Dissertationen zum Thema „Troubles du neurodéveloppement“
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Salvador-Prince, Lucie. „Impact des pesticides sur le neurodéveloppement et la maladie d'Alzheimer“. Thesis, Université de Montpellier (2022-….), 2022. http://www.theses.fr/2022UMONT009.
Der volle Inhalt der QuelleThe massive use of pesticides in the world causes pollution of all environments and contamination of foodstuffs by multiple residues. Many epidemiological studies show some correlations between high exposure to pesticides and neurodevelopmental pathologies such as autism or ADHD (attention deficit disorder with or without hyperactivity). Neurodevelopment corresponds to a period of susceptibility to environmental pollutants and according to Thomas Arendt's hypothesis, alterations during neurodevelopment, and in particular the corticogenesis, could have repercussions on brain aging by promoting the development of neurodegenerative diseases. However, it is difficult from an epidemiological point of view to determine the impact of in utero exposure to low doses of pesticides and throughout life on the human brain. It is therefore important to mimic this silent contamination on animal models. After having shown that chronic exposure to low doses of fungicides (cyprodinil, mepanipyrim, pyrimethanil) induced an aggravation of Alzheimer's disease (AD) markers in the J20 transgenic mouse model (Lafon PA. et al., 2020), we asked whether in utero exposure to these same compounds could: (i) induce neurodevelopmental defects; and (ii) whether these neurodevelopmental defects could lead to dysregulation of AD markers during aging.Based on this hypothesis, we set up a model of mother to child contamination, in which wild-type females were exposed during gestation, either to fungicide alone, or to a cocktail of the three fungicides (cyprodinil, mepanipyrim and pyrimethanil) to the dose of 0.1 μg/L/pesticide (regulatory dose authorized in distributed water in Europe). A first study of the brains of newborns, at 3 days postnatal (P3), showed that gestational exposure to fungicides has an impact on neurogenesis with an increase in Nestin+ neural precursors and DCX+ immature neurons, and a decrease in NeuN+ mature neurons, linked to the PI3K/Akt and Wnt/β-catenin signaling pathway. An extraction of adult neural stem cells from mice treated for 4 months revealed an increase in their proliferation and differentiation properties, but paradoxically a reduction in their migration property. In addition, changes in the expression of post-synaptic proteins, such as PSD95 and NMDA receptors, have been identified (Wang et al., 2021). To go further, we analyzed the hippocampal synaptic activity of the mice exposed in utero to the cocktail of fungicides at P10, P18 and P30. The results showed that in mice treated with the cocktail of fungicides, some changes occured in the ratio of NMDA/AMPA glutamate receptors, a defect in synapse maturation with a delay in the GluN2a/GluN2b subunits switch during development, epileptic or poly-synaptic type signals and a synaptic plasticity defect (LTD). We also studied corticogenesis in newborns at P10 exposed in utero to the cocktail of fungicides, thanks to an in utero electroporation technique with multi-color fluorescent tracers "MAGIC markers" which allow to follow the progeny of neural precursors. The results showed that the treated mice exhibit defects in the morphology and organization of neurons, as well as in the formation of cortical layers. To complete, behavioral studies have shown that mice exposed in utero to the cocktail of fungicides exhibit hypoactivity and memory defects. Finally, mice treated from gestation and up to 6 and 9 months of age are subjected to biochemical and histological analyzes in order to determine whether exposure to fungicides can have an impact on the increase of Alzheimer's disease markers during aging
Margarido, Pinheiro Vera. „L’interactome de Scrib1 et son importance pour la plasticitè synaptique & les troubles de neurodéveloppement“. Thesis, Bordeaux, 2014. http://www.theses.fr/2014BORD0318/document.
Der volle Inhalt der QuelleThe brain is made up of billions of nerve cells, or neurons. Neurons communicate with each other through functionally distinct structures - the axon and the dendrite - which are able to release and receive an electrical or chemical signal from a pre- to a post-synaptic compartment, respectively. We focused our study on hippocampal neurons synapses, which ultimately underlie high-order brain functions, such as learning and memory. In particular, we studied the development and maintenance of dendritic spines, whose changes in morphology are intimately correlated with synaptic plasticity, or the ability to respond to synaptic activity. Dendritic spines originate from motile dendritic filopodia, which mature into spines following axonal contact. The filopodia-to-spine transition involves a plethora of molecular actors, including glutamate receptors, scaffold proteins and the actin cytoskeleton, able to receive, transmit and integrate the pre-synaptic signal. The spatial and temporal coordination of all these molecular components throughout the formation and maturation of a synapse remains, however, unclear. Scribble1 (Scrib1) is planar cell polarity protein (PCP) classically implicated in the homeostasis of epithelial tissues and tumour growth. In the mammalian brain, Scrib1 is a critical scaffold protein in brain development and function. The main goal of this work was, therefore, to investigate the molecular mechanisms underlying Scrib1 role in synapse formation and maintenance. In a first part, we depict the importance of Scrib1 PDZ-dependent interactions on glutamate receptors trafficking as well as bidirectional plasticity signalling pathway underying spatial memory. In a second part, we focus on the functional consequences of a recently identified autism spectrum disorder (ASD) mutation of Scrib1 on neuronal morpholgy and function. We demonstrated that Scrib1 regulates dendritic arborization as well as spine formation and functional maintenance via an actin-dependent mechanism, whose disruption might underlie the ASD phenotype. Taken altogether, this thesis highlights the PCP protein Scrib1 as key scaffold protein in brain development and function, playing a plethora of roles from the subcelular to the cognitive level
Chastang, Julie. „Troubles du neurodéveloppement de l’enfant : vécu des parents et des enseignants, qualité de vie et outil de repérage“. Electronic Thesis or Diss., Sorbonne université, 2023. http://www.theses.fr/2023SORUS598.
Der volle Inhalt der QuelleIn France, neurodevelopmental disorders (NDD) affect 10 to 15% of children. Early detection of NDD is of crucial importance due to the maximum brain plasticity in the first 3 years of a child's life. Early detection should allow children to access early interventions that optimize their neurodevelopmental trajectory. This thesis initially focused on the experiences of parents of children with NDD and their quality of life. Parents described a complex journey, marked by waiting times for diagnosis which had significant repercussions on their quality of life, difficulties in accessing care, as well as a challenging journey facing the challenges related to their child(ren)'s schooling. Being supported by their primary care physician seemed to enhance their quality of life, while the delay to diagnosis negatively impacted it. Complementarily, this thesis also studied the experiences of teachers. It emerged that many of the difficulties identified by parents are shared by teachers. Both parents and teachers reported feelings of abandonment and loneliness in addressing the children's needs. They shared observations about the difficulties in identifying disorders, delays in diagnosis, complicated pathways, and a lack of support and resources. A recurring theme was the lack of coordination between parents, teachers, and the healthcare sector. Given the finding that no readily accessible tool existed for frontline use to identify deviations from the expected neurodevelopmental trajectory, a multidisciplinary group of experts was convened under the auspices of the inter-ministerial delegation to the national strategy for autism and neurodevelopmental disorders. This working group developed a detection grid based on existing literature and pre-existing tools, and this grid has been usable since 2019. The purpose of this thesis was to evaluate, for the first time, the use of this detection grid in the general population in primary care. The results obtained align with existing literature regarding the expected prevalence of NDD at the tested ages and factors associated with early identification of deviations in the neurodevelopmental trajectory. In summary, this thesis sought to explore the experiences of parents and teachers and the challenges they face, highlighting the complexities in the life journey of children with NDD and their families. From these observations, it aimed to find a solution for early detection of NDD by introducing, for the first time in primary care, a tool for detecting NDD
Gay, Olivier. „Marqueurs neurodéveloppementaux en psychiatrie : intérêt dans les troubles schizophréniques“. Thesis, Sorbonne Paris Cité, 2016. http://www.theses.fr/2016USPCB016/document.
Der volle Inhalt der QuelleThe term neurodevelopment in its broadest sense refers to all of the processes encompassing development of the nervous system from the earliest stages of formation in utero to later stages of maturation during adolescence to produce the fully functional adult nervous system. Work over the last thirty years has led to a neurodevelopmental model of human psychiatric disorders, including schizophrenia, based on genetic, epidemiological and imaging evidence. This model asserts that disease is fundamentally linked to or develops from abnormality(s) in the formation processes (early neurodevelopment) and maturation (late neurodevelopment) of the nervous system due to a combination of genetic and environmental factors. In this context this thesis aims to clarify the effects of neurodevelopmental abnormalities on psychiatric disorders, including schizophrenia, through the study of different markers. The first study aims to investigate correlations between markers of early brain development: a clinical marker (neurological soft signs) and an imaging marker (sulcation of the cerebral cortex) in a population of subjects with schizophrenia. A correlation between these two markers is presented: the sulcation index was found to be lower in subjects that had significant neurological soft signs. We concluded that the combined study of different markers may help to isolate subgroups of patients with greater early neurodevelopmental damage. The second study aims to characterize effects of different markers of early neurodevelopmental abnormalities on cognitive functioning in patients with schizophrenia. Effects on executive control (as measured by the Trail Making Test) were correlated with clinical markers (neurological soft signs, handedness) and imaging (sulcation of the anterior cingulate cortex and enlargment of the ventricles). We found interactions between different markers with a mainly non-linear summation effect. Our interpretation is that different markers reflect separate insults, though all early, on brain development with a common final effect on executive function. The third study aims to clarify the specificity of sulcation as a marker of early neurodevelopmental abnormalities by studying a population of adult subjects with autism spectrum disorder (ASD), a patholody beginning in early childhood and linked with evidence of early neurodevelopmental damage. Sulcation abnormalities of the anterior cingulate cortex, similar to those observed in patients with schizophrenia are detected in patients with ASD. These results suggest early neurodevelopmental abnormalities are shared by different psychiatric disorders and that changes in cortical sulcation are not specific to a given disorder but the early damage. In conclusion, we suggest that the study of neurodevelopmental abnormalities should be integrated into a dimensional approach in psychiatry
Dupont, Charkaluk Marie-Laure. „Prématurité et neurodéveloppement : analyse longitudinale et recherche de facteurs pronostiques précoces à partir de l'étude de la cohorte EPIPAGE (Enquête épidémiologique sur les petits âges gestationnels)“. Paris 6, 2011. http://www.theses.fr/2011PA066485.
Der volle Inhalt der QuellePujol, Camille. „Le récepteur 5-HT6 et la dynamique de son réceptosome : rôle dans la différenciation neuronale et potentiel thérapeutique pour le traitement des troubles du spectre de l’autisme“. Thesis, Montpellier, 2018. http://www.theses.fr/2018MONTT059.
Der volle Inhalt der QuelleCognitive symptoms observed in neurodevelopmental pathologies such as schizophrenia or autism spectrum disorders are highly debilitating and poorly controlled by currently available treatments. Accordingly, there is still an urgent need for new therapeutic approaches. It has become clear in the last few years that these cognitive deficits are caused by neurodevelopmental alterations. The 5-HT6 receptor has emerged as one promising targets for the treatment of these deficits in light of its early expression during brain development, its role in key neurodevelopmental processes such as neuronal migration ad neurite growth and the pro-cognitive effects of antagonists in various cognitive tasks in rodents. In order to identify novel molecular substrates of the control of cognition and neural development by 5-HT6 receptors, our team has recently characterized the receptor interactome thanks to complementary proteomic strategies. Further functional studies revealed that the Cdk5 pathway under the control of 5-HT6 receptor plays a crucial role in in the migration and positioning of cortical pyramidal neurons as well as in the initiation of neurite outgrowth. The new protein partners of the receptor identified also include G protein-regulated inducer of neurite outgrowth 1 (GPRIN1), a Cdk5 substrate, known to promote neurite outgrowth. This thesis aims at characterizing the impact of the 5-HT6 receptor/GPRIN1 interaction upon receptor activity and neuronal differentiation in a neuroblastoma cell line (NG108-15 cells) commonly used as a cellular model for studying molecular mechanisms underlying neuronal differentiation. I showed that GPRIN1 interacts with a receptor sequence comprising the 22 N-terminal residues of its C-terminal domain via a mechanism depending on its association with activated Gαs protein and regulated by receptor phosphorylation at Ser350 by Cdk5, thus demonstrating that the receptor recruits either Cdk5 or GPRIN1 in a dynamic manner. I then showed that the physical interaction between GPRIN1 and the 5-HT6 receptor stabilizes an active receptor conformation able to activate Gs and the production of cAMP in an agonist-independent manner and exhibiting a low apparent affinity for inverse agonists. This interaction also promotes neurite extension and branching both in NG108-15 cells and primary cultured neurons originating from different regions of the mouse brain. These effects upon neuronal differentiation are mediated by agonist-independent activation of the Gs/adenylyl cyclase/PKA pathway. Collectively, my results indicate that neuronal differentiation under the control of 5-HT6 receptors requires a complex sequence of signaling mechanisms that depends on the sequential association of the receptor with Cdk5 and GPRIN1: while the 5-HT6/Cdk5 interaction is required for the initiation of neurite growth, neurite extension and branching depends on receptor association with GPRIN1. Finally, I demonstrated that sub-chronic administration to mice depleted of Mu opioid receptor (Oprm1-/- mice, preclinical model of autism spectrum disorders - ASDs -) improves a range of primary symptoms, including alteration of social cognition and stereotypic behaviors, suggesting that 5-HT6 receptor blockade might be a relevant strategy for the treatment of some behavioral symptoms in ASDs. Collectively, this thesis highlights the role of the 5-HT6 receptor interactome and of its dynamics in neuronal differentiation and the establishment of neuronal connectivity and opens new perspectives for the treatment of psychiatric disorders of neuro-developmental origin, such as ASDs
Zhang, Xinyan. „Uncovering the sleep pathway in the social profile of Rett syndrome“. Electronic Thesis or Diss., Lyon 1, 2022. http://www.theses.fr/2022LYO10128.
Der volle Inhalt der QuelleSleep is essential for maintaining optimal health. In children with neurodevelopmental and psychiatric disorders, problematic sleep is found with greater frequency and severity. Furthermore, problematic sleep is associated with poorer psychosocial functioning during the daytime. Rett Syndrome (RTT), one of the most common and severe genetic multi-disabilities in females, is strongly linked to the mutant methyl-CpG binding protein 2 gene (MECP2) on the X chromosome. Variant phenotypic forms of RTT present a spectrum of symptomatology similar to that of classical RTT but show subtle differences in some clinical features, including the Early Seizure Variant (ESV, Hanefeld variant, linked to mutant gene X-linked cyclin-dependent kinase-like 5, CDKL5), congenital variant (CV, Rolando variant, linked to the forkhead box G1 gene, FOXG1) and preserved speech variant (PSV, Zappella variant, also linked to MECP2). RTT affects 1 in 10,000 to 15,000 births, which represents 40 to 50 new cases each year in France. RTT is characterized by developmental arrest around 6-18 months after birth, the presence of stereotypical hand movements, and gait abnormalities coinciding with the loss of acquired purposeful hand skills and spoken language. The child withdraws socially. Other signs also described in RTT clinical profiles include epileptic seizure, breathing difficulties, abnormal muscle tone, scoliosis/kyphosis, as well as disturbed sleep. Accumulating pathophysiological findings in RTT suggest abnormal cortical activities and dysmaturity of the brainstem function, which is key in maintaining proper status during sleep or wakefulness. However, there is no scientific study investigating the relationship between sleep abnormalities and social impairments in RTT. Therefore, this doctoral work is subjected to this topic to link the day and night together in RTT. First, we undertook five systematic reviews of all previous studies on non-verbal social performance and sleep in RTT. Then, we analyzed polysomnographic recordings in a clinical sample of RTT individuals with MECP2 mutations. We studied their sleep macrostructure and respiration during sleep. In addition, we examined possible phenotypic traits via a stratified analytical approach to clinical and genetic characteristics. Lastly, to examine social profiles in RTT individuals, we extracted 25 social behavior items from the Rett Syndrome Behavior Questionnaire, and correlated them to their sleep. Overall, we can conclude that sleep in the social phenotype of individuals with RTT is related to progressive sensorimotor impairments. Therefore, in the future, the pathophysiology of the sensorimotor system should receive more attention in the study of sleep and the social life of individuals with RTT. In addition, we look forward to furthering research demonstrating the effects of sensorimotor therapies on sleep and social impairments
Wantzen, Prany. „La mémoire chez l’adolescent avec autisme : électrophysiologie, cognition et prise en charge“. Thesis, Paris Sciences et Lettres (ComUE), 2019. http://www.theses.fr/2019PSLEP071.
Der volle Inhalt der QuelleAutism spectrum disorders (ASD) are neurodevelopmental disorders, characterized by difficulties in social communication with restricted and repetitive behaviors. ASD are associated with structural, functional and connectivity brain abnormalities that contribute to atypical cognitive functioning in this population. This work includes three projects aimed at characterizing the neurocognitive profile of ASD adolescents and young adults and proposing new rehabilitation programs. The first shows abnormal resting-state brain connectivity using electroencephalography that can account for the multimodal integration difficulties that directly impact introspection processes. The second project deepens the study of introspection processes in the context of autobiographical memory (ABM). The data collected confirm the ABM difficulties in ASD adolescents, with an atypical sensory profile, but also the existence of a positive effect of prompting and visual cues during recall. Beyond, our work highlights the importance of ABM rehabilitation, used as a key vector in social interactions. Then, the third project concerns the creation of an ABM rehabilitation program based on an individual and collective approach. Preliminary results show a beneficial effect on the social identity of adolescents with autism. ABM is, therefore, very relevant to study in autism, integrating a unique and ecological multimodal dimension, and an interesting tool of rehabilitation
Mouaffak, Fayçal. „Schizophrénie Ultra Résistante : un trouble neurodéveloppemental : caractérisation clinique et génétique“. Paris 6, 2011. http://www.theses.fr/2011PA066725.
Der volle Inhalt der QuelleHerzine, Ameziane. „Etudes des effets neurodéveloppementaux induits par l’exposition périnatale à un pesticide, le glufosinate d’ammonium : de la neurogenèse au comportement“. Thesis, Orléans, 2016. http://www.theses.fr/2016ORLE2008/document.
Der volle Inhalt der QuelleGlufosinate ammonium (GLA) is one of the most widely used herbicides in agriculture. As for almost all pesticides, potential adverse effects of GLA have not been investigated in the brain developmental neurotoxicity perspective. Indeed, early pesticides exposure may weaken the developing brain and cause permanent brain alteration which could lead to a wide range of the lifelong effects on health and/or behavior. As an illustration, we showed that perinatal exposure to low doses of GLA induced behavioral defects in mice adulthood, characterized by many similarities with Autism Spectrum Disorders phenotype. My thesis deals with the molecular aspect of this perinatal GLA exposure. I demonstrated that GLA induced disturbances of proliferation and neuroblast migration from the subventricular zone to the olfactory bulbs. These defects were associated with significant change in the expression of many genes involved in neuroblast migration and cytoskeleton regulation as observed by brain transcriptome analysis. I showed that GLA act on the cytoskeleton through modification of polyglutamylation of tubulin which lead to cell division/migration disturbances and cell differentiation defect. My work thus provides a new molecular link between pre- and post-natal exposure to the herbicide GLA and the onset of ASD like phenotype later in life. It also raises the fundamental concerns about the ability of current safety testing to assess risks of pesticide exposure during critical developmental periods
Dor-Nedonsel, Emmanuelle. „Les schizophrénies précoces : épidémiologie, exploration clinique et neurocognitive, phénotypage de familles d'enfants avec schizophrénie et autisme“. Electronic Thesis or Diss., Université Côte d'Azur (ComUE), 2017. http://theses.univ-cotedazur.fr/2017AZUR4093.
Der volle Inhalt der QuelleEarly Onset Schizophrenia (EOS), a rare neurodevelopmental disorder (≈0.01%) is categorized into two types: Very Early Onset Schizophrenia, before age 13 and Adolescent Schizophrenia between ages 13 and 18. This diagnosis is a difficult one to make and considering the lack of knowledge on EOS, we can presume that it is in fact under-diagnosed and that our treatment and management options are still not very specific. We conducted a first epidemiological prevalence study consisted in evaluating: (1) the rate of subjects with EOS diagnostic criteria among 302 children who receive care in psychosocial and sanitary care facilities in the PACA region; (2) the clinical and neurocognitive characteristics of those children with EOS; (3) the rate of children with both EOS and ASD criteria within the same sample. In a second study, focusing on a subgroup of children with comorbid EOS and ASD, we analyzed first-degree relatives from a psychopathological, personality and cognitive viewpoint. The results are: a high rate of patients (8.9%) with an EOS diagnosis, a male gender majority (59.3%), an average age of 12.4 (SD=3.2), an average intelligence quotient of 72.5 (SD=21.4), a rate of 82.8% of subjects with hallucinations, 70% with EOS negative symptoms, 41.2% with comorbid autism, and 51.5% with antipsychotic medications. The study of family members shows that mothers have a higher rate of personality disorders, autistic traits and psychiatric disorders, as well as a lower average IQ. The creation and the characterization of a phenotype of this cohort have led to a family-genetic analysis based on exome sequencing in the parents and children with EOS following this study
Martinez, Gilles. „Continuum autisme-schizophrénie : apport de l’étude de la cognition sociale et de marqueurs phénotypiques développementaux“. Thesis, Sorbonne Paris Cité, 2017. http://www.theses.fr/2017USPCB065/document.
Der volle Inhalt der QuelleAutism and schizophrenia are both neurodevelopmental psychiatric disorders. Research on early-onset schizophrenia, commonly associated to autism spectrum disorders (ASD), suggested a possible developmental continuum between both of these disorders. Clinical and epidemiological evidence, and research from molecular genetics or brain imaging, come to support this hypothesis. In this context, social cognition is a matter of special interest. Impairments are reported both in the two disorders, but with inconsistent results, revealing common features as well as differences. Otherwise, links between social cognition impairments and neurodevelopmental burden have been until now poorly explored. Through the contribution of our three studies, we confirmed the importance of social cognition impairment in autism and schizophrenia. The MASC test (Movie for the Assessment of Social Cognition), an original tool which was by our findings validated in a French version, revealed higher overall impairment of mentalizing capabilities in ASD than in schizophrenia. Animated Shapes (non verbal test of attribution of intentions) revealed qualitative differences: whereas hypomentalizing is common both to ASD and schizophrenia, overmentalizing seemed to be more important in schizophrenia. Furthermore, along a continuum between autism and schizophrenia, social cognition impairment was linked to thought and language disorganization, and to neurological soft signs (a marker for neurodevelopmental load). In addition, in subjects with schizophrenia, overmentalizing was correlated to the precocity of onset of the disease. Altogether, our results highlight the need to screen developmental feature in adulthood. In that way, we presented preliminary results in order to validate a developmental disorders screening self-rated questionnaire. As a conclusion, our results bring evidence in favour of a hypothesis of a continuum between autism and schizophrenia, showing a social cognition impairment in both disorders, correlated to the neurodevelopmental load existing in both of them in a transnosographic way. We contributed to emphasize the sub-group of subjects with schizophrenia with early-onset of disease, characterized by a tendency to overmentalizing and presenting a marked disorganization. Our work provides avenue to further studies, integrating neuroimaging and genetic data, that will help to advance in a deeper comprehension of the pathophysiology of autism and schizophrenia. Furthermore, we used and validated in this work promising tools to improve finely psychopathological evaluation and differential diagnosis in adults suffering from autism and from schizophrenia
Dor-Nedonsel, Emmanuelle. „Les schizophrénies précoces : épidémiologie, exploration clinique et neurocognitive, phénotypage de familles d'enfants avec schizophrénie et autisme“. Thesis, Université Côte d'Azur (ComUE), 2017. http://www.theses.fr/2017AZUR4093/document.
Der volle Inhalt der QuelleEarly Onset Schizophrenia (EOS), a rare neurodevelopmental disorder (≈0.01%) is categorized into two types: Very Early Onset Schizophrenia, before age 13 and Adolescent Schizophrenia between ages 13 and 18. This diagnosis is a difficult one to make and considering the lack of knowledge on EOS, we can presume that it is in fact under-diagnosed and that our treatment and management options are still not very specific. We conducted a first epidemiological prevalence study consisted in evaluating: (1) the rate of subjects with EOS diagnostic criteria among 302 children who receive care in psychosocial and sanitary care facilities in the PACA region; (2) the clinical and neurocognitive characteristics of those children with EOS; (3) the rate of children with both EOS and ASD criteria within the same sample. In a second study, focusing on a subgroup of children with comorbid EOS and ASD, we analyzed first-degree relatives from a psychopathological, personality and cognitive viewpoint. The results are: a high rate of patients (8.9%) with an EOS diagnosis, a male gender majority (59.3%), an average age of 12.4 (SD=3.2), an average intelligence quotient of 72.5 (SD=21.4), a rate of 82.8% of subjects with hallucinations, 70% with EOS negative symptoms, 41.2% with comorbid autism, and 51.5% with antipsychotic medications. The study of family members shows that mothers have a higher rate of personality disorders, autistic traits and psychiatric disorders, as well as a lower average IQ. The creation and the characterization of a phenotype of this cohort have led to a family-genetic analysis based on exome sequencing in the parents and children with EOS following this study
Paraschivescu, Cristina. „Le rôle régulateur des cytokines dans le neurodéveloppement et le comportement au début de la période postnatale : Étude de l'impact du TNF sur le comportement de la souris au début de la période postnatale et une nouvelle approche d'analyse de données appliquée au modèle murin de l'autisme basée sur l'activation de l’immunité maternelle“. Electronic Thesis or Diss., Université Côte d'Azur (ComUE), 2019. http://www.theses.fr/2019AZUR6027.
Der volle Inhalt der QuelleBoth preclinical and clinical studies have shown that immune activation and inflammation during the early stages of neurodevelopment increase the risk of neurodevelopment disorders and behaviour abnormalities in adults. While the underlying mechanisms have only been partially elucidated, experiments in the maternal immune activation mouse model (MIA) – in which pregnant dams are injected with the viral mimic poly(I:C) – have demonstrated the critical role of two cytokines: interleukin (IL)-6 and IL-17A. However, the vast majority of the studies performed to date have used behavioural tests in adult mice as a read out to study the impact of cytokines on neurodevelopment. Therefore, it is not clear whether altered levels of other cytokines during the perinatal period could impact neurodevelopment and behaviour in infant mice. To address this issue, we have analysed the progeny of several cohorts of poly(I:C)- and saline-injected mothers for behaviour between postnatal day 5 (P5) and P15 and serum cytokine levels at P15. Because both perinatal neurodevelopment and cytokine production are known or believed to be impacted by many environmental variables, we analysed our data using a multivariable statistical model to identify features associated with being born to a poly(I:C)-injected mother (as opposed to being born to a saline-injected mother). We found that the drop of body weight and temperature of the mother after poly(I:C) injection, the litter size, the pup weight at P15, the number of ultrasonic vocalizations (USV) emitted by the pup at P6, the distance travelled by the pup and the time it spent mobile at P13, as well as serum levels of Tumour Necrosis Factor (TNF), IL-5, IL-15 and C-X-C motif chemokine (CXCL)10 were all associated with altered odds of being born to a poly(I:C)-injected mother. To further explore the role of TNF during the early postnatal period, we injected mouse pups daily from P1 to P5 and assessed these animals for both developmental milestones and behaviour from P8 to P15. Unexpectedly, injection of recombinant TNF did not have a detrimental impact on neurodevelopment but rather promoted sensorimotor reflexes acquisition and exploratory behaviour. Altogether, our results confirm that cytokines play a critical role during neurodevelopment and that altered levels of specific cytokines, and in particular TNF, could regulate the acquisition of developmental milestones and behaviour in infant mice. While we have only obtained preliminary insights into underlying mechanisms, the protocols that we have developed provide a framework for further studies
Uzquiano, López Ana. „Progenitor cell mechanisms contributing to cortical malformations : studying the role of the heterotopia gene Eml1/EML1 in radial glia“. Electronic Thesis or Diss., Sorbonne université, 2019. https://accesdistant.sorbonne-universite.fr/login?url=https://theses-intra.sorbonne-universite.fr/2019SORUS392.pdf.
Der volle Inhalt der QuelleCerebral cortical development is a finely regulated process, depending on diverse progenitor cells. Abnormal behavior of the latter can give rise to cortical malformations. Mutations in Eml1/EML1 were identified in the HeCo mouse, as well as in three families presenting severe subcortical heterotopia (SH). SH is characterized by the presence of mislocalized neurons in the white matter. At early stages of corticogenesis, abnormally positioned apical radial glia progenitors (aRG) were found cycling outside the proliferative ventricular zone (VZ) in the HeCo cortical wall. I focused my research on characterizing aRG in the VZ to assess why some cells leave this region and thus to further understand SH mechanisms. Combining confocal and electron microscopy (EM), I uncovered abnormalities of centrosomes and primary cilia in Eml1-mutant aRGs: primary cilia are shorter, and often remain basally oriented within vesicles. Searching for Eml1-interacting partners using mass spectrometry (MS), combined with exome sequencing of SH patient DNAs, allowed us to identify a ciliary Eml1-interacting partner, RPGRIP1L, showing mutations in a SH patient. Gene ontology analyses of MS data pointed to Golgi apparatus and protein transport as enriched categories. Indeed, Golgi abnormalities were identified in HeCo aRGs. Altogether, these data indicate that the Golgi-to-primary cilium axis is perturbed in Eml1mutant conditions, pointing to new intracellular pathways involved in severe neurodevelopmental disorders
Mallet, Jasmina. „Marqueurs neurodéveloppementaux, cognition et facteurs environnementaux précoces et tardifs dans le phénotype psychotique des pathologies mentales Heavy cannabis use prior psychosis in schizophrenia : clinical, cognitive and neurological evidences for a new endophenotype? Etude et apport de la latéralité comme marqueur neurodéveloppemental dans les troubles schizophréniques et bipolaires Cigarette smoking and schizophrenia : a specific clinical and therapeutic profile? Results from the Face-Schizophrenia cohort Tobacco smoking is associated with antipsychotic medication, physical aggressiveness and alcohol use disorder in schizophrenia : results from the Face-SZ national cohort Tabagisme et schizophrénie, impact sur la cognition Tobacco smoking and psychotic-like experiences in a general population sample Poster congrès français de psychiatrie 2018 : Expériences psychotiques chez 50 patients adolescents hospitalisés pour la 1ère fois : approche trans-diagnostique et prospective avec la PQ16“. Thesis, Sorbonne Paris Cité, 2018. https://wo.app.u-paris.fr/cgi-bin/WebObjects/TheseWeb.woa/wa/show?t=2403&f=17360.
Der volle Inhalt der QuelleMental diseases represent a very heterogeneous categorical group, even within a given nosographic entity. Multifactorial approaches allow accounting for the clinical heterogeneity of mental disorders, the continuum between certain clinical dimensions, and even between the normal and the pathological. Among such dimensions, the psychotic phenotype constitutes an essential dimension of schizophrenic disorder. The dimensional approach allows for the search of psychotic experiences in most mental disorders as well as in the general population. We make the general hypothesis that certain psychiatric disorders with psychotic symptoms could be the result of the interaction between early- (obstetric traumas for example) and late- environmental factors (toxics, traumatisms) and the neurodevelopment of the individual. The initial step in this thesis work was to better define the concepts of vulnerability in psychiatry, and, based on the example of schizophrenia, to conduct a review of the literature on risk factors according to their early or late interaction with neurodevelopment. Subsequently, the first axis of research of the present thesis was to evaluate early neurodevelopmental markers (neurological soft signs, laterality, cognition). Our first work concerned the clinical, neurological and cognitive characterization of 64 patients suffering from schizophrenia, according to their cannabis use (or not) prior to psychosis. It provided evidence for a lower burden of neurodevelopment in cannabis users, and the potential impact of this substance on vulnerable individuals. Our second work concerns the clinical and cognitive impact of lateralization in patients with schizophrenia (n = 667) and bipolar disorder (n = 2445). We bring arguments for a neurodevelopmental weight (measured with this lateralization index) that is more important in schizophrenia. Our second axis of research focused on tobacco smoking as a late environmental factor in schizophrenia and psychotic phenotype. We showed in two studies on the FACE-SZ cohort (n = 361, n = 474) that SZ patients consumed almost twice as much as the general population and that they could represent a SZ subgroup with specific socio-demographic and clinical characteristics. In a third study, we compare the cognitive functions of these patients (n = 785) and show that the self-medication hypothesis alone cannot account for the high prevalence of their smoking. In a fourth work, we studied the impact of smoking on the psychotic phenotype with a dimensional approach, and showed an association between smoking and certain psychotic-type experiences in a representative sample of the US general population (NESARC, n = 34653). Finally, in a last line of research, we evaluated the psychotic phenotype in a population of adolescents and young adults hospitalized for a first psychiatric episode (n = 50). In a preliminary study, we show a high prevalence of psychotic-like experiences in these young adults, regardless of the diagnosis made six months afterwards, highlighting the trans-nosographic character of the psychotic phenotype during the emergence of different mental disorders. Overall, the present thesis underscores the clinical heterogeneity of mental illnesses and the importance of dimensional and trajectory approaches in identifying risk (or protective) factors, towards a better etiopathogenic understanding, better prevention opportunities, and a personalized patient care
Bitton, Jonathan Y. „Implications des spasmes infantiles sur le neurodéveloppement des enfants“. Thèse, 2016. http://hdl.handle.net/1866/18576.
Der volle Inhalt der QuelleWest syndrome (WS), commonly referred to as infantile spasms (IS), is an epileptic disorder usually characterized by the triad of infantile spasms, a pathognomonic electroencephalogram (EEG) pattern called hypsarrhythmia, and developmental regression. While previous treatment studies were able to achieve relatively adequate spasm control and hypsarrhythmia resolution in this population of patients, they have failed to provide conclusive and definite therapeutic options aimed at improving the poor cognitive outcome often associated to IS. Our study, on which this thesis is based, was the first to use an add-on treatment to conventional antiepileptic drugs, with the intent to improve long-term cognitive outcome in this population. Patients recruited in our original randomized clinical trial (RCT) followed a standardized treatment protocol consisting of vigabatrin (VGB) as first-line treatment for two weeks, followed by adrenocorticotropic hormone (ACTH) in non-responders for another two-week period, and topiramate in refractory cases. In addition, patients were randomized to either receive placebo or flunarizine adjunct therapy for six months. Our multi-centric RCT recruited and evaluated 68 patients, most of which were followed at 8 different time points over a five-year period, to precisely evaluate their neurodevelopmental progress. Our clinical trial generated three main studies which comprise the core of this thesis. In a first study, clinical and cognitive data from the first two years were analyzed. Spasm arrest and hypsarrhythmia resolution were the short-term clinical endpoint measures, while the Vineland Adaptive Behavior Scale (VABS) and Bayley Scales of Infant Development (BSID) were used as cognitive outcome measures at 2 years. This first study most importantly reports on the superior short-term clinical response rate achieved in our study population. Preliminary cognitive results were also presented in this work. Our second study essentially presented long-term cognitive data 5 years after the start of the study. Cognitive outcome measures were similar to those used at two years with the addition of the Stanford-Binet Intelligence Scale, Fifth Edition (SB5) for higher functioning patients. Most IS patients, particularly those with no known etiology, displayed a significant and progressive improvement of cognitive functions, irrespective of adjunctive therapy. Risk factors of long term poor cognitive outcome were also revealed in this study. Our last study tried to understand the relationship between IS and autism spectrum disorders (ASD). Autism was initially screened by means of the Checklist for Autism in Toddlers (CHAT) at 24 months, and formally assessed at the 30-and 60-month follow-up visits using the Autism Diagnostic Observation Schedule (ADOS). ADOS was performed in 44 patients, 10 of which were diagnosed with ASD. A description of risk factors associated with an ASD outcome in the IS population were presented in this article. Finally, based on our study results and in conjunction with literature information on the topic, we attempted to elucidate the pathophysiological characteristics of the disorder. A conceivable description of the underlying biological mechanisms implicated in West syndrome and associated target treatments were presented. Although our complementary treatment, flunarizine, did not prove to be beneficial in our cohort, our treatment protocol was nonetheless able to demonstrate superior clinical and cognitive outcomes in patients with unknown etiologies. These findings, as well as the identification of new potential neurodevelopmental risk factors, could be used clinically to improve the diagnosis and medical follow-up of patients with West syndrome.
Pujol, Camille. „Le récepteur 5-HT6 et la dynamique de son réceptosome : rôle dans la différenciation neuronale et potentiel thérapeutique pour le traitement des troubles de spectre de l'autisme“. Thesis, 2018. http://www.theses.fr/2018MONTT059/document.
Der volle Inhalt der QuelleThe serotonin 5-HT6 receptor, one of the most recently cloned serotonin receptors, is a promising target for the treatment of cognitive deficits of both schizophrenia and Alzheimer’s disease. 5-HT6 receptor blockade by antagonists exerts pro-cognitive effects in a wide range of models of cognitive impairment in rodents and some of them are in phase III of clinical trials in schizophrenia and Alzheimer’s disease. The 5-HT6 receptor is exclusively expressed in the central nervous system, where it is detected at early phases of brain development. Studies have shown that 5-HT6 receptors have a key influence upon migration of both pyramidal neurons and interneurons of the cerebral cortex (Riccio et al. Mol Psychiatry 14(3):280-90, 2009 ; Transl Psychiatry 11;1:e47, 2011; Jacobshagen et al. Development, in revision). Using a proteomic strategy, our team recently identified a network of proteins interacting with the carboxy-terminal domain of the receptor. These include Cyclin-dependent kinase (Cdk)5 and some of its substrates, which are known to control neuro-developmental processes such as neuronal migration, neurite growth and dendritic spine morphogenesis. We have also demonstrated that the expression of the 5-HT6 receptor elicits neurite growth in an agonist-independent manner through a mechanism involving receptor phosphorylation at a serine residue by associated Cdk5 and engagement of the Rho GTPase Cdc42 (Duhr et al. Nature Chem. Biol., in revision). These studies show for the first time a constitutive activation of a G protein-coupled receptor mediated by its phosphorylation by an associated protein kinase. Preliminary experiments performed by the team also revealed that 5-HT6 receptors activation decreases the number of dendritic spines and modify spine morphology in hippocampal neurons in primary culture. This thesis project aims at characterizing the signalling mechanisms underlying the control of dendritic spine morphogenesis by the 5-HT6 receptors. Particular attention will be paid to Cdk5 and its substrate WAVE1, a protein known to induce neurite growth via the activation of the Arp2/3 complex (also identified in the 5-HT6 receptor interactome), which promotes actin polymerization. As phosphorylation of WAVE1 by Cdk5 inhibits its activity, we hypothesize that Cdk5-elicited phosphorylation of WAVE1 in the receptor-associated complex might underlies its control of spine morphogenesis. This project will combine in vitro studies performed on primary cultured hippocampal neurons and in vivo studies using transgenic mice expressing GFP tagged 5-HT6 receptors (this mouse line is currently being generated). We will also take advantage of this model to perform a novel interactomics screen to identify in an authentic tissue context novel receptor partners potentially involved in dendritic spine formation. This project should reveal novel cellular targets for the alleviation of the currently untreated and strongly debilitating cognitive deficits of schizophrenia, which are thought to result from abnormalities of brain development. It will be realized at the Institute of Functional Genomics in the “Neuroproteomics and signaling of neurodegenerative and psychiatric disorders” team under the supervision of Philippe Marin and Séverine Chaumont-Dubel
Berryer, Martin H. „Bases moléculaires et cellulaires d’un trouble neurodéveloppemental causé par l’haploinsuffisance de SYNGAP1“. Thèse, 2015. http://hdl.handle.net/1866/13907.
Der volle Inhalt der QuelleDufranne, Quentin. „Phénotypage de l’interaction sociale au cours du développement, en lien avec les symptômes autistiques, anxieux et TDAH“. Thesis, 2020. http://hdl.handle.net/1866/24718.
Der volle Inhalt der QuelleAutism Spectrum Disorder (ASD) is defined by two main domains of impairment: decreased social reciprocity and behavioural inflexibility. There is no diagnostic test or measurement of the mechanisms involved. A study with ASD adults used a dynamic, dyadic and integrative interaction game which alternately presents a social or non-social context, it resulted in a computational phenotype of social reciprocity revealing insensitivity to the type of context, a use of strategy specific to this group and a variation in performance depending on the opponent’s sophistication. This study aims to extend this understanding of social reciprocity in the pediatric ASD population and to distinguish psychopathological symptoms such as anxiety or ADHD symptoms, which are sometimes associated or confused with autistic symptoms. Analysis of the participants’ performance data validated its use in the pediatric population by replicating the impact of the algorithm on the participants’ performance. A dimensional approach using standardized tools and allowing the quantification of the autistic, ADHD and anxiety disorders symptoms’ severity, permits the emphasis of the impact of autistic and anxious symptoms on participants’ performance against a ToM-0 agent. This study is a step in the understanding of the mechanisms developed in social interaction during development and in the ability to measure them. Complementary computational analyzes will help refine this computational phenotype by giving more details about the strategies used during the game and the participants' flexibility to vary in their use.
Fragasso, Angela. „Approche famille-partenaire : perspective des gestionnaires, des intervenants et des parents d’enfants ayant un trouble neurodéveloppemental“. Thèse, 2018. http://hdl.handle.net/1866/22101.
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