53 recherche sur le mot-clé 'Animals'

Distinct, dosage-sensitive requirements for the autism-associated factor CHD8 during cortical development / S. HURLEY in Molecular Autism, 12 (2021)  

Public ISBD [article]  inMolecular Autism > 12 (2021) . - 16 p. Titre : Distinct, dosage-sensitive requirements for the autism-associated factor CHD8 during cortical development Type de document : Texte imprimé et/ou numérique Auteurs : S. HURLEY, Auteur ; C. MOHAN, Auteur ; P. SUETTERLIN, Auteur ; R. ELLINGFORD, Auteur ; K. L. H. RIEGMAN, Auteur ; J. ELLEGOOD, Auteur ; A. CARUSO, Auteur ; C. MICHETTI, Auteur ; O. BROCK, Auteur ; R. EVANS, Auteur ; F. RUDARI, Auteur ; A. DELOGU, Auteur ; M. L. SCATTONI, Auteur ; J. P. LERCH, Auteur ; C. FERNANDES, Auteur ; M. A. BASSON, Auteur Article en page(s) : 16 p. Langues : Anglais (eng) Mots-clés : Animals  Animals, Newborn  Autistic Disorder/genetics  Behavior, Animal  Brain/diagnostic imaging/embryology/growth & development  Cell Proliferation  DNA-Binding Proteins/deficiency/genetics  Disease Models, Animal  Female  Gene Expression Regulation, Developmental  Mice, Transgenic  Phenotype  Pregnancy  Stem Cells  Tumor Suppressor Protein p53/genetics  Apoptosis  Autism  Chd8  Chromatin  Conditional knockout  Cortex  Gene expression  Hypomorph  Intermediate progenitor  Mouse  Neural progenitor  Proliferation  Tbr2  p53  Pathways plc. This work is unrelated to COMPASS Pathways plc. No other competing  interests to declare. Index. décimale : PER Périodiques Résumé : BACKGROUND: CHD8 haploinsufficiency causes autism and macrocephaly with high penetrance in the human population. Chd8 heterozygous mice exhibit relatively subtle brain overgrowth and little gene expression changes in the embryonic neocortex. The purpose of this study was to generate new, sub-haploinsufficient Chd8 mouse models to allow us to identify and study the functions of CHD8 during embryonic cortical development. METHODS: To examine the possibility that certain phenotypes may only appear at sub-heterozygous Chd8 levels in the mouse, we created an allelic series of Chd8-deficient mice to reduce CHD8 protein levels to approximately 35% (mild hypomorph), 10% (severe hypomorph) and 0% (neural-specific conditional knockout) of wildtype levels. We used RNA sequencing to compare transcriptional dysregulation, structural MRI and brain weight to investigate effects on brain size, and cell proliferation, differentiation and apoptosis markers in immunostaining assays to quantify changes in neural progenitor fate. RESULTS: Mild Chd8 hypomorphs displayed significant postnatal lethality, with surviving animals exhibiting more pronounced brain hyperplasia than heterozygotes. Over 2000 genes were dysregulated in mild hypomorphs, including autism-associated neurodevelopmental and cell cycle genes. We identify increased proliferation of non-ventricular zone TBR2+ intermediate progenitors as one potential cause of brain hyperplasia in these mutants. Severe Chd8 hypomorphs displayed even greater transcriptional dysregulation, including evidence for p53 pathway upregulation. In contrast to mild hypomorphs, these mice displayed reduced brain size and increased apoptosis in the embryonic neocortex. Homozygous, conditional deletion of Chd8 in early neuronal progenitors resulted in pronounced brain hypoplasia, partly caused by p53 target gene derepression and apoptosis in the embryonic neocortex. Limitations Our findings identify an important role for the autism-associated factor CHD8 in controlling the proliferation of intermediate progenitors in the mouse neocortex. We propose that CHD8 has a similar function in human brain development, but studies on human cells are required to confirm this. Because many of our mouse mutants with reduced CHD8 function die shortly after birth, it is not possible to fully determine to what extent reduced CHD8 function results in autism-associated behaviours in mice. CONCLUSIONS: Together, these findings identify important, dosage-sensitive functions for CHD8 in p53 pathway repression, neurodevelopmental gene expression and neural progenitor fate in the embryonic neocortex. We conclude that brain development is acutely sensitive to reduced CHD8 expression and that the varying sensitivities of different progenitor populations and cellular processes to CHD8 dosage result in non-linear effects on gene transcription and brain growth. Shaun Hurley, Conor Mohan and Philipp Suetterlin have contributed equally to this work. En ligne : http://dx.doi.org/10.1186/s13229-020-00409-3 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=459 [article] Distinct, dosage-sensitive requirements for the autism-associated factor CHD8 during cortical development [Texte imprimé et/ou numérique] / S. HURLEY, Auteur ; C. MOHAN, Auteur ; P. SUETTERLIN, Auteur ; R. ELLINGFORD, Auteur ; K. L. H. RIEGMAN, Auteur ; J. ELLEGOOD, Auteur ; A. CARUSO, Auteur ; C. MICHETTI, Auteur ; O. BROCK, Auteur ; R. EVANS, Auteur ; F. RUDARI, Auteur ; A. DELOGU, Auteur ; M. L. SCATTONI, Auteur ; J. P. LERCH, Auteur ; C. FERNANDES, Auteur ; M. A. BASSON, Auteur . - 16 p. Langues : Anglais (eng) in Molecular Autism > 12 (2021) . - 16 p. Mots-clés : Animals  Animals, Newborn  Autistic Disorder/genetics  Behavior, Animal  Brain/diagnostic imaging/embryology/growth & development  Cell Proliferation  DNA-Binding Proteins/deficiency/genetics  Disease Models, Animal  Female  Gene Expression Regulation, Developmental  Mice, Transgenic  Phenotype  Pregnancy  Stem Cells  Tumor Suppressor Protein p53/genetics  Apoptosis  Autism  Chd8  Chromatin  Conditional knockout  Cortex  Gene expression  Hypomorph  Intermediate progenitor  Mouse  Neural progenitor  Proliferation  Tbr2  p53  Pathways plc. This work is unrelated to COMPASS Pathways plc. No other competing  interests to declare. Index. décimale : PER Périodiques Résumé : BACKGROUND: CHD8 haploinsufficiency causes autism and macrocephaly with high penetrance in the human population. Chd8 heterozygous mice exhibit relatively subtle brain overgrowth and little gene expression changes in the embryonic neocortex. The purpose of this study was to generate new, sub-haploinsufficient Chd8 mouse models to allow us to identify and study the functions of CHD8 during embryonic cortical development. METHODS: To examine the possibility that certain phenotypes may only appear at sub-heterozygous Chd8 levels in the mouse, we created an allelic series of Chd8-deficient mice to reduce CHD8 protein levels to approximately 35% (mild hypomorph), 10% (severe hypomorph) and 0% (neural-specific conditional knockout) of wildtype levels. We used RNA sequencing to compare transcriptional dysregulation, structural MRI and brain weight to investigate effects on brain size, and cell proliferation, differentiation and apoptosis markers in immunostaining assays to quantify changes in neural progenitor fate. RESULTS: Mild Chd8 hypomorphs displayed significant postnatal lethality, with surviving animals exhibiting more pronounced brain hyperplasia than heterozygotes. Over 2000 genes were dysregulated in mild hypomorphs, including autism-associated neurodevelopmental and cell cycle genes. We identify increased proliferation of non-ventricular zone TBR2+ intermediate progenitors as one potential cause of brain hyperplasia in these mutants. Severe Chd8 hypomorphs displayed even greater transcriptional dysregulation, including evidence for p53 pathway upregulation. In contrast to mild hypomorphs, these mice displayed reduced brain size and increased apoptosis in the embryonic neocortex. Homozygous, conditional deletion of Chd8 in early neuronal progenitors resulted in pronounced brain hypoplasia, partly caused by p53 target gene derepression and apoptosis in the embryonic neocortex. Limitations Our findings identify an important role for the autism-associated factor CHD8 in controlling the proliferation of intermediate progenitors in the mouse neocortex. We propose that CHD8 has a similar function in human brain development, but studies on human cells are required to confirm this. Because many of our mouse mutants with reduced CHD8 function die shortly after birth, it is not possible to fully determine to what extent reduced CHD8 function results in autism-associated behaviours in mice. CONCLUSIONS: Together, these findings identify important, dosage-sensitive functions for CHD8 in p53 pathway repression, neurodevelopmental gene expression and neural progenitor fate in the embryonic neocortex. We conclude that brain development is acutely sensitive to reduced CHD8 expression and that the varying sensitivities of different progenitor populations and cellular processes to CHD8 dosage result in non-linear effects on gene transcription and brain growth. Shaun Hurley, Conor Mohan and Philipp Suetterlin have contributed equally to this work. En ligne : http://dx.doi.org/10.1186/s13229-020-00409-3 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=459

Altered medial prefrontal cortex and dorsal raphé activity predict genotype and correlate with abnormal learning behavior in a mouse model of autism-associated 2p16.3 deletion / Rebecca B. HUGHES in Autism Research, 15-4 (April 2022)  

Public ISBD [article]  inAutism Research > 15-4 (April 2022) . - p.614-627 Titre : Altered medial prefrontal cortex and dorsal raphé activity predict genotype and correlate with abnormal learning behavior in a mouse model of autism-associated 2p16.3 deletion Type de document : Texte imprimé et/ou numérique Auteurs : Rebecca B. HUGHES, Auteur ; Jayde WHITTINGHAM-DOWD, Auteur ; Steven J. CLAPCOTE, Auteur ; Susan J. BROUGHTON, Auteur ; Neil DAWSON, Auteur Article en page(s) : p.614-627 Langues : Anglais (eng) Mots-clés : Animals  Autism Spectrum Disorder/genetics  Autistic Disorder  Disease Models, Animal  Dorsal Raphe Nucleus  Genotype  Humans  Male  Mice  Prefrontal Cortex/diagnostic imaging  Reversal Learning  cognitive neuroscience  copy number variation/copy number variants  frontal lobe  genotype-phenotype correlation  imaging genetics  mouse models  serotonin Index. décimale : PER Périodiques Résumé : 2p16.3 deletion, involving NEUREXIN1 (NRXN1) heterozygous deletion, substantially increases the risk of developing autism and other neurodevelopmental disorders. We have a poor understanding of how NRXN1 heterozygosity impacts on brain function and cognition to increase the risk of developing the disorder. Here we characterize the impact of Nrxn1? heterozygosity on cerebral metabolism, in mice, using (14) C-2-deoxyglucose imaging. We also assess performance in an olfactory-based discrimination and reversal learning (OB-DaRL) task and locomotor activity. We use decision tree classifiers to test the predictive relationship between cerebral metabolism and Nrxn1? genotype. Our data show that Nrxn1? heterozygosity induces prefrontal cortex (medial prelimbic cortex, mPrL) hypometabolism and a contrasting dorsal raphé nucleus (DRN) hypermetabolism. Metabolism in these regions allows for the predictive classification of Nrxn1? genotype. Consistent with reduced mPrL glucose utilization, prefrontal cortex insulin receptor signaling is decreased in Nrxn1?(+/-) mice. Behaviorally, Nrxn1?(+/-) mice show enhanced learning of a novel discrimination, impaired reversal learning and an increased latency to make correct choices. In addition, male Nrxn1?(+/-) mice show hyperlocomotor activity. Correlative analysis suggests that mPrL hypometabolism contributes to the enhanced novel odor discrimination seen in Nrxn1?(+/-) mice, while DRN hypermetabolism contributes to their increased latency in making correct choices. The data show that Nrxn1? heterozygosity impacts on prefrontal cortex and serotonin system function, which contribute to the cognitive alterations seen in these animals. The data suggest that Nrxn1?(+/-) mice provide a translational model for the cognitive and behavioral alterations seen in autism and other neurodevelopmental disorders associated with 2p16.3 deletion. LAY SUMMARY: Deletion of the chromosomal region 2p16.3, involving reduced NEUREXIN1 gene expression, dramatically increases the risk of developing autism. Here, we show that reduced Neurexin1? expression, in mice, impacts on the prefrontal cortex and impairs cognitive flexibility. The data suggest that 2p16.3 deletion increases the risk of developing autism by impacting on the prefrontal cortex. Mice with the deletion are a useful model for testing new drugs to treat the cognitive flexibility problems experienced by people with autism. En ligne : https://dx.doi.org/10.1002/aur.2685 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=473 [article] Altered medial prefrontal cortex and dorsal raphé activity predict genotype and correlate with abnormal learning behavior in a mouse model of autism-associated 2p16.3 deletion [Texte imprimé et/ou numérique] / Rebecca B. HUGHES, Auteur ; Jayde WHITTINGHAM-DOWD, Auteur ; Steven J. CLAPCOTE, Auteur ; Susan J. BROUGHTON, Auteur ; Neil DAWSON, Auteur . - p.614-627. Langues : Anglais (eng) in Autism Research > 15-4 (April 2022) . - p.614-627 Mots-clés : Animals  Autism Spectrum Disorder/genetics  Autistic Disorder  Disease Models, Animal  Dorsal Raphe Nucleus  Genotype  Humans  Male  Mice  Prefrontal Cortex/diagnostic imaging  Reversal Learning  cognitive neuroscience  copy number variation/copy number variants  frontal lobe  genotype-phenotype correlation  imaging genetics  mouse models  serotonin Index. décimale : PER Périodiques Résumé : 2p16.3 deletion, involving NEUREXIN1 (NRXN1) heterozygous deletion, substantially increases the risk of developing autism and other neurodevelopmental disorders. We have a poor understanding of how NRXN1 heterozygosity impacts on brain function and cognition to increase the risk of developing the disorder. Here we characterize the impact of Nrxn1? heterozygosity on cerebral metabolism, in mice, using (14) C-2-deoxyglucose imaging. We also assess performance in an olfactory-based discrimination and reversal learning (OB-DaRL) task and locomotor activity. We use decision tree classifiers to test the predictive relationship between cerebral metabolism and Nrxn1? genotype. Our data show that Nrxn1? heterozygosity induces prefrontal cortex (medial prelimbic cortex, mPrL) hypometabolism and a contrasting dorsal raphé nucleus (DRN) hypermetabolism. Metabolism in these regions allows for the predictive classification of Nrxn1? genotype. Consistent with reduced mPrL glucose utilization, prefrontal cortex insulin receptor signaling is decreased in Nrxn1?(+/-) mice. Behaviorally, Nrxn1?(+/-) mice show enhanced learning of a novel discrimination, impaired reversal learning and an increased latency to make correct choices. In addition, male Nrxn1?(+/-) mice show hyperlocomotor activity. Correlative analysis suggests that mPrL hypometabolism contributes to the enhanced novel odor discrimination seen in Nrxn1?(+/-) mice, while DRN hypermetabolism contributes to their increased latency in making correct choices. The data show that Nrxn1? heterozygosity impacts on prefrontal cortex and serotonin system function, which contribute to the cognitive alterations seen in these animals. The data suggest that Nrxn1?(+/-) mice provide a translational model for the cognitive and behavioral alterations seen in autism and other neurodevelopmental disorders associated with 2p16.3 deletion. LAY SUMMARY: Deletion of the chromosomal region 2p16.3, involving reduced NEUREXIN1 gene expression, dramatically increases the risk of developing autism. Here, we show that reduced Neurexin1? expression, in mice, impacts on the prefrontal cortex and impairs cognitive flexibility. The data suggest that 2p16.3 deletion increases the risk of developing autism by impacting on the prefrontal cortex. Mice with the deletion are a useful model for testing new drugs to treat the cognitive flexibility problems experienced by people with autism. En ligne : https://dx.doi.org/10.1002/aur.2685 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=473

Autism spectrum disorder: prospects for treatment using gene therapy / M. BENGER in Molecular Autism, 9 (2018)  

Public ISBD [article]  inMolecular Autism > 9 (2018) . - 39p. Titre : Autism spectrum disorder: prospects for treatment using gene therapy Type de document : Texte imprimé et/ou numérique Auteurs : M. BENGER, Auteur ; M. KINALI, Auteur ; N. D. MAZARAKIS, Auteur Article en page(s) : 39p. Langues : Anglais (eng) Mots-clés : Animals  Autism Spectrum Disorder/genetics/therapy  Genetic Therapy/methods  ASD models  Autistic spectrum disorder  Gene therapy  Synaptic dysfunction  Viral vector Index. décimale : PER Périodiques Résumé : Autism spectrum disorder (ASD) is characterised by the concomitant occurrence of impaired social interaction; restricted, perseverative and stereotypical behaviour; and abnormal communication skills. Recent epidemiological studies have reported a dramatic increase in the prevalence of ASD with as many as 1 in every 59 children being diagnosed with ASD. The fact that ASD appears to be principally genetically driven, and may be reversible postnatally, has raised the exciting possibility of using gene therapy as a disease-modifying treatment. Such therapies have already started to seriously impact on human disease and particularly monogenic disorders (e.g. metachromatic leukodystrophy, SMA type 1). In regard to ASD, technical advances in both our capacity to model the disorder in animals and also our ability to deliver genes to the central nervous system (CNS) have led to the first preclinical studies in monogenic ASD, involving both gene replacement and silencing. Furthermore, our increasing awareness and understanding of common dysregulated pathways in ASD have broadened gene therapy's potential scope to include various polygenic ASDs. As this review highlights, despite a number of outstanding challenges, gene therapy has excellent potential to address cognitive dysfunction in ASD. En ligne : https://dx.doi.org/10.1186/s13229-018-0222-8 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=371 [article] Autism spectrum disorder: prospects for treatment using gene therapy [Texte imprimé et/ou numérique] / M. BENGER, Auteur ; M. KINALI, Auteur ; N. D. MAZARAKIS, Auteur . - 39p. Langues : Anglais (eng) in Molecular Autism > 9 (2018) . - 39p. Mots-clés : Animals  Autism Spectrum Disorder/genetics/therapy  Genetic Therapy/methods  ASD models  Autistic spectrum disorder  Gene therapy  Synaptic dysfunction  Viral vector Index. décimale : PER Périodiques Résumé : Autism spectrum disorder (ASD) is characterised by the concomitant occurrence of impaired social interaction; restricted, perseverative and stereotypical behaviour; and abnormal communication skills. Recent epidemiological studies have reported a dramatic increase in the prevalence of ASD with as many as 1 in every 59 children being diagnosed with ASD. The fact that ASD appears to be principally genetically driven, and may be reversible postnatally, has raised the exciting possibility of using gene therapy as a disease-modifying treatment. Such therapies have already started to seriously impact on human disease and particularly monogenic disorders (e.g. metachromatic leukodystrophy, SMA type 1). In regard to ASD, technical advances in both our capacity to model the disorder in animals and also our ability to deliver genes to the central nervous system (CNS) have led to the first preclinical studies in monogenic ASD, involving both gene replacement and silencing. Furthermore, our increasing awareness and understanding of common dysregulated pathways in ASD have broadened gene therapy's potential scope to include various polygenic ASDs. As this review highlights, despite a number of outstanding challenges, gene therapy has excellent potential to address cognitive dysfunction in ASD. En ligne : https://dx.doi.org/10.1186/s13229-018-0222-8 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=371

Beyond the three-chamber test: toward a multimodal and objective assessment of social behavior in rodents / Renad JABARIN in Molecular Autism, 13 (2022)  

Public ISBD [article]  inMolecular Autism > 13 (2022) . - 41 p. Titre : Beyond the three-chamber test: toward a multimodal and objective assessment of social behavior in rodents Type de document : Texte imprimé et/ou numérique Auteurs : Renad JABARIN, Auteur ; Shai NETSER, Auteur ; Shlomo WAGNER, Auteur Article en page(s) : 41 p. Langues : Anglais (eng) Mots-clés : Animals  Humans  Rodentia  Autism Spectrum Disorder  Social Behavior  Behavior, Animal  Emotions  Animal models  Autism spectrum disorder  Behavioral phenotyping  Emotional states  Social vocalizations  Three-chamber test Index. décimale : PER Périodiques Résumé : MAIN: In recent years, substantial advances in social neuroscience have been realized, including the generation of numerous rodent models of autism spectrum disorder. Still, it can be argued that those methods currently being used to analyze animal social behavior create a bottleneck that significantly slows down progress in this field. Indeed, the bulk of research still relies on a small number of simple behavioral paradigms, the results of which are assessed without considering behavioral dynamics. Moreover, only few variables are examined in each paradigm, thus overlooking a significant portion of the complexity that characterizes social interaction between two conspecifics, subsequently hindering our understanding of the neural mechanisms governing different aspects of social behavior. We further demonstrate these constraints by discussing the most commonly used paradigm for assessing rodent social behavior, the three-chamber test. We also point to the fact that although emotions greatly influence human social behavior, we lack reliable means for assessing the emotional state of animals during social tasks. As such, we also discuss current evidence supporting the existence of pro-social emotions and emotional cognition in animal models. We further suggest that adequate social behavior analysis requires a novel multimodal approach that employs automated and simultaneous measurements of multiple behavioral and physiological variables at high temporal resolution in socially interacting animals. We accordingly describe several computerized systems and computational tools for acquiring and analyzing such measurements. Finally, we address several behavioral and physiological variables that can be used to assess socio-emotional states in animal models and thus elucidate intricacies of social behavior so as to attain deeper insight into the brain mechanisms that mediate such behaviors. CONCLUSIONS: In summary, we suggest that combining automated multimodal measurements with machine-learning algorithms will help define socio-emotional states and determine their dynamics during various types of social tasks, thus enabling a more thorough understanding of the complexity of social behavior. En ligne : http://dx.doi.org/10.1186/s13229-022-00521-6 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=491 [article] Beyond the three-chamber test: toward a multimodal and objective assessment of social behavior in rodents [Texte imprimé et/ou numérique] / Renad JABARIN, Auteur ; Shai NETSER, Auteur ; Shlomo WAGNER, Auteur . - 41 p. Langues : Anglais (eng) in Molecular Autism > 13 (2022) . - 41 p. Mots-clés : Animals  Humans  Rodentia  Autism Spectrum Disorder  Social Behavior  Behavior, Animal  Emotions  Animal models  Autism spectrum disorder  Behavioral phenotyping  Emotional states  Social vocalizations  Three-chamber test Index. décimale : PER Périodiques Résumé : MAIN: In recent years, substantial advances in social neuroscience have been realized, including the generation of numerous rodent models of autism spectrum disorder. Still, it can be argued that those methods currently being used to analyze animal social behavior create a bottleneck that significantly slows down progress in this field. Indeed, the bulk of research still relies on a small number of simple behavioral paradigms, the results of which are assessed without considering behavioral dynamics. Moreover, only few variables are examined in each paradigm, thus overlooking a significant portion of the complexity that characterizes social interaction between two conspecifics, subsequently hindering our understanding of the neural mechanisms governing different aspects of social behavior. We further demonstrate these constraints by discussing the most commonly used paradigm for assessing rodent social behavior, the three-chamber test. We also point to the fact that although emotions greatly influence human social behavior, we lack reliable means for assessing the emotional state of animals during social tasks. As such, we also discuss current evidence supporting the existence of pro-social emotions and emotional cognition in animal models. We further suggest that adequate social behavior analysis requires a novel multimodal approach that employs automated and simultaneous measurements of multiple behavioral and physiological variables at high temporal resolution in socially interacting animals. We accordingly describe several computerized systems and computational tools for acquiring and analyzing such measurements. Finally, we address several behavioral and physiological variables that can be used to assess socio-emotional states in animal models and thus elucidate intricacies of social behavior so as to attain deeper insight into the brain mechanisms that mediate such behaviors. CONCLUSIONS: In summary, we suggest that combining automated multimodal measurements with machine-learning algorithms will help define socio-emotional states and determine their dynamics during various types of social tasks, thus enabling a more thorough understanding of the complexity of social behavior. En ligne : http://dx.doi.org/10.1186/s13229-022-00521-6 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=491

Cerebellar demyelination and neurodegeneration associated with mTORC1 hyperactivity may contribute to the developmental onset of autism-like neurobehavioral phenotype in a rat model / Viera KUTNA in Autism Research, 15-5 (May 2022)  

Public ISBD [article]  inAutism Research > 15-5 (May 2022) . - p.791-805 Titre : Cerebellar demyelination and neurodegeneration associated with mTORC1 hyperactivity may contribute to the developmental onset of autism-like neurobehavioral phenotype in a rat model Type de document : Texte imprimé et/ou numérique Auteurs : Viera KUTNA, Auteur ; Valerie BRID O'LEARY, Auteur ; Cyril HOSCHL, Auteur ; Saak V. OVSEPIAN, Auteur Article en page(s) : p.791-805 Langues : Anglais (eng) Mots-clés : Animals  Autism Spectrum Disorder  Autistic Disorder  Cerebellum/metabolism  Demyelinating Diseases/complications/metabolism  Epilepsy/complications  Humans  Mechanistic Target of Rapamycin Complex 1/genetics/metabolism  Phenotype  Rats  Tuberous Sclerosis  Purkinje neurons  cerebellum  demyelination  mTORC1 signaling  microglia activation  synaptophysin Index. décimale : PER Périodiques Résumé : The cerebellum hosts more than half of all neurons of the human brain, with their organized activity playing a key role in coordinating motor functions. Cerebellar activity has also been implicated in the control of speech, communication, and social behavior, which are compromised in autism spectrum disorders (ASD). Despite major research advances, there is a shortage of mechanistic data relating cellular and molecular changes in the cerebellum to autistic behavior. We studied the impact of tuberous sclerosis complex 2 haploinsufficiency (Tsc2+/-) with downstream mTORC1 hyperactivity on cerebellar morphology and cellular organization in 1, 9, and 18?m.o. Eker rats, to determine possible structural correlates of an autism-like behavioural phenotype in this model. We report a greater developmental expansion of the cerebellar vermis, owing to enlarged white matter and thickened molecular layer. Histochemical and immunofluorescence data suggest age-related demyelination of central tract of the vermis, as evident from reduced level of myelin-basic protein in the arbora vitae. We also observed a higher number of astrocytes in Tsc2+/- rats of older age while the number of Purkinje cells (PCs) in these animals was lower than in wild-type controls. Unlike astrocytes and PCs, Bergmann glia remained unaltered at all ages in both genotypes, while the number of microglia was higher in Tsc2+/- rats of older age. The convergent evidence for a variety of age-dependent cellular changes in the cerebellum of rats associated with mTORC1 hyperactivity, thus, predicts an array of functional impairments, which may contribute to the developmental onset of an autism-like behavioral phenotype in this model. LAY SUMMARY: This study elucidates the impact of constitutive mTORC1 hyperactivity on cerebellar morphology and cellular organization in a rat model of autism and epilepsy. It describes age-dependent degeneration of Purkinje neurons, with demyelination of central tract as well as activation of microglia, and discusses the implications of these changes for neuro-behavioral phenotypes. The described changes provide new indications for the putative mechanisms underlying cerebellar impairments with their age-related onset, which may contribute to the pathobiology of autism, epilepsy, and related disorders. En ligne : http://dx.doi.org/10.1002/aur.2688 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=473 [article] Cerebellar demyelination and neurodegeneration associated with mTORC1 hyperactivity may contribute to the developmental onset of autism-like neurobehavioral phenotype in a rat model [Texte imprimé et/ou numérique] / Viera KUTNA, Auteur ; Valerie BRID O'LEARY, Auteur ; Cyril HOSCHL, Auteur ; Saak V. OVSEPIAN, Auteur . - p.791-805. Langues : Anglais (eng) in Autism Research > 15-5 (May 2022) . - p.791-805 Mots-clés : Animals  Autism Spectrum Disorder  Autistic Disorder  Cerebellum/metabolism  Demyelinating Diseases/complications/metabolism  Epilepsy/complications  Humans  Mechanistic Target of Rapamycin Complex 1/genetics/metabolism  Phenotype  Rats  Tuberous Sclerosis  Purkinje neurons  cerebellum  demyelination  mTORC1 signaling  microglia activation  synaptophysin Index. décimale : PER Périodiques Résumé : The cerebellum hosts more than half of all neurons of the human brain, with their organized activity playing a key role in coordinating motor functions. Cerebellar activity has also been implicated in the control of speech, communication, and social behavior, which are compromised in autism spectrum disorders (ASD). Despite major research advances, there is a shortage of mechanistic data relating cellular and molecular changes in the cerebellum to autistic behavior. We studied the impact of tuberous sclerosis complex 2 haploinsufficiency (Tsc2+/-) with downstream mTORC1 hyperactivity on cerebellar morphology and cellular organization in 1, 9, and 18?m.o. Eker rats, to determine possible structural correlates of an autism-like behavioural phenotype in this model. We report a greater developmental expansion of the cerebellar vermis, owing to enlarged white matter and thickened molecular layer. Histochemical and immunofluorescence data suggest age-related demyelination of central tract of the vermis, as evident from reduced level of myelin-basic protein in the arbora vitae. We also observed a higher number of astrocytes in Tsc2+/- rats of older age while the number of Purkinje cells (PCs) in these animals was lower than in wild-type controls. Unlike astrocytes and PCs, Bergmann glia remained unaltered at all ages in both genotypes, while the number of microglia was higher in Tsc2+/- rats of older age. The convergent evidence for a variety of age-dependent cellular changes in the cerebellum of rats associated with mTORC1 hyperactivity, thus, predicts an array of functional impairments, which may contribute to the developmental onset of an autism-like behavioral phenotype in this model. LAY SUMMARY: This study elucidates the impact of constitutive mTORC1 hyperactivity on cerebellar morphology and cellular organization in a rat model of autism and epilepsy. It describes age-dependent degeneration of Purkinje neurons, with demyelination of central tract as well as activation of microglia, and discusses the implications of these changes for neuro-behavioral phenotypes. The described changes provide new indications for the putative mechanisms underlying cerebellar impairments with their age-related onset, which may contribute to the pathobiology of autism, epilepsy, and related disorders. En ligne : http://dx.doi.org/10.1002/aur.2688 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=473

Closing the species gap: Translational approaches to studying sensory processing differences relevant for autism spectrum disorder / Kaela E. SCOTT in Autism Research, 14-7 (July 2021)  

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Developmental outcomes of early adverse care on amygdala functional connectivity in nonhuman primates / Elyse L. MORIN in Development and Psychopathology, 32-5 (December 2020)  

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Differential effects by sex with Kmt5b loss / R. N. WICKRAMASEKARA in Autism Research, 14-8 (August 2021)  

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Hippocampal neurons isolated from rats subjected to the valproic acid model mimic in vivo synaptic pattern: evidence of neuronal priming during early development in autism spectrum disorders / M. E. TRAETTA in Molecular Autism, 12 (2021)  

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Imbalance of flight-freeze responses and their cellular correlates in the Nlgn3(-/y) rat model of autism / Natasha J. ANSTEY in Molecular Autism, 13 (2022)  

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