Compreender as bases do comportamento social e do desenvolvimento socioafetivo humano é essencial tanto para indivíduos com desenvolvimento típico (DT) quanto com transtornos neuropsiquiátricos. A Síndrome de Williams (SW) é uma condição neurogenética rara ocasionada pela deleção de aproximadamente 28 genes no cromossomo 7q11.23. A sintomatologia inclui desde dismorfismos faciais a alterações do funcionamento cognitivo e socioafetivo, com a presença de deficiência intelectual de grau leve a moderado. O processamento de estímulos afetivos tem sido foco de grande interesse em indivíduos com SW. Apesar de parte das pesquisas apontarem que esta população tem habilidade preservada de reconhecimento de expressões facias de emoções positivas e prejuízos no reconhecimento de emoções negativas, este ainda não é um campo consensual. Ao mesmo tempo, estudos indicam maior interesse desta população em relação a música e diferenças no neuroprocessamento de trechos musicais com valência afetiva. O presente trabalho teve por objetivo caracterizar o processamento de estímulos afetivos musicais e visuais em crianças e adolescentes com Síndrome de Williams. O Estudo I buscou validar trechos musicais com valência afetiva em cultura brasileira e analisar o efeito do treino musical na compreensão de emoções em música. Músicas com valência afetiva foram avaliadas pelos participantes de maneira correspondente à emoção pretendida pelo compositor e de forma similar entre as populações brasileiras e canadenses. O efeito do treino musical sobre a habilidade de reconhecer as emoções em música tiveram maior impacto em emoções com maior grau de dificuldade para os participantes como todo. O Estudo II visou caracterizar o perfil musical de crianças e adolescentes com SW e diferenciar o processamento de estímulos afetivos musicais em crianças e adolescentes com SW com as de DT. Pessoas com SW foram avaliadas com maior habilidade musical global. Não foram encontradas diferenças no que diz respeito ao interesse por atividades musicais. O Estudo III teve como objetivos diferenciar habilidade de reconhecimento de emoções o padrão de rastreamento do olhar frente a estímulos afetivos visuais em crianças e adolescentes com SW e SW com sintomas de TEA (SW/TEA). Pessoas com SW desprenderam maior tempo de fixação nos olhos e em faces alegres quando comparadas a faces tristes. Resultados indicam diferença no reconhecimento de emoções e rastreamento de olhar em indivíduos com SW/TEA. Padrão de reconhecimento em estímulos musicais e visuais foi semelhante na população SW, com acentuado prejuízo no reconhecimento de emoções negativas e preservação do reconhecimento de emoções positivas. Este achado reforça a modularidade do processamento neurológico das emoções básicas. Crianças com SW reconheceram mais facilmente estímulos musicais de valência positiva em comparação aos visuais sugerindo que o domínio da música seja um ponto de força desta população / Understand the foundation of social behavior and human social and affective development is essential for both individuals with typical developmental (TD) and neuropsychiatric disorders. Williams Syndrome (WS) is a rare neurogenetic condition caused by the deletion of approximately 28 genes on chromosome 7q11.23. The symptomatology includes from facial dysmorphisms to changes in cognitive and social and affective functioning, with the presence of mild to moderate intellectual deficiency. The processing of affective stimuli has been a focus of great interest in individuals with WS. Although part of the research indicates that this population has preserved ability to recognize face expressions of positive emotions and impairment in the recognition of negative emotions, this is not yet a consensual field. At the same time, studies indicate greater interest of this population in relation to music and differences in the neuroprocessing of musical excerpts with affective valence. The present work aimed to characterize the processing of musical and visual affective stimuli in children and adolescents with Williams Syndrome. Study I sought to validate musical excerpts with affective valence in Brazilian culture and to analyze the effect of musical training on the understanding of emotions in music. Songs with affective valence were evaluated by the participants corresponding to the emotion pretended by the composer and similarly between the Brazilian and Canadian populations. The effect of musical training on the ability to recognize emotions in music has had a greater impact on emotions with a greater degree of difficulty for participants as a whole. Study II aimed to characterize the musical profile of children and adolescents with WS and to differentiate the processing of musical affective stimuli in children and adolescents with WS compered to TD. People with WS were assessed with greater overall musical ability. No differences were found regarding the interest in musical activities. The aim of Study III was to differentiate between the ability to recognize emotions and the pattern of eye tracking in relation to visual affective stimuli in children and adolescents with SW and WS with ASD symptoms. People with SW gave more fixation time to the eyes and happy faces when compared to sad faces. Results indicate difference in the recognition of emotions and eye tracking in individuals with SW / ASD. Recognition pattern in musical and visual stimuli was similar in the WS population, with marked impairment in the recognition of negative emotions and preservation of the recognition of positive emotions. This finding reinforces the modularity of neurological processing of basic emotions. Children with WS recognized easily positive musical stimuli compared to visual ones suggesting that the domain of music is the strength of this population

The development of the central nervous system is dysregulated in neurodevelopmental disorders such as intellectual disability, autism spectrum disorder, and epilepsy. These three disorders have different clinical features, yet there is high comorbidity between them. They can be difficult to study due to their highly complex aetiologies, however there are various monogenic diseases that can cause all of them, including SYNGAP1 haploinsufficiency where the synaptic guanosine triphosphatase (GTPase)-activating protein (SYNGAP) protein levels are highly reduced; Fragile X syndrome where the fragile X mental retardation protein (FMRP) is no longer translated; and DNM1 epileptic encephalopathy where mutations in the Dynamin1 gene alter the protein function. These monogenic conditions are synaptopathies as the proteins affected play important roles in synapse stability and neurotransmission. Because of the high comorbidity between these disorders, it is hypothesised that there may be a common mechanism underlying them. We hypothesise that a deficit in presynaptic vesicle recycling may be part of a common mechanism underlying intellectual disability, autism spectrum disorder, and epilepsy especially in SYNGAP1 haploinsufficiency, Fragile X syndrome, and DNM1 epileptic encephalopathy. Using various fluorescent presynaptic activity reporters including synaptic pHluorins, tetramethylrhodamine dextran and calcium dyes to compare presynaptic activity in in vitro models of these monogenic conditions, we found differences in synaptic vesicle (SV) endocytosis in the genetically altered conditions compared to wildtype controls. We observed various SV endocytosis defects in clathrin-mediated endocytosis (CME) or activity-dependent bulk endocytosis (ADBE) in our models. We observed enhanced CME in SynGAP1 KO mouse hippocampal neurons. This enhanced SV endocytosis was accompanied by decreased SV cargo on the plasma membrane. Rat SynGAP1 KO hippocampal neurons did not display enhanced SV endocytosis, nor did neurons with the GTPase-activating (GAP) domain of SynGAP deleted. This was perhaps due to the altered time course of development between these rodent species. In mouse and rat models of Fragile X syndrome, CME was not altered compared to wildtype controls. However, in a rat model, we observed fewer nerve terminals undergoing ADBE which is the dominant SV endocytosis mode during elevated neuronal activity. De novo epileptic encephalopathy-associated mutations in DNM1 had differential effects on SV recycling through both CME and ADBE. Mouse hippocampal neurons overexpressing Dyn1R237W, Dyn1I289F and Dyn1H396D all showed less CME compared to overexpression of Dyn1WT. Moreover, fewer nerve terminals overexpressing Dyn1H396D were found to undergo ADBE. We also found that a large-conductance potassium (BK) channel opener can accelerate clathrin-mediated endocytosis and thus may be able to rescue the impaired SV endocytosis caused by these mutants. Although there is not yet a common underlying pathway at the presynaptic level between these conditions, SV recycling dysfunction is present across all of these models. Furthermore, we propose an axis of pathophysiology model where optimal SV endocytosis is required for optimised neural performance. We propose that either decreased or increased SV endocytosis can lead to the synaptic dysfunction observed in these models.

Submitted by Suzana Dias (suzana.dias@famerp.br) on 2018-11-06T15:03:20Z No. of bitstreams: 1 MariaFernandaLopesFerreira_dissert.pdf: 1193846 bytes, checksum: 166134b8cb10ff377557a520ecc3c877 (MD5) / Made available in DSpace on 2018-11-06T15:03:20Z (GMT). No. of bitstreams: 1 MariaFernandaLopesFerreira_dissert.pdf: 1193846 bytes, checksum: 166134b8cb10ff377557a520ecc3c877 (MD5) Previous issue date: 2018-05-16 / Studies have shown a high prevalence of mental disorders in child and adolescent population in Brazil, and in the world. Investigations on pre-school children behavior in the state of São Paulo, Brazil, have identified a 12.5 % prevalence of children with behavioral problems. Objective: to evaluate the behavioral development of pre-school children in a swimming program. Method: convenience sample longitudinal study, through quantitative-qualitative analysis, performed at a swimming school in the city of São José do Rio Preto. One parent or responsible for the participants has answered to CBCL / 1 1/2 and 5-year questionnaire, before and after the swimming program, classifying the children as having "clinical" or "non-clinical" problems. A p < 0. 05 significance has been used for data analysis. Results: comparing results before and after the program, children have shown a significant improvement in 6 syndromes out of the 15 assessed by CBCL. A little significant improvement has been observed in the kids’ general behavior, and, considering gender, girls have presented a slightly more important improvement than boys. Conclusion: after the proposed swimming program, the descriptive analysis has shown significant improvement in the children’s behavior compared to the statistical analysis. / Estudos constatam a alta prevalência de transtornos mentais na população infanto-juvenil no Brasil e no mundo. Investigações sobre o comportamento de crianças em idade escolar, no interior do estado de São Paulo, Brasil, identificaram uma prevalência de 12,5% de crianças com problemas de comportamento. Objetivo: avaliar o desenvolvimento comportamental de crianças pré-escolares em um programa de natação. Método: estudo longitudinal, com amostra de conveniência de 45 participantes, com analise quanti-qualitativa, realizado em uma escola de natação, na cidade de São José do Rio Preto. Os responsáveis pelos participantes responderam ao questionário Child Behavior Check List CBCL / 1 12⁄ e 5 anos, antes e depois do programa de natação, classificando-os como portadores de problemas “clínicos” e “não clínicos”, e para análise de dados adotou-se nível de significância p<0,05. Resultados: os resultados comparados pré e pós o programa mostraram uma melhora significativa em 6 síndromes das 15 comtempladas pela CBCL. Descobriu-se pouca melhora significativa no comportamento das crianças em geral e, observando por gênero, as meninas obtiveram uma melhora mais significativa em comparação com os meninos. Conclusão: houve melhora no comportamento das crianças após o programa de natação proposto, observando-se melhora considerável, na análise descritiva, em comparação com a análise estatística.

The 16p11.2 copy-number variant (CNV) represents a well-characterized, high-risk factor for autism spectrum disorder that additionally predisposes deletion carriers (16pdel) to increased head circumference, known as macrocephaly. The 16p11.2 CNV consists of 29 known genes, many of which are associated with neurobiological processes relevant for macrocephaly such as cell proliferation and apoptosis, differentiation and cell growth. Our lab’s previous work has demonstrated that induced pluripotent stem cell (iPSC)-derived neurons from 16pdel carriers show altered cellular morphology related to growth, which include increased soma size, total dendritic length and dendritic complexity. However, specific CNV genes responsible for these phenotypes have not been established. Here, we investigate the relationship between three 16p11.2 genes and the observed cellular phenotypes. We differentiated neurons from control iPSC-derived neural progenitor cells (NPCs) and used short hairpin RNA (shRNA) to reduce the expression of these CNV genes: KCTD13, MAPK3 and C16ORF53. We then assessed neuronal morphology by evaluating soma size, total dendritic length and dendritic complexity. We demonstrate that knocking down KCTD13 and C16ORF53 increases soma size and total dendrite length, respectively, similar to that observed in 16pdel iPSC-derived neurons. For this reason, we speculate that these genes may have a role in cell growth and might underlie macrocephaly. Thus, our study investigates genes in the 16p11.2 CNV that contribute to neuronal morphology, which may have a role in influencing brain size.

The contribution of deficits in limb position sense to the motor impairments of children with cerebral palsy, as well as other neurodevelopmental disorders, is increasingly being recognized. A more complete understanding of the development of multi-joint upper limb position sense is needed and has been limited, to date, by the absence of a reliable measurement technique to produce clinically meaningful information. The KINARM Exoskeleton’s bilateral position matching task, which involves passive movement of one of the subject’s arms to one of eight positions requiring different combinations of elbow and shoulder positions and active matching by the participant’s other arm, was evaluated for interrater and retest reliability. Intraclass correlation coefficients, absolute difference, minimum detectable difference that would be considered a significant change in performance, standard error of the measure, coefficient of variation, index of reliability, limit of agreement and confidence intervals were used to determine reliability on three measures of multi-joint position sense: (1) inter-trial variability in end-point position, (2) the ratio between actual and matched position, or spatial contraction/expansion, which provides a measure of the absolute accuracy of position matching, and (3) systematic errors in matching. Interrater index of reliability was very good to excellent with values of 72% for systematic errors in matching to 93% for contraction/expansion. Interrater intraclass correlation values were fair to excellent at 0.46 for systematic errors in matching to 0.81 for contraction/expansion. Standard errors in measurement were low and ranged from 0.002 to 0.06, for inter-trial variability and contraction/expansion respectively. Similarly, minimal detectable difference values for retest reliability ranged from 0.005 for inter-trial variability to 0.161 for contraction/expansion. Retest intraclass correlation values were fair to excellent at 0.38 for systematic errors in matching to 0.82 for contraction/expansion. Moderate to strong interrater and retest reliability and high measurement precision support the use of robot-based assessment of multi-joint position sense for developmental studies and promises to be a reliable clinical and research tool in the advancement of knowledge on sensory-motor coordination difficulties in children with neurodevelopmental disorders. / Thesis (Master, Rehabilitation Science) -- Queen's University, 2011-09-29 05:43:47.255

<p>Neurodevelopmental disorders develop over time and are characterized by a wide variety of mental, behavioral, and physical phenotypes. The categorization of neurodevelopmental disorders encompasses a broad range of conditions including intellectual disability, autism spectrum disorder, attention deficit hyperactivity disorder, cerebral palsy, schizophrenia, bipolar disorder, and epilepsy, among others. Diagnostic classifications of neurodevelopmental disorders are complicated by comorbidities among these neurodevelopmental disorders, unidentified causal genes, and growing evidence of shared genetic risk factors. </p><p>We sought to identify the genetic underpinnings of a variety of neurodevelopmental disorders, with a particular emphasis on the epilepsies, by employing next&ndash;generation sequencing to thoroughly interrogate genetic variation in the human genome/exome. First, we investigated four families presenting with a seemingly identical and previously undescribed neurodevelopmental disorder characterized by congenital microcephaly, intellectual disability, progressive cerebral atrophy, and intractable seizures. These families all exhibited an apparent autosomal recessive pattern of inheritance. Second, we investigated a heterogeneous cohort of &sim;60 undiagnosed patients, the majority of whom suffered from severe neurodevelopmental disorders with a suspected genetic etiology. Third, we investigated 264 patients with epileptic encephalopathies &mdash; severe childhood epilepsy disorders &mdash; looking specifically at infantile spasms and Lennox&ndash;Gastaut syndrome. Finally, we investigated &sim;40 large multiplex epilepsy families with complex phenotypic constellations and unclear modes of inheritance. The studied neurodevelopmental disorders exhibited a range of genetic complexity, from clear Mendelian disorders to common complex disorders, resulting in varying degrees of success in the identification of clearly causal genetic variants. </p><p>In the first project, we successfully identified the disease&ndash;causing gene. We show that recessive mutations in <italic>ASNS </italic> (encoding asparagine synthetase) are responsible for this previously undescribed neurodevelopmental disorder. We also characterized the causal mutations <italic>in vitro</italic> and studied Asns&ndash;deficient mice that mimicked aspects of the patient phenotype. This work describes ASNS deficiency as a novel neurodevelopmental disorder, identifies three distinct causal mutations in the ASNS gene, and indicates that asparagine synthesis is essential for the proper development and function of the brain.</p><p>In the second project, we exome sequenced 62 undiagnosed patients and their unaffected biological parents (trios). By analyzing all identified variants that were annotated as putatively functional and observed as a novel genotype in the probands (not observed in the unaffected parents or controls), we obtained a genetic diagnosis for 32% (20/62) of these patients. Additionally, we identify strong candidate variants in 31% (13/42) of the undiagnosed cases. We also present additional analysis methods for moving beyond traditional screens, e.g., considering only securely implicated genes, or subjecting qualifying variants from any gene to two unique analysis approaches. This work adds to the growing evidence for the utility of diagnostic exome sequencing, increases patient sizes for rare neurodevelopmental disorders (enabling more detailed analyses of the phenotypic spectrum), and proposes novel analysis approaches which will likely become beneficial as the number of sequenced undiagnosed patients grows. </p><p>In the third project, we again employ a trio&ndash;based exome sequencing design to investigate the role of <italic>de novo</italic> mutations in two classical forms of epileptic encephalopathy. We find a significant excess of <italic>de novo</italic> mutations in the &sim;4,000 genes that are the most intolerant to functional genetic variation in the human population (P = 2.9 x 10<super>&ndash;3</super>, likelihood analysis). We provide clear statistical evidence for two novel genes associated with epileptic encephalopathy &mdash; <italic>GABRB3</italic> and <italic>ALG13</italic>. Together with the 15 well&ndash;established epileptic encephalopathy genes, we statistically confirm the association of an additional ten putative epileptic encephalopathy genes. We show that only &sim;12% of epileptic encephalopathy patients in our cohort are explained by <italic>de novo</italic> mutations in one of these 24 genes, highlighting the extreme locus heterogeneity of the epileptic encephalopathies. </p><p>Finally, we investigated multiplex epilepsy families to uncover novel epilepsy susceptibility factors. Candidate variants emerging from sequencing within discovery families were further assessed by cosegregation testing, variant association testing in a case&ndash;control cohort, and gene&ndash;based resequencing in a cohort of additional multiplex epilepsy families. Despite employing multiple approaches, we did not identify any clear genetic associations with epilepsy. This work has, however, identified a set of candidates that may include real risk factors for epilepsy; the most promising of these is the <italic>MYCBP2</italic> gene. This work emphasizes the extremely high locus and allelic heterogeneity of the epilepsies and demonstrates that very large sample sizes are needed to uncover novel genetic risk factors. </p><p>Collectively, this body of work has securely implicated three novel neurodevelopmental disease genes that inform the underlying pathology of these disorders. Furthermore, in the final three studies, this work has highlighted additional candidate variants and genes that may ultimately be validated as disease&ndash;causing as sample sizes increase.</p> / Dissertation

Working memory is involved in a variety of cognitive tasks, with working memory capacity predicting an individual's ability to process information and focus attention on taskrelated information. Subsequently, recent research has investigated whether working memory capacity can be improved through training and whether improvements generalise to other cognitive, behavioural or emotional domains. This training is typically adaptive in nature, changing in difficulty according to participant ability, and can be completed in the participant's home on a computer, giving it the potential to be an easily accessible intervention for a range of clinical populations. The first paper presents a systematic review evaluating the effectiveness of computerised working memory training for individuals with neurodevelopmental disorders, which are often associated with working memory difficulties. The review found that to date, working memory training has been investigated in four neurodevelopmental disorders: attention deficit/hyperactivity disorder; autism spectrum disorder; intellectual disability and specific learning disorder. The findings indicate that although training appears to produce short-term improvements in the working memory capacity, this does not reliably generalise to other cognitive processes or disorder-specific symptoms. The second paper presents a randomised controlled trial investigating the effects of working memory training for reducing worry in high-worriers. Working memory capacity limitations, and subsequent difficulties in attentional control, are believed to be central to the maintenance of worry. Participants were randomly assigned to complete 15 days of nonadaptive working memory training using a 1-back task, or adaptive working memory training using a n-back task. Training led to improvements in working memory capacity and worry symptoms post-training and at four-week follow-up, with improvements on the adaptive training task significantly correlating with improvements in working memory capacity and worry. These findings are discussed in terms of implications for clinical practice and future research, together with the limitations of the study.

Compreender as bases do comportamento social e do desenvolvimento socioafetivo humano é essencial tanto para indivíduos com desenvolvimento típico (DT) quanto com transtornos neuropsiquiátricos. A Síndrome de Williams (SW) é uma condição neurogenética rara ocasionada pela deleção de aproximadamente 28 genes no cromossomo 7q11.23. A sintomatologia inclui desde dismorfismos faciais a alterações do funcionamento cognitivo e socioafetivo, com a presença de deficiência intelectual de grau leve a moderado. O processamento de estímulos afetivos tem sido foco de grande interesse em indivíduos com SW. Apesar de parte das pesquisas apontarem que esta população tem habilidade preservada de reconhecimento de expressões facias de emoções positivas e prejuízos no reconhecimento de emoções negativas, este ainda não é um campo consensual. Ao mesmo tempo, estudos indicam maior interesse desta população em relação a música e diferenças no neuroprocessamento de trechos musicais com valência afetiva. O presente trabalho teve por objetivo caracterizar o processamento de estímulos afetivos musicais e visuais em crianças e adolescentes com Síndrome de Williams. O Estudo I buscou validar trechos musicais com valência afetiva em cultura brasileira e analisar o efeito do treino musical na compreensão de emoções em música. Músicas com valência afetiva foram avaliadas pelos participantes de maneira correspondente à emoção pretendida pelo compositor e de forma similar entre as populações brasileiras e canadenses. O efeito do treino musical sobre a habilidade de reconhecer as emoções em música tiveram maior impacto em emoções com maior grau de dificuldade para os participantes como todo. O Estudo II visou caracterizar o perfil musical de crianças e adolescentes com SW e diferenciar o processamento de estímulos afetivos musicais em crianças e adolescentes com SW com as de DT. Pessoas com SW foram avaliadas com maior habilidade musical global. Não foram encontradas diferenças no que diz respeito ao interesse por atividades musicais. O Estudo III teve como objetivos diferenciar habilidade de reconhecimento de emoções o padrão de rastreamento do olhar frente a estímulos afetivos visuais em crianças e adolescentes com SW e SW com sintomas de TEA (SW/TEA). Pessoas com SW desprenderam maior tempo de fixação nos olhos e em faces alegres quando comparadas a faces tristes. Resultados indicam diferença no reconhecimento de emoções e rastreamento de olhar em indivíduos com SW/TEA. Padrão de reconhecimento em estímulos musicais e visuais foi semelhante na população SW, com acentuado prejuízo no reconhecimento de emoções negativas e preservação do reconhecimento de emoções positivas. Este achado reforça a modularidade do processamento neurológico das emoções básicas. Crianças com SW reconheceram mais facilmente estímulos musicais de valência positiva em comparação aos visuais sugerindo que o domínio da música seja um ponto de força desta população / Understand the foundation of social behavior and human social and affective development is essential for both individuals with typical developmental (TD) and neuropsychiatric disorders. Williams Syndrome (WS) is a rare neurogenetic condition caused by the deletion of approximately 28 genes on chromosome 7q11.23. The symptomatology includes from facial dysmorphisms to changes in cognitive and social and affective functioning, with the presence of mild to moderate intellectual deficiency. The processing of affective stimuli has been a focus of great interest in individuals with WS. Although part of the research indicates that this population has preserved ability to recognize face expressions of positive emotions and impairment in the recognition of negative emotions, this is not yet a consensual field. At the same time, studies indicate greater interest of this population in relation to music and differences in the neuroprocessing of musical excerpts with affective valence. The present work aimed to characterize the processing of musical and visual affective stimuli in children and adolescents with Williams Syndrome. Study I sought to validate musical excerpts with affective valence in Brazilian culture and to analyze the effect of musical training on the understanding of emotions in music. Songs with affective valence were evaluated by the participants corresponding to the emotion pretended by the composer and similarly between the Brazilian and Canadian populations. The effect of musical training on the ability to recognize emotions in music has had a greater impact on emotions with a greater degree of difficulty for participants as a whole. Study II aimed to characterize the musical profile of children and adolescents with WS and to differentiate the processing of musical affective stimuli in children and adolescents with WS compered to TD. People with WS were assessed with greater overall musical ability. No differences were found regarding the interest in musical activities. The aim of Study III was to differentiate between the ability to recognize emotions and the pattern of eye tracking in relation to visual affective stimuli in children and adolescents with SW and WS with ASD symptoms. People with SW gave more fixation time to the eyes and happy faces when compared to sad faces. Results indicate difference in the recognition of emotions and eye tracking in individuals with SW / ASD. Recognition pattern in musical and visual stimuli was similar in the WS population, with marked impairment in the recognition of negative emotions and preservation of the recognition of positive emotions. This finding reinforces the modularity of neurological processing of basic emotions. Children with WS recognized easily positive musical stimuli compared to visual ones suggesting that the domain of music is the strength of this population

La gravité terrestre est une contrainte mécanique fondamentale exercée sur les organismes vivants et contre laquelle nous avons adapté nos stratégies de posture et de locomotion ainsi que toutes les régulations métaboliques et cardiovasculaires. Outre le stimulus mécanique direct, la gravité est mesurée par l'organe vestibulaire, premier système sensoriel à émerger chez les protochordés il y a environ 500 millions d'années, aussi précocement que le système visuel. Le système vestibulaire a alors été asservi aux fonctions d'équilibre et de stabilisation du regard, par des réflexes posturaux et oculaires, fonctions récemment enrichies d’un rôle clé dans la cognition spatiale et sociale chez l’adulte. Ses capacités d’encodage des mouvements de la tête, des accélérations du corps et de la gravité terrestre font de ce système un acteur majeur dans la perception de la verticalité, la navigation, l’orientation et la mémorisation spatiale. Nous avons émis l'hypothèse que la perception sensorielle vestibulaire de la gravité via les otolithes pourrait jouer un rôle crucial non seulement chez l’adulte mais également dans les premières étapes du développement des fonctions sensorimotrices et cognitives. Pour la première fois, nous avons étudié un modèle de souris original (souris Head-tilt, B6Ei.GL-Nox3Het / J) présentant une absence congénitale sélective de gravisenseurs vestibulaires. Les souris présentaient un retard dans l'acquisition des réflexes sensorimoteurs, des capacités d’orientation spatiale par guidage olfactif, d'une communication mère-petits par ultrasons alors que les soins maternels étaient normaux. Un retard dans la locomotion et des troubles hyperactifs avec stéréotypies ont également été montré. Nous démontrons ainsi que le développement des individus sur Terre possède une période critique dépendante de la perception sensorielle vestibulaire de la gravité, au moins entre les jours post-nataux 6 à 10 chez les rongeurs. Les informations otolithiques jouent également un rôle clé chez l’adulte dans les fonctions motrices, les processus mnésiques spatiaux et non spatiaux et dans la régulation émotionnelle. Une corrélation entre ces troubles et le retard développemental a été mis en évidence. Nous travaillons actuellement sur les effets de stimulations sensorielles précoces sur le développement et les fonctions adultes chez la souris Het ainsi que sur la caractérisation structurale et fonctionnelle au niveau cérébral des atteintes développementales et comportementales observées. Les observations chez les souris Het corroborent les symptômes rapportés chez les enfants vestibulo-déficients, soutenant le besoin d'un meilleur dépistage des maladies vestibulaires pendant l'enfance. De manière intéressante, les symptômes de ces souris correspondent à ceux présentés par des modèles murins validés d'autisme et réactualiseraient l’importance de la graviception vestibulaire dans la physiopathologie et la thérapie des troubles du spectre autistique (TSA) et autres maladies neurodégénératives au cours du développement. / Earth’s gravity is a fundamental mechanical constraint for living organisms against which we have adapted our strategies of posture and locomotion as well as all metabolic and cardiovascular regulations. Beyond the mechanical stimulus, the vestibular organ is the first sensory system to emerge in protochordates about 500 million years ago, as early as the visual system, encoding the gravity strength into the brain. The vestibular system has since then been devoted to balance and gaze stabilization supported by postural and ocular reflexes, recently fortified with a key role in spatial and social cognition in adults. Its encoding abilities of head movements, body accelerations and Earth's gravity make this system a major player in the perception of verticality, navigation, orientation and spatial memorization. We have hypothesized that vestibular sensory perception of gravity might play a crucial role not only in adults, but also during the first stages of development in both sensorimotor and cognitive functions. For the first time, we have investigated an original mouse model (Head-Tilt mice, B6Ei.GL-Nox3Het/J) with selective congenital absence of vestibular gravisensors. Our data highlights that mouse pups suffered from a delay in the acquisition of sensorimotor reflexes, spatial olfactive guidance, path integration and ultrasonic communication while maternal care remained normal. In addition, a delay in locomotor development and the appearance of were observed during the late stage of development. We demonstrate that development on Earth has a critical period dependent on the vestibular sensory perception of gravity, at least between postnatal days 6 to 10 in rodents. We have shown that otolithic information plays a key role in the adult motor functions, spatial and non-spatial memory processes, reference frames choice but also in emotional regulation. These disorders have been correlated with early developmental delay. We are currently working on the effects of early sensory stimulation on development and adult functions in our Het mouse model as well as on the structural and functional characterization at the cerebral level of observed developmental and behavioral impairments. Observations in Het mice corroborate with symptoms reported in vestibulo-deficient children, supporting the need for better screening of vestibular diseases during childhood. Remarkably, the symptoms of our vestibulo-congenital deficient mice investigated here matched with the profile of validated mouse models of autism and re-update the significance of vestibular graviception in the physiopathology and therapy of autism spectrum disorders during its development.

Skolvägran hos barn med autism är vanligare än hos neurotypiska barn (Munkhaugen et al.,2017) och barn med ADHD riskerar att inte nå godkänt betyg i skolan (Jangmo et al., 2019). Lärares bristande kunskaper om NPF samt otillräckliga anpassningar i skolan har lyfts somorsaker till detta (Anderson, 2020). Denna kvantitativa studie hade som syfte att få svar på hur föräldrar till elever medautism och/eller ADHD i mellanstadieåldern uppfattar att skolan fungerar överlag för derasbarn, samt vilka faktorer som har störst inverkan och korrelation med denna upplevelse.Däribland frånvaro, lärares- och skollednings kunskap om NPF, förståelse från skolpersonal,andra elevers bemötande samt anpassningar i skolan. Kön, skolform, medicinering och typ avdiagnos har också funnits med som variabler och kunnat kontrolleras för eventuell inverkanpå hur skolan upplevs fungera överlag. Studien har gjorts via en webbaserad enkät där deltagarna (n=144) rekryterats medbekvämlighetsurval. Resultaten visar att lärares- och skollednings kunskap om NPF, samt frånvarosignifikant korrelerar med hur skolan bedöms fungera överlag. Detta ger en indikation på attflera lärare saknar adekvat kunskap om autism och ADHD och att en kunskapshöjning inomdessa områden behövs. / School absenteeism is more common for children with autism than neurotypical developingchildren (Munkhaugen et al., 2017) and children with ADHD risk not reaching a passinggrade (Jangmo et al., 2019). Teacher’s lack of knowledge about neurodevelopmentaldisorders and insufficient adaptation strategies in school have been highlighted as a reason(Anderson, 2020). The purpose of this quantitative study was to obtain answers to how parents ofchildren with autism and/or ADHD perceive how school works in general, and what factorshave the greatest impact and correlation with that experience. Factors examined areabsenteeism, teacher and school management knowledge of autism and/or ADHD,understanding from school staff, attitude from other pupils and adaptations in school. Gender,type of school, medical treatment and type of diagnosis (autism/ADHD) are additionalvariables that have been able to be examined on their impact on the overall schoolexperience. The data was collected through an online survey where the participants (n=144) wererecruited with a convenience sample. The results show that teacher and school management's knowledge of autism and/orADHD, as well as absence, significantly correlates with how the school is judged to functionoverall. This indicates that an increase in knowledge among existing teachers who lackadequate knowledge about autism and ADHD is required.