and phonological working memory), words and pseudo words reading, reading comprehension, writing and math skills. The skills of phonological processing and visual memory were correlated with reading, writing and math in both groups. It was used the Pearson\'s Correlation Test to correlate these skills, and the Chi-square Test and Mann-Whitney Test to compare the performance between the groups, adopting a significance level of 5%. Family history of learning problems was present in more than half of the group with dyslexia, demonstrating that this is an important risk factor. Individuals with dyslexia performed worse in the phonological processing, but there was a small number of dyslexics that showed no alterations in phonological awareness and lexicon access. Regarding phonological working memory, individuals with dyslexia presented worse performance, however, nearly half of good readers also had this ability altered. Most dyslexics presented the profile of alterations in the three phonological processing skills and a small group presented phonological awareness and lexicon access preserved. There were no significant differences between groups as regards the visual memory. Much of dyslexics had difficulties in math skills, which were found in a small group of good readers. This study found comorbidity between dyslexia and mathematical difficulties in 83% of cases, which is a prevalence higher than what is described in the literature. Spelling exchanges like replacing letters that represent voiced and unvoiced phonemes and inversions appears to be a profile of the spelling of dyslexic. The phonological awareness skills, lexical access and phonological working memory showed higher correlation in reading and writing in the group with dyslexia, suggesting that phonological processing is replaced by lower participation in reading and writing insofar as individuals become fluent readers. The visual memory correlates with mathematics in both groups.

No description available.

Os fatores genéticos e hereditários têm ganhado um foco especial como causa da dislexia, entretanto, há muito a ser estudado na busca de sua etiologia. Há vasta literatura associando o processamento fonológico ao aprendizado da leitura e escrita, porém pouco é investigado sobre a participação do processamento visual nas habilidades de leitura. Atualmente, a relação entre processamento fonológico e matemática tem sido apontada nas publicações científicas, sendo ainda pouco estudada, havendo necessidade de melhor compreensão entre a relação dessas habilidades, bem como as comorbidades entre dislexia e problemas na matemática. Este estudo teve como objetivo geral descrever o perfil endofenótipo dos sujeitos com dislexia referente à hereditariedade e influência do processamento fonológico e memória sequencial visual nas dificuldades da linguagem escrita e na matemática, no intuito de identificar semelhanças e diferenças no processamento da informação escrita entre indivíduos com dislexia e bons leitores. Participaram 35 indivíduos com o diagnóstico de dislexia e 46 bons leitores, de 8 a 13 anos e ambos os sexos. Nos dois grupos foram avaliadas as habilidades do processamento fonológico (consciência fonológica, acesso ao léxico e memória de trabalho fonológica), leitura de palavras, pseudopalavras, compreensão de texto, escrita e habilidades matemáticas. As habilidades do processamento fonológico e memória visual foram correlacionadas com a leitura, escrita e matemática nos dois grupos. Foi utilizado o Teste de Correlação de Pearson para correlacionar tais habilidades, e o Teste Qui-Quadrado e Teste U de Mann-Whitney para comparar o desempenho entre os grupos, adotando-se nível de significância de 5%. Encontrou-se que o histórico familial de problemas de aprendizagem esteve presente em mais da metade do grupo com dislexia, demonstrando que este é um importante fator de risco. Os indivíduos com dislexia apresentam pior desempenho no processamento fonológico, porém houve um pequeno número de disléxicos que não apresentou alterações na consciência fonológica e no acesso ao léxico. Em relação à memória de trabalho fonológica, os indivíduos com dislexia apresentaram pior desempenho, no entanto, quase metade dos bons leitores também apresentaram esta habilidade alterada. A maioria dos disléxicos apresentou o perfil de alteração nas três habilidades do processamento fonológico e um pequeno grupo apresentou a consciência fonológica e o acesso ao léxico preservado. Não houve diferenças significantes entre os grupos quanto à memória visual. Grande parte dos disléxicos apresentou dificuldades em habilidades matemáticas, o que foi encontrado em um pequeno grupo de bons leitores. Este estudo encontrou comorbidade entre dislexia e dificuldades matemáticas em 83% dos casos, sendo esta uma prevalência acima do que é descrito na literatura. As trocas ortográficas do tipo substituição de letras que representam fonemas surdos e sonoros e inversões parece ser um perfil da ortografia dos disléxicos. As habilidades de consciência fonológica, acesso ao léxico e memória de trabalho fonológica mostraram maior correlação na leitura e na escrita no grupo com dislexia, sugerindo que o processamento fonológico passa a ter menor participação na leitura e na escrita na medida em que os indivíduos se tornam leitores fluentes. A memória visual correlaciona-se com a matemática nos dois grupos. / Genetic and hereditarity factors have gained a special focus as the cause of dyslexia, however, there is much to be studied in the search for its etiology. There is extensive literature linking phonological processing to reading and writing learning, but the participation of visual processing in reading skills is little investigated. Currently, the relationship between phonological processing and mathematics has been identified in scientific publications, but still scarcely studied, there is need for better understanding the relationship between these skills as well as the comorbidities between dyslexia and problems in mathematics. This study aimed to describe the endophenotype profile of the subjects with dyslexia related to hereditarity and influence of phonological processing and visual sequential memory difficulties in written language and mathematics, in order to identify similarities and differences in written information processing between individuals with dyslexia and good readers. Participated in the study 35 diagnosed with dyslexia and 46 good readers, from 8 to 13 years old, both genders. Both groups were assessed the phonological processing skills (phonological awareness, lexical access and phonological working memory), words and pseudo words reading, reading comprehension, writing and math skills. The skills of phonological processing and visual memory were correlated with reading, writing and math in both groups. It was used the Pearson\'s Correlation Test to correlate these skills, and the Chi-square Test and Mann-Whitney Test to compare the performance between the groups, adopting a significance level of 5%. Family history of learning problems was present in more than half of the group with dyslexia, demonstrating that this is an important risk factor. Individuals with dyslexia performed worse in the phonological processing, but there was a small number of dyslexics that showed no alterations in phonological awareness and lexicon access. Regarding phonological working memory, individuals with dyslexia presented worse performance, however, nearly half of good readers also had this ability altered. Most dyslexics presented the profile of alterations in the three phonological processing skills and a small group presented phonological awareness and lexicon access preserved. There were no significant differences between groups as regards the visual memory. Much of dyslexics had difficulties in math skills, which were found in a small group of good readers. This study found comorbidity between dyslexia and mathematical difficulties in 83% of cases, which is a prevalence higher than what is described in the literature. Spelling exchanges like replacing letters that represent voiced and unvoiced phonemes and inversions appears to be a profile of the spelling of dyslexic. The phonological awareness skills, lexical access and phonological working memory showed higher correlation in reading and writing in the group with dyslexia, suggesting that phonological processing is replaced by lower participation in reading and writing insofar as individuals become fluent readers. The visual memory correlates with mathematics in both groups.

O transtorno bipolar (TB) é um transtorno grave, crônico e recorrente, e com um alto grau de prejuízo social e ocupacional. Pacientes com TB apresentam déficits em funções cognitivas como atenção, memória de trabalho verbal, funcionamento executivo. Estudos recentes têm sugerido que algumas dessas funções cognitivas podem ser candidatas a endofenótipos para o TB. Pacientes com TB também apresentam déficits na função cognitiva de reconhecimento de emoções faciais, mas o papel dessa função cognitiva como candidata a endofenótipo para o TB tem sido pouco estudado. O objetivo deste estudo foi avaliar a existência de déficits no reconhecimento de emoções em pacientes com TB e em seus parentes de primeiro grau quando comparados a um grupo de controles saudáveis. Foram estudados 23 pacientes com TB tipo I, 22 parentes de primeiro grau desses pacientes, e 27 controles saudáveis. Os instrumentos utilizados nas avaliações neuropsicológicas foram: Bateria de Reconhecimento de Emoções da Pennsylvannia (PENNCNP), e os subtestes de Vocabulário e Raciocínio Matricial da Escala Wechsler de Inteligência Abreviada (WASI). A partir dos dados obtidos, realizaram-se análise de variância (ANOVA) para variáveis que seguiam distribuição normal ou teste de Kruskal-Wallis para as demais. Os resultados mostraram que houve diferença estatisticamente significativa no número de respostas corretas para o reconhecimento de emoção tipo medo (p = 0,01) entre os três grupos. Pacientes com TB apresentaram menor número de respostas corretas para a emoção medo quando comparados a seus parentes e a controles saudáveis. Não houve diferença no reconhecimento de emoções faciais para tristeza, felicidade, raiva e neutra. Houve também uma diferença estatisticamente significativa entre os três grupos no tempo médio de resposta para a emoção do tipo felicidade (p = 0,00). Conclui-se assim que distúrbios no reconhecimento de emoções em faces podem não ser candidatos a endofenótipos para o TB tipo I / Bipolar disorder (BD) is a severe, chronic and recurrent disorder, and with a high degree of social and occupational impairment. TB patients have deficits in cognitive functions such as attention, verbal working memory, executive functioning. Recent studies have suggested that some of these cognitive functions may be candidate endophenotypes for TB. TB patients also have deficits in cognitive function of recognition of facial emotions, but the role that cognitive function as a candidate endophenotype for TB has been little studied. The aim of this study was to evaluate the existence of deficits in emotion recognition in patients with TB and their first-degree relatives when compared to a group of healthy controls. 23 patients with BD type I, 22 firstdegree relatives of these patients, and 27 healthy controls were studied. The instruments used in neuropsychological evaluations were: Battery Recognition of Emotions Pennsylvannia (PENNCNP), and subtests Vocabulary and Matrix Reasoning Scale of the Wechsler Abbreviated Intelligence (WAS ). From the data obtained, performed analysis of variance (ANOVA) for variables that followed a normal distribution or the Kruskal - Wallis test to the other. The results showed a statistically significant difference in the number of correct answers for the recognition of emotion fear (p = 0.01) between the three groups type. TB patients had a lower number of correct responses to the emotion fear when compared to their relatives and healthy controls. There was no difference in the recognition of facial emotions sadness, happiness, anger and neutral. There was also a statistically significant difference between groups in the average response time for the emotion of happiness type (p = 0.00). It follows therefore that disturbances in recognizing emotions in faces may not be Candidates for endophenotypes for BD type I

Autism spectrum disorder (ASD) is a highly heritable neurodevelopmental disorder associated with altered neural connectivity and deficits in self-monitoring, response inhibition, and planning. One promising avenue of research to improve understanding of the symptoms and heritable nature of ASD may be the identification of neural endophenotypes of ASD. The error-related negativity (ERN) and post-error positivity (Pe), scalp-recorded event-related potentials (ERPs), reflect performance monitoring processes and may qualify as candidate endophenotypes of ASD. We collected ERP and behavioral data (error rates, response times) from 18 ASD probands and their families (mother, father, sibling) and 38 control youth and their parents to examine the utility of the ERN and Pe as endophenotypes of ASD. In order to examine differences based on group (ASD vs. control) and kinship (proband, sibling, mother, father), we conducted separate multiple regression analyses on behavioral and ERP data with group and kinship as predictors and families as clusters. We hypothesized that ASD probands would display reduced-amplitude ERN and impaired behavioral performance relative to control youth but no differences in Pe amplitude and that families of ASD probands would display reduced error minus correct (ΔERN) amplitudes and impaired behavioral performance relative to control families but no differences in ΔPe amplitude. We did not observe significant ERN amplitude group differences among ASD probands relative to control youth. Likewise, control youth did not differ from ASD probands on behavioral measures or Pe amplitudes. Analyses by family revealed that group and kinship did not significantly predict ΔERN amplitudes. However, fathers of ASD probands displayed significantly reduced ΔPe amplitudes relative to control fathers and parents displayed significantly larger ΔPe amplitudes and better performance than youth. Together, results do not provide sufficient evidence to support the ERN or Pe as an endophenotype or biomarker of ASD. These findings add to an overall heterogeneous literature on performance monitoring in ASD and point to the need for additional research to understand the state-related or trait-related factors that may contribute to ERN amplitudes in ASD.

La schizophrénie, pathologie sévère et fréquente, regroupe des entités différentes au sein desquelles la schizophrénie déficitaire a été identifiée. C’est une entité clinique homogène caractérisée par des symptômes négatifs primaires et durables. Une des principales difficultés de la recherche dans la schizophrénie est la mauvaise corrélation entre le phénotype clinique et le génotype. Les nouvelles approches cherchent à identifier des endophénotypes pertinents permettant de déterminer un sous groupe homogène de la schizophrénie. L’objectif de cette thèse était de déterminer les marqueurs de vulnérabilité les plus pertinents pour la schizophrénie : (1) caractériser les anomalies électrophysiologiques dans la schizophrénie, (2) rechercher les perturbations spécifiques des mouvements oculaires dans la schizophrénie déficitaire, (3) mesurer les performances attentionnelles et exécutives, puis identifier des associations entre ces dernières et 6 polymorphismes des gènes COMT et DRD2. Les patients répondant aux critères DSM-IV de la schizophrénie ont été sélectionnés. Ils sont cliniquement stables depuis au moins 28 jours et ne prennent aucun traitement pouvant altérer les mouvements oculaires. Les patients ont été évalués à l’aide de la traduction française de l’échelle de déficit de Kirkpatrick, la PANSS, l’ESRS et le WCST. Les apparentés sains ont passé la version française de la SADS-LA. Les volontaires sains, recrutés dans la population générale, ont passé la Diagnostic Interview Schedule et le WCST. Les mouvements oculaires de l’ensemble des sujets ont été détectés par réflectométrie infrarouge et analysés sur un ordinateur par le logiciel SAMO. Les paradigmes utilisés sont : la poursuite oculaire sinusoïdale, la poursuite oculaire non prédictive, les saccades et les antisaccades. L’onde P50 des potentiels évoqués auditifs a également été étudiée. Nous avons trouvé chez les schizophrènes et dans une moindre mesure chez leurs apparentés une diminution du gain lors de la poursuite oculaire : la dégradation de la prédiction est à l’origine de l’altération des performances de la poursuite oculaire dans la schizophrénie. Chez les patients comparativement aux volontaires sains, une diminution du nombre d’antisaccades réussies et une augmentation de leur latence ont été mises en évidence. Cette dernière est plus importante chez les apparentés sains par rapport aux volontaires sains. L’augmentation de la latence des antisaccades réussies est plus importante chez les schizophrènes déficitaires par rapport aux non déficitaires et elle y est corrélée au nombre d’erreurs persévératives du WCST. Le ratio T/C de l’onde P50 est significativement plus élevé chez les patients comparativement aux volontaires sains. Pour tous les sujets, l’attention a été évaluée à l’aide du test de Stroop Color-Word et du test des réseaux attentionnels ANT. Le fonctionnement exécutif a été étudié avec le test du Wisconsin. Les patients porteurs du génotype de vulnérabilité TT de rs6275 en DRD2 et ceux porteurs du génotype de vulnérabilité CC de rs2242592 en DRD2, ont des performances significativement plus faibles au Stroop-WC par rapport aux non porteurs. Les patients de génotype Val/Val (COMT) font plus d’erreurs persévératives que les patients porteurs de l’allèle Met. Pour rs165599 (COMT), les patients porteurs de l’allèle de vulnérabilité G font plus d’erreurs persévératives que les patients porteurs du génotype AA. La pathologie schizophrénique et des facteurs génétiques interagissent sur le contrôle exécutif de l’attention, principalement sur le Stroop Color-Word et légèrement sur l’ANT. Les polymorphismes du DRD2, rs6275 et rs2242592, augmentent le conflit, tandis que ceux de la COMT n’auraient pas d’action. Concernant le fonctionnement exécutif, l’allèle G de la COMT et la pathologie schizophrénique interagissent ensemble. (...) / Schizophrenia is a complex disorder where the deficit syndrome has been identified as the presence of primary, enduring negative symptoms such as restricted affect, diminished emotional range, poverty of speech, curbing of interest, diminished sense of purpose, diminished social drive. The deficit syndrome is associated with specific neurological and neuropsychological impairments, biochemical characteristics, attentional impairments, structural and functional brain abnormalities. The identification of intermediate phenotypes associated with schizophrenia may improve understanding of the neurobiology of the disease and contribute to the genetic dissection of this disease. Endophenotypes would also be useful for establishing a biological underpinning for diagnosis and classification of schizophrenia. The aim of this work was to determine the most relevant vulnerability markers of schizophrenia: (1) describe electrophysiological abnormalities in schizophrenia, (2) specify eye movements impairments in deficit schizophrenia, (3) assess attentional, executive function and analyze their association with four SNPs in the DRD2/ANKK1 locus (rs6275, rs6277, rs2242592 and rs1800497) and two SNPs in the COMT gene (rs4680 and rs165599). Patients meeting DSM IV criteria for schizophrenia were recruited. They were clinically stabilized for a minimum of 28 days with no change in neuroleptic dose at the time of their participation in the study. None of them was treated with drugs known to affect eye movements. The patients were subtyped into deficit and nondeficit subgroups, using the french translation of the Schedule for the Deficit Syndrome. Patients were also assessed using PANSS, ESRS and WCST. Healthy parents of patients were interviewed using the french translation of the SADS-LA. The unrelated healthy controls (no personal or family history of neurological or psychiatric disease, free of any psychotropic treatment) were recruited from the hospital staff and screened by the Diagnostic Interview Schedule and the WCST. Horizontal eye movements were recorded by an infrared photoelectric limbus eye tracking device. Subjects were tested in five tasks: smooth pursuit, unpredictable pursuit, P50 eventrelated potential, reflexive saccades and antisaccades. Schizophrenia patients and parents had a high prevalence of eye tracking dysfunction: the impaired predictive mechanisms were involved. Both groups showed a high rate of inhibitory deficits measured by the P50 event-related potential and antisaccade paradigms. The latency of successful antisaccades was significantly increased in deficit patients as compared with non-deficit patients and healthy controls. In deficit patients only, we found a significant correlation between the latency of successful antisaccades and the WCST perseverative errors. Patients and healthy controls have performed the Stroop Color-Word Test, the Attention Network Test, and the Wisconsin Card Sorting Test to assess attention and executive functions. Patients with schizophrenia performed significantly worse than controls in all cognitive performance. The TT genotype of rs6275 and CC genotype of rs22422592 were associated with a marked deterioration of selective attention (Stroop Color-Word) and this effect is more important in participants with schizophrenia. We showed an interaction between schizophrenia and the genetic effect of rs6275 and rs22422592 on Stroop-PI, but the effect of the disease appears to be more prominent. The COMT Val/Val genotype and schizophrenia were associated with increased number of perseverative errors. Schizophrenia and genetics interact on the executive control of attention, mostly on Stroop-PI and slightly on ANT. Rs6275 and rs2242592 of the DRD2 increased the conflict while COMT SNPs do not. Regarding executive cognition, the COMT and schizophrenia also interact. (...)

Einleitung: Tiermodelle spielen für die Aufklärung pathophysiologischer Mechanismen und die Entwicklung erfolgsversprechender Therapieoptionen zentralnervöser Bewegungsstörungen eine unverzichtbare Rolle. Die Identifizierung von Gendefekten für die Parkinson-Krankheit und Dystonien ermöglichte die Generierung von Tiermodellen mit einer hohen „construct validity“. Weibliche transgene Thy1-aSyn Mäuse sowie DYT1 Knock-in (KI) Mäuse zeigen jedoch keine motorischen Störungen. In der vorliegenden Arbeit sollten zur Aufdeckung sensomotorischer Beeinträchtigungen, die bei Parkinson- und Dystoniepatienten beobachtet werden, detaillierte Untersuchungen des Verhaltens an diesen beiden Mausmodellen durchgeführt werden. Zielstellung: Zunächst sollte ein sensitiver Verhaltenstest konstruiert und entwickelt werden, bei dem sich ändernde sensorische Stimuli während der Ausübung der motorischen Aufgabe impliziert werden. Bei der Etablierung dieses sogenannten „adaptiven rotierenden Balkentests“ (ARB-Test) sollte auch der Einfluss des genetischen Hintergrunds bei Wildtyp-Mäusen evaluiert werden. Daraufhin sollte überprüft werden, ob dieser Test den Endophänotyp der weiblichen Thy1-aSyn Mäuse aufdecken kann. In dem DYT1 KI Mausmodell sollte der Frage nachgegangen werden, ob die Tiere Verhaltensdefizite in spezifischen Tests zeigen, die sensomotorische Verschaltungen untersuchen. Material und Methoden: Die mRNA-Expression von α-Synuclein in der Substantia nigra bei männlichen und weiblichen Thy1-aSyn Mäusen wurde mithilfe der quantitativen Echtzeit-PCR (qPCR) ermittelt. Im Anschluss an die Entwicklung des neuen Verhaltensapparates für den ARB-Test wurden Thy1-aSyn Tiere beider Geschlechter in diesem Versuch getestet und ihre Leistung den Ergebnissen auf etablierten motorischen Verhaltenstests („challenging beam test“, „pole test“) gegenübergestellt. Um den Einfluss des Hintergrundstammes auf das Verhalten der Tiere auf dem ARB-Test zu untersuchen, wurden Wildtypen der reinen C57BL/6J-Linie sowie Hybrid-Tiere des Stammes C57Bl/6J × DBA2 (BDF1) allen drei o. g. Versuchen unterzogen. Bei den Mäusen des DYT1 KI Modells wurde der „adhesive removal test“ und der ARB-Test zur Analyse der Sensomotorik durchgeführt. Im Vergleich dazu wurden vielfältige Verhaltensparameter in einer Reihe vorwiegend motorischer (Offenfeld-Test, „challenging beam test“, „pole test“, Zylinder-Test, Block-Test, Nestbau-Test) und kognitiver („y-maze test“) Verhaltenstests ausgewertet. Ergebnisse: Bei den weiblichen Thy1-aSyn Mäusen wurde eine geringere Expression des Transgens im Vergleich zu den männlichen Tieren festgestellt. Der neue ARB-Test wurde erfolgreich etabliert und konnte signifikante Verhaltensdefizite der weiblichen und männlichen Mutanten des Parkinson-Modells im Vergleich zu den Kontrolltieren aufdecken. Der genetische Hintergrund beeinflusste die Leistung der Wildtypen auf diesem Balkentest. Während die DYT1 KI Tiere in den rein motorischen und kognitiven Versuchen keine Beeinträchtigungen des Verhaltens zeigten, konnten der „adhesive removal test“ sowie der neue ARB-Test signifikante sensomotorische Defizite der KI Mäuse im Unterschied zu den Wildtypen zum Vorschein bringen. Schlussfolgerung: Im Thy1-aSyn Mausmodell konnte die Bedeutung der sensomotorischen Integration für die Ausprägung motorischer Defizite sowie für eine mögliche Kompensation solcher motorischen Beeinträchtigungen demonstriert werden. Hierfür hat sich der neu entwickelte, sensitive ARB-Test als geeignet herausgestellt. Die Aufdeckung von Beeinträchtigungen der Sensomotorik spricht auch bei den DYT1 KI Tieren für den Einfluss einer gestörten sensomotorischen Integration bei der Ausprägung der Symptomatik. Damit eignet sich dieses Mausmodell für die Untersuchung weiterer Parameter, die Auswirkungen auf die Aufdeckung des Phänotyps und die Penetranz der Erkrankung haben sowie um die zugrunde liegenden pathophysiologischen Mechanismen zu erforschen.

Only 200 years ago, virtually nothing was known about the biological workings of the mind. Today, there is a deep (though far from complete) understanding of the cellular and molecular mechanisms underlying the encoding of memory, arguably the most fundamental aspect of a cognitive being. In this thesis, I describe experiments that help complete this understanding and identify the very first molecules underlying curiosity. By using an inducible rtTA2-M2 double transgenic system to selectively overexpress the calcium sensor Ncs1 in the adult murine dentate gyrus, I created an animal with facilitated long-term potentiation, enhanced rapid acquisition of spatial memory and greater curiosity. These phenotypes are reversed by direct infusion of a small membrane-permeant interfering peptide designed to block complex formation between NCS-1 and Dopamine type-2 receptors (D2 receptors). Pharmacological antagonism of D2 receptors also attenuates plasticity in wild-type mice and direct antagonism of D2 receptors in the dentate of cannulized wild-type mice prevents spatial memory formation. Conversely, application of a dominant negative NCS-1 peptide reduces synaptic transmission in the dentate gyrus and impairs spatial fear learning. Far less understood than the mechanisms governing learning and memory, are the mechanisms used by the brain to generate curiosity. Strikingly, Ncs1 overexpressing mice also demonstrate increased exploratory behaviours in a variety of novel, non-fearful environments. But they do not explore novel fearful environments any more than their littermate controls. I argue that the specificity of this phenotype represents an effect on curiosity, thereby identifying NCS-1 and D2 receptors as the first known regulators of this primordial mental state. I propose that the generation of curiosity is a fundamental feature of the nervous system and is upstream of learning and cognition. As such, molecular cascades involved in curiosity likely also play roles in mental illnesses. To investigate this theory, I generated an NCS-1 point mutant mouse line. NCS-1P144S/P144S mice show endophenotypes of schizophrenia and depression, supporting the link between curiosity and mental illness. I integrate my findings with the current literature and propose a means to investigate the role of NCS-1 in humans with mental illnesses.