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Tau reduction attenuates autism-like features in Fmr1 knockout mice / Xiangyu JIANG ; Linkun HAN ; Yiru JIANG ; Yong WANG ; Jian MENG ; Xiang ZHU ; Xian ZHANG ; Hong LUO ; Yun-Wu ZHANG in Molecular Autism, 14 (2023)
[article]
Titre : Tau reduction attenuates autism-like features in Fmr1 knockout mice Type de document : Texte imprimé et/ou numérique Auteurs : Xiangyu JIANG, Auteur ; Linkun HAN, Auteur ; Yiru JIANG, Auteur ; Yong WANG, Auteur ; Jian MENG, Auteur ; Xiang ZHU, Auteur ; Xian ZHANG, Auteur ; Hong LUO, Auteur ; Yun-Wu ZHANG, Auteur Article en page(s) : 42 p. Langues : Anglais (eng) Mots-clés : Animals Mice Male Female Mice, Knockout *Autism Spectrum Disorder *Autistic Disorder/genetics tau Proteins/genetics/metabolism Fragile X Mental Retardation Protein/genetics/metabolism *Fragile X Syndrome/genetics/metabolism Disease Models, Animal Antisense oligonucleotide Autism spectrum disorder Fmr1 Fragile X syndrome P38/MAPK signaling Tau Index. décimale : PER Périodiques Résumé : BACKGROUND: Fragile X syndrome (FXS) is a leading cause of autism spectrum disorder (ASD) and resulted from a loss of the FMR1-encoded fragile X messenger ribonucleoprotein 1 (FMRP) protein due to large CGG repeat expansions in the promoter region of the FMR1 gene. The microtubule-associated protein Tau is a promising target for Tauopathic diseases and our preliminary study found that Tau protein levels were increased in the brain of Fmr1 knockout (KO) mice, a model of FXS. However, whether Tau reduction can prevent autism-like features in Fmr1 KO mice and become a novel strategy for FXS treatment remain unknown. METHODS: Tau was genetically reduced in Fmr1 KO mice through crossing Fmr1(+) female mice with Mapt(+) male mice. The male offspring with different genotypes were subjected to various autism-related behavioral tests, RNA sequencing, and biochemical analysis. Fmr1 KO male mice were treated with Tau-targeting antisense oligonucleotide (ASO) and then subjected to behavioral tests and biochemical analysis. RESULTS: Tau expression was increased in the cortex of Fmr1 KO mice. Genetically reducing Tau prevented social defects, stereotyped and repetitive behavior, and spine abnormality in Fmr1 KO mice. Tau reduction also reversed increased periodic activity and partially rescued Per1 expression reduction in Fmr1 KO mice. Moreover, Tau reduction reversed compromised P38/MAPK signaling in Fmr1 KO mice. Finally, Tau-targeting ASO also effectively alleviated autism-like phenotypes and promoted P38/MAPK signaling in Fmr1 KO mice. LIMITATIONS: Our study is limited to male mice, in agreement with the higher incidence of FXS in males than females. Whether Tau reduction also exerts protection in females deserves further scrutiny. Moreover, although Tau reduction rescues impaired P38/MAPK signaling in Fmr1 KO mice, whether this is the responsible molecular mechanism requires further determination. CONCLUSION: Our data indicate that Tau reduction prevents autism-like phenotypes in Fmr1 KO mice. Tau may become a new target for FXS treatment. En ligne : https://dx.doi.org/10.1186/s13229-023-00574-1 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=518
in Molecular Autism > 14 (2023) . - 42 p.[article] Tau reduction attenuates autism-like features in Fmr1 knockout mice [Texte imprimé et/ou numérique] / Xiangyu JIANG, Auteur ; Linkun HAN, Auteur ; Yiru JIANG, Auteur ; Yong WANG, Auteur ; Jian MENG, Auteur ; Xiang ZHU, Auteur ; Xian ZHANG, Auteur ; Hong LUO, Auteur ; Yun-Wu ZHANG, Auteur . - 42 p.
Langues : Anglais (eng)
in Molecular Autism > 14 (2023) . - 42 p.
Mots-clés : Animals Mice Male Female Mice, Knockout *Autism Spectrum Disorder *Autistic Disorder/genetics tau Proteins/genetics/metabolism Fragile X Mental Retardation Protein/genetics/metabolism *Fragile X Syndrome/genetics/metabolism Disease Models, Animal Antisense oligonucleotide Autism spectrum disorder Fmr1 Fragile X syndrome P38/MAPK signaling Tau Index. décimale : PER Périodiques Résumé : BACKGROUND: Fragile X syndrome (FXS) is a leading cause of autism spectrum disorder (ASD) and resulted from a loss of the FMR1-encoded fragile X messenger ribonucleoprotein 1 (FMRP) protein due to large CGG repeat expansions in the promoter region of the FMR1 gene. The microtubule-associated protein Tau is a promising target for Tauopathic diseases and our preliminary study found that Tau protein levels were increased in the brain of Fmr1 knockout (KO) mice, a model of FXS. However, whether Tau reduction can prevent autism-like features in Fmr1 KO mice and become a novel strategy for FXS treatment remain unknown. METHODS: Tau was genetically reduced in Fmr1 KO mice through crossing Fmr1(+) female mice with Mapt(+) male mice. The male offspring with different genotypes were subjected to various autism-related behavioral tests, RNA sequencing, and biochemical analysis. Fmr1 KO male mice were treated with Tau-targeting antisense oligonucleotide (ASO) and then subjected to behavioral tests and biochemical analysis. RESULTS: Tau expression was increased in the cortex of Fmr1 KO mice. Genetically reducing Tau prevented social defects, stereotyped and repetitive behavior, and spine abnormality in Fmr1 KO mice. Tau reduction also reversed increased periodic activity and partially rescued Per1 expression reduction in Fmr1 KO mice. Moreover, Tau reduction reversed compromised P38/MAPK signaling in Fmr1 KO mice. Finally, Tau-targeting ASO also effectively alleviated autism-like phenotypes and promoted P38/MAPK signaling in Fmr1 KO mice. LIMITATIONS: Our study is limited to male mice, in agreement with the higher incidence of FXS in males than females. Whether Tau reduction also exerts protection in females deserves further scrutiny. Moreover, although Tau reduction rescues impaired P38/MAPK signaling in Fmr1 KO mice, whether this is the responsible molecular mechanism requires further determination. CONCLUSION: Our data indicate that Tau reduction prevents autism-like phenotypes in Fmr1 KO mice. Tau may become a new target for FXS treatment. En ligne : https://dx.doi.org/10.1186/s13229-023-00574-1 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=518 Enhanced fear limits behavioral flexibility in Shank2-deficient mice / Miru YUN in Molecular Autism, 13 (2022)
[article]
Titre : Enhanced fear limits behavioral flexibility in Shank2-deficient mice Type de document : Texte imprimé et/ou numérique Auteurs : Miru YUN, Auteur ; Eunjoon KIM, Auteur ; Min Whan JUNG, Auteur Article en page(s) : 40 p. Langues : Anglais (eng) Mots-clés : Animals Autism Spectrum Disorder/genetics/psychology Conditioning, Classical Disease Models, Animal Fear Male Mice Mice, Knockout Nerve Tissue Proteins/genetics Water Classical conditioning Reversal learning Shank2 Index. décimale : PER Périodiques Résumé : BACKGROUND: A core symptom of autism spectrum disorder (ASD) is repetitive and restrictive patterns of behavior. Cognitive inflexibility has been proposed as a potential basis for these symptoms of ASD. More generally, behavioral inflexibility has been proposed to underlie repetitive and restrictive behavior in ASD. Here, we investigated whether and how behavioral flexibility is compromised in a widely used animal model of ASD. METHODS: We compared the behavioral performance of Shank2-knockout mice and wild-type littermates in reversal learning employing a probabilistic classical trace conditioning paradigm. A conditioned stimulus (odor) was paired with an unconditioned appetitive (water, 6Â Âul) or aversive (air puff) stimulus in a probabilistic manner. We also compared air puff-induced eye closure responses of Shank2-knockout and wild-type mice. RESULTS: Male, but not female, Shank2-knockout mice showed impaired reversal learning when the expected outcomes consisted of a water reward and a strong air puff. Moreover, male, but not female, Shank2-knockout mice showed stronger anticipatory eye closure responses to the air puff compared to wild-type littermates, raising the possibility that the impairment might reflect enhanced fear. In support of this contention, male Shank2-knockout mice showed intact reversal learning when the strong air puff was replaced with a mild air puff and when the expected outcomes consisted of only rewards. LIMITATIONS: We examined behavioral flexibility in one behavioral task (reversal learning in a probabilistic classical trace conditioning paradigm) using one ASD mouse model (Shank2-knockout mice). Thus, future work is needed to clarify the extent to which our findings (that enhanced fear limits behavioral flexibility in ASD) can explain the behavioral inflexibility associated with ASD. Also, we examined only the relationship between fear and behavioral flexibility, leaving open the question of whether abnormalities in processes other than fear contribute to behavioral inflexibility in ASD. Finally, the neurobiological mechanisms linking Shank2-knockout and enhanced fear remain to be elucidated. CONCLUSIONS: Our results indicate that enhanced fear suppresses reversal learning in the presence of an intact capability to learn cue-outcome contingency changes in Shank2-knockout mice. Our findings suggest that behavioral flexibility might be seriously limited by abnormal emotional responses in ASD. En ligne : http://dx.doi.org/10.1186/s13229-022-00518-1 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=491
in Molecular Autism > 13 (2022) . - 40 p.[article] Enhanced fear limits behavioral flexibility in Shank2-deficient mice [Texte imprimé et/ou numérique] / Miru YUN, Auteur ; Eunjoon KIM, Auteur ; Min Whan JUNG, Auteur . - 40 p.
Langues : Anglais (eng)
in Molecular Autism > 13 (2022) . - 40 p.
Mots-clés : Animals Autism Spectrum Disorder/genetics/psychology Conditioning, Classical Disease Models, Animal Fear Male Mice Mice, Knockout Nerve Tissue Proteins/genetics Water Classical conditioning Reversal learning Shank2 Index. décimale : PER Périodiques Résumé : BACKGROUND: A core symptom of autism spectrum disorder (ASD) is repetitive and restrictive patterns of behavior. Cognitive inflexibility has been proposed as a potential basis for these symptoms of ASD. More generally, behavioral inflexibility has been proposed to underlie repetitive and restrictive behavior in ASD. Here, we investigated whether and how behavioral flexibility is compromised in a widely used animal model of ASD. METHODS: We compared the behavioral performance of Shank2-knockout mice and wild-type littermates in reversal learning employing a probabilistic classical trace conditioning paradigm. A conditioned stimulus (odor) was paired with an unconditioned appetitive (water, 6Â Âul) or aversive (air puff) stimulus in a probabilistic manner. We also compared air puff-induced eye closure responses of Shank2-knockout and wild-type mice. RESULTS: Male, but not female, Shank2-knockout mice showed impaired reversal learning when the expected outcomes consisted of a water reward and a strong air puff. Moreover, male, but not female, Shank2-knockout mice showed stronger anticipatory eye closure responses to the air puff compared to wild-type littermates, raising the possibility that the impairment might reflect enhanced fear. In support of this contention, male Shank2-knockout mice showed intact reversal learning when the strong air puff was replaced with a mild air puff and when the expected outcomes consisted of only rewards. LIMITATIONS: We examined behavioral flexibility in one behavioral task (reversal learning in a probabilistic classical trace conditioning paradigm) using one ASD mouse model (Shank2-knockout mice). Thus, future work is needed to clarify the extent to which our findings (that enhanced fear limits behavioral flexibility in ASD) can explain the behavioral inflexibility associated with ASD. Also, we examined only the relationship between fear and behavioral flexibility, leaving open the question of whether abnormalities in processes other than fear contribute to behavioral inflexibility in ASD. Finally, the neurobiological mechanisms linking Shank2-knockout and enhanced fear remain to be elucidated. CONCLUSIONS: Our results indicate that enhanced fear suppresses reversal learning in the presence of an intact capability to learn cue-outcome contingency changes in Shank2-knockout mice. Our findings suggest that behavioral flexibility might be seriously limited by abnormal emotional responses in ASD. En ligne : http://dx.doi.org/10.1186/s13229-022-00518-1 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=491 Brinp1(-/-) mice exhibit autism-like behaviour, altered memory, hyperactivity and increased parvalbumin-positive cortical interneuron density / S. R. BERKOWICZ in Molecular Autism, 7 (2016)
[article]
Titre : Brinp1(-/-) mice exhibit autism-like behaviour, altered memory, hyperactivity and increased parvalbumin-positive cortical interneuron density Type de document : Texte imprimé et/ou numérique Auteurs : S. R. BERKOWICZ, Auteur ; T. J. FEATHERBY, Auteur ; Z. QU, Auteur ; A. GIOUSOH, Auteur ; N. A. BORG, Auteur ; J. I. HENG, Auteur ; J. C. WHISSTOCK, Auteur ; P. I. BIRD, Auteur Article en page(s) : 22p. Langues : Anglais (eng) Mots-clés : Animals Attention Deficit Disorder with Hyperactivity/metabolism/pathology Autism Spectrum Disorder/metabolism/pathology Behavior, Animal Brain/metabolism/pathology Disease Models, Animal Female Genotype Glycoproteins/genetics/metabolism Interneurons/metabolism Male Memory, Short-Term Mice Mice, Inbred C57BL Mice, Knockout Motor Activity Nerve Tissue Proteins/deficiency/genetics/metabolism Parvalbumins/genetics/metabolism Phenotype Real-Time Polymerase Chain Reaction Vocalization, Animal Autism spectrum disorder Brinp1 Cortex Hyperactivity Interneuron Knock-out Neurodevelopment Parvalbumin Index. décimale : PER Périodiques Résumé : BACKGROUND: BMP/RA-inducible neural-specific protein 1 (Brinp1) is highly conserved in vertebrates, and continuously expressed in the neocortex, hippocampus, olfactory bulb and cerebellum from mid-embryonic development through to adulthood. METHODS: Brinp1 knock-out (Brinp1(-/-)) mice were generated by Cre-recombinase-mediated removal of the third exon of Brinp1. Knock-out mice were characterised by behavioural phenotyping, immunohistochemistry and expression analysis of the developing and adult brain. RESULTS: Absence of Brinp1 during development results in a behavioural phenotype resembling autism spectrum disorder (ASD), in which knock-out mice show reduced sociability and changes in vocalisation capacity. In addition, Brinp1(-/-) mice exhibit hyper-locomotor activity, have impaired short-term memory, and exhibit poor reproductive success. Brinp1(-/-) mice show increased density of parvalbumin-expressing interneurons in the adult mouse brain. Brinp1(-/-) mice do not show signs of altered neural precursor proliferation or increased apoptosis during late embryonic brain development. The expression of the related neuronal migration genes Astn1 and Astn2 is increased in the brains of Brinp1(-/-) mice, suggesting that they may ameliorate the effects of Brinp1 loss. CONCLUSIONS: Brinp1 plays an important role in normal brain development and function by influencing neuronal distribution within the cortex. The increased cortical PV-positive interneuron density and altered behaviour of Brinp1(-/-) mice resemble features of a subset of human neurological disorders; namely autism spectrum disorder (ASD) and the hyperactivity aspect of attention deficit hyperactivity disorder (ADHD). En ligne : http://dx.doi.org/10.1186/s13229-016-0079-7 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=328
in Molecular Autism > 7 (2016) . - 22p.[article] Brinp1(-/-) mice exhibit autism-like behaviour, altered memory, hyperactivity and increased parvalbumin-positive cortical interneuron density [Texte imprimé et/ou numérique] / S. R. BERKOWICZ, Auteur ; T. J. FEATHERBY, Auteur ; Z. QU, Auteur ; A. GIOUSOH, Auteur ; N. A. BORG, Auteur ; J. I. HENG, Auteur ; J. C. WHISSTOCK, Auteur ; P. I. BIRD, Auteur . - 22p.
Langues : Anglais (eng)
in Molecular Autism > 7 (2016) . - 22p.
Mots-clés : Animals Attention Deficit Disorder with Hyperactivity/metabolism/pathology Autism Spectrum Disorder/metabolism/pathology Behavior, Animal Brain/metabolism/pathology Disease Models, Animal Female Genotype Glycoproteins/genetics/metabolism Interneurons/metabolism Male Memory, Short-Term Mice Mice, Inbred C57BL Mice, Knockout Motor Activity Nerve Tissue Proteins/deficiency/genetics/metabolism Parvalbumins/genetics/metabolism Phenotype Real-Time Polymerase Chain Reaction Vocalization, Animal Autism spectrum disorder Brinp1 Cortex Hyperactivity Interneuron Knock-out Neurodevelopment Parvalbumin Index. décimale : PER Périodiques Résumé : BACKGROUND: BMP/RA-inducible neural-specific protein 1 (Brinp1) is highly conserved in vertebrates, and continuously expressed in the neocortex, hippocampus, olfactory bulb and cerebellum from mid-embryonic development through to adulthood. METHODS: Brinp1 knock-out (Brinp1(-/-)) mice were generated by Cre-recombinase-mediated removal of the third exon of Brinp1. Knock-out mice were characterised by behavioural phenotyping, immunohistochemistry and expression analysis of the developing and adult brain. RESULTS: Absence of Brinp1 during development results in a behavioural phenotype resembling autism spectrum disorder (ASD), in which knock-out mice show reduced sociability and changes in vocalisation capacity. In addition, Brinp1(-/-) mice exhibit hyper-locomotor activity, have impaired short-term memory, and exhibit poor reproductive success. Brinp1(-/-) mice show increased density of parvalbumin-expressing interneurons in the adult mouse brain. Brinp1(-/-) mice do not show signs of altered neural precursor proliferation or increased apoptosis during late embryonic brain development. The expression of the related neuronal migration genes Astn1 and Astn2 is increased in the brains of Brinp1(-/-) mice, suggesting that they may ameliorate the effects of Brinp1 loss. CONCLUSIONS: Brinp1 plays an important role in normal brain development and function by influencing neuronal distribution within the cortex. The increased cortical PV-positive interneuron density and altered behaviour of Brinp1(-/-) mice resemble features of a subset of human neurological disorders; namely autism spectrum disorder (ASD) and the hyperactivity aspect of attention deficit hyperactivity disorder (ADHD). En ligne : http://dx.doi.org/10.1186/s13229-016-0079-7 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=328 Communication and social interaction in the cannabinoid-type 1 receptor null mouse: Implications for autism spectrum disorder / W. FYKE in Autism Research, 14-9 (September 2021)
[article]
Titre : Communication and social interaction in the cannabinoid-type 1 receptor null mouse: Implications for autism spectrum disorder Type de document : Texte imprimé et/ou numérique Auteurs : W. FYKE, Auteur ; M. PREMOLI, Auteur ; V. ECHEVERRY ALZATE, Auteur ; J. A. LÓPEZ-MORENO, Auteur ; V. LEMAIRE-MAYO, Auteur ; W. E. CRUSIO, Auteur ; G. MARSICANO, Auteur ; M. WOHR, Auteur ; S. PIETROPAOLO, Auteur Article en page(s) : p.1854-1872 Langues : Anglais (eng) Mots-clés : Animals Autism Spectrum Disorder/genetics Communication Disease Models, Animal Female Male Mice Mice, Knockout Receptor, Cannabinoid, CB1/genetics Social Behavior Social Interaction cannabinoid receptor mouse models phenotype sex differences ultrasounds Index. décimale : PER Périodiques Résumé : Clinical and preclinical findings have suggested a role of the endocannabinoid system (ECS) in the etiopathology of autism spectrum disorder (ASD). Previous mouse studies have investigated the role of ECS in several behavioral domains; however, none of them has performed an extensive assessment of social and communication behaviors, that is, the main core features of ASD. This study employed a mouse line lacking the primary endocannabinoid receptor (CB1r) and characterized ultrasonic communication and social interaction in CB1(-/-) , CB1(+/-) , and CB1(+/+) males and females. Quantitative and qualitative alterations in ultrasonic vocalizations (USVs) were observed in CB1 null mice both during early development (i.e., between postnatal days 4 and 10), and at adulthood (i.e., at 3 months of age). Adult mutants also showed marked deficits in social interest in the three-chamber test and social investigation in the direct social interaction test. These behavioral alterations were mostly observed in both sexes and appeared more marked in CB1(-/-) than CB1(+/-) mutant mice. Importantly, the adult USV alterations could not be attributed to differences in anxiety or sensorimotor abilities, as assessed by the elevated plus maze and auditory startle tests. Our findings demonstrate the role of CB1r in social communication and behavior, supporting the use of the CB1 full knockout mouse in preclinical research on these ASD-relevant core domains. LAY SUMMARY: The endocannabinoid system (ECS) is important for brain development and neural function and is therefore likely to be involved in neurodevelopmental disorders such as Autism Spectrum Disorder (ASD). Here we investigated changes in social behavior and communication, which are core features of ASD, in male and female mice lacking the chief receptor of this system. Our results show that loss of this receptor results in several changes in social behavior and communication both during early development and in adulthood, thus supporting the role of the ECS in these ASD-core behavioral domains. En ligne : http://dx.doi.org/10.1002/aur.2562 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=449
in Autism Research > 14-9 (September 2021) . - p.1854-1872[article] Communication and social interaction in the cannabinoid-type 1 receptor null mouse: Implications for autism spectrum disorder [Texte imprimé et/ou numérique] / W. FYKE, Auteur ; M. PREMOLI, Auteur ; V. ECHEVERRY ALZATE, Auteur ; J. A. LÓPEZ-MORENO, Auteur ; V. LEMAIRE-MAYO, Auteur ; W. E. CRUSIO, Auteur ; G. MARSICANO, Auteur ; M. WOHR, Auteur ; S. PIETROPAOLO, Auteur . - p.1854-1872.
Langues : Anglais (eng)
in Autism Research > 14-9 (September 2021) . - p.1854-1872
Mots-clés : Animals Autism Spectrum Disorder/genetics Communication Disease Models, Animal Female Male Mice Mice, Knockout Receptor, Cannabinoid, CB1/genetics Social Behavior Social Interaction cannabinoid receptor mouse models phenotype sex differences ultrasounds Index. décimale : PER Périodiques Résumé : Clinical and preclinical findings have suggested a role of the endocannabinoid system (ECS) in the etiopathology of autism spectrum disorder (ASD). Previous mouse studies have investigated the role of ECS in several behavioral domains; however, none of them has performed an extensive assessment of social and communication behaviors, that is, the main core features of ASD. This study employed a mouse line lacking the primary endocannabinoid receptor (CB1r) and characterized ultrasonic communication and social interaction in CB1(-/-) , CB1(+/-) , and CB1(+/+) males and females. Quantitative and qualitative alterations in ultrasonic vocalizations (USVs) were observed in CB1 null mice both during early development (i.e., between postnatal days 4 and 10), and at adulthood (i.e., at 3 months of age). Adult mutants also showed marked deficits in social interest in the three-chamber test and social investigation in the direct social interaction test. These behavioral alterations were mostly observed in both sexes and appeared more marked in CB1(-/-) than CB1(+/-) mutant mice. Importantly, the adult USV alterations could not be attributed to differences in anxiety or sensorimotor abilities, as assessed by the elevated plus maze and auditory startle tests. Our findings demonstrate the role of CB1r in social communication and behavior, supporting the use of the CB1 full knockout mouse in preclinical research on these ASD-relevant core domains. LAY SUMMARY: The endocannabinoid system (ECS) is important for brain development and neural function and is therefore likely to be involved in neurodevelopmental disorders such as Autism Spectrum Disorder (ASD). Here we investigated changes in social behavior and communication, which are core features of ASD, in male and female mice lacking the chief receptor of this system. Our results show that loss of this receptor results in several changes in social behavior and communication both during early development and in adulthood, thus supporting the role of the ECS in these ASD-core behavioral domains. En ligne : http://dx.doi.org/10.1002/aur.2562 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=449 Deep phenotyping reveals movement phenotypes in mouse neurodevelopmental models / Ugne KLIBAITE in Molecular Autism, 13 (2022)
[article]
Titre : Deep phenotyping reveals movement phenotypes in mouse neurodevelopmental models Type de document : Texte imprimé et/ou numérique Auteurs : Ugne KLIBAITE, Auteur ; Mikhail KISLIN, Auteur ; Jessica L. VERPEUT, Auteur ; Silke BERGELER, Auteur ; Xiaoting SUN, Auteur ; Joshua W. SHAEVITZ, Auteur ; Samuel S.-H. WANG, Auteur Article en page(s) : 12 p. Langues : Anglais (eng) Mots-clés : Animals Autism Spectrum Disorder/genetics Disease Models, Animal Female Male Membrane Proteins/genetics Mice Mice, Inbred C57BL Mice, Knockout Nerve Tissue Proteins/genetics Phenotype Tuberous Sclerosis Complex 1 Protein/genetics Autism Behavior Cerebellum Clustering Mouse Pose estimation Index. décimale : PER Périodiques Résumé : BACKGROUND: Repetitive action, resistance to environmental change and fine motor disruptions are hallmarks of autism spectrum disorder (ASD) and other neurodevelopmental disorders, and vary considerably from individual to individual. In animal models, conventional behavioral phenotyping captures such fine-scale variations incompletely. Here we observed male and female C57BL/6J mice to methodically catalog adaptive movement over multiple days and examined two rodent models of developmental disorders against this dynamic baseline. We then investigated the behavioral consequences of a cerebellum-specific deletion in Tsc1 protein and a whole-brain knockout in Cntnap2 protein in mice. Both of these mutations are found in clinical conditions and have been associated with ASD. METHODS: We used advances in computer vision and deep learning, namely a generalized form of high-dimensional statistical analysis, to develop a framework for characterizing mouse movement on multiple timescales using a single popular behavioral assay, the open-field test. The pipeline takes virtual markers from pose estimation to find behavior clusters and generate wavelet signatures of behavior classes. We measured spatial and temporal habituation to a new environment across minutes and days, different types of self-grooming, locomotion and gait. RESULTS: Both Cntnap2 knockouts and L7-Tsc1 mutants showed forelimb lag during gait. L7-Tsc1 mutants and Cntnap2 knockouts showed complex defects in multi-day adaptation, lacking the tendency of wild-type mice to spend progressively more time in corners of the arena. In L7-Tsc1 mutant mice, failure to adapt took the form of maintained ambling, turning and locomotion, and an overall decrease in grooming. However, adaptation in these traits was similar between wild-type mice and Cntnap2 knockouts. L7-Tsc1 mutant and Cntnap2 knockout mouse models showed different patterns of behavioral state occupancy. LIMITATIONS: Genetic risk factors for autism are numerous, and we tested only two. Our pipeline was only done under conditions of free behavior. Testing under task or social conditions would reveal more information about behavioral dynamics and variability. CONCLUSIONS: Our automated pipeline for deep phenotyping successfully captures model-specific deviations in adaptation and movement as well as differences in the detailed structure of behavioral dynamics. The reported deficits indicate that deep phenotyping constitutes a robust set of ASD symptoms that may be considered for implementation in clinical settings as quantitative diagnosis criteria. En ligne : http://dx.doi.org/10.1186/s13229-022-00492-8 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=477
in Molecular Autism > 13 (2022) . - 12 p.[article] Deep phenotyping reveals movement phenotypes in mouse neurodevelopmental models [Texte imprimé et/ou numérique] / Ugne KLIBAITE, Auteur ; Mikhail KISLIN, Auteur ; Jessica L. VERPEUT, Auteur ; Silke BERGELER, Auteur ; Xiaoting SUN, Auteur ; Joshua W. SHAEVITZ, Auteur ; Samuel S.-H. WANG, Auteur . - 12 p.
Langues : Anglais (eng)
in Molecular Autism > 13 (2022) . - 12 p.
Mots-clés : Animals Autism Spectrum Disorder/genetics Disease Models, Animal Female Male Membrane Proteins/genetics Mice Mice, Inbred C57BL Mice, Knockout Nerve Tissue Proteins/genetics Phenotype Tuberous Sclerosis Complex 1 Protein/genetics Autism Behavior Cerebellum Clustering Mouse Pose estimation Index. décimale : PER Périodiques Résumé : BACKGROUND: Repetitive action, resistance to environmental change and fine motor disruptions are hallmarks of autism spectrum disorder (ASD) and other neurodevelopmental disorders, and vary considerably from individual to individual. In animal models, conventional behavioral phenotyping captures such fine-scale variations incompletely. Here we observed male and female C57BL/6J mice to methodically catalog adaptive movement over multiple days and examined two rodent models of developmental disorders against this dynamic baseline. We then investigated the behavioral consequences of a cerebellum-specific deletion in Tsc1 protein and a whole-brain knockout in Cntnap2 protein in mice. Both of these mutations are found in clinical conditions and have been associated with ASD. METHODS: We used advances in computer vision and deep learning, namely a generalized form of high-dimensional statistical analysis, to develop a framework for characterizing mouse movement on multiple timescales using a single popular behavioral assay, the open-field test. The pipeline takes virtual markers from pose estimation to find behavior clusters and generate wavelet signatures of behavior classes. We measured spatial and temporal habituation to a new environment across minutes and days, different types of self-grooming, locomotion and gait. RESULTS: Both Cntnap2 knockouts and L7-Tsc1 mutants showed forelimb lag during gait. L7-Tsc1 mutants and Cntnap2 knockouts showed complex defects in multi-day adaptation, lacking the tendency of wild-type mice to spend progressively more time in corners of the arena. In L7-Tsc1 mutant mice, failure to adapt took the form of maintained ambling, turning and locomotion, and an overall decrease in grooming. However, adaptation in these traits was similar between wild-type mice and Cntnap2 knockouts. L7-Tsc1 mutant and Cntnap2 knockout mouse models showed different patterns of behavioral state occupancy. LIMITATIONS: Genetic risk factors for autism are numerous, and we tested only two. Our pipeline was only done under conditions of free behavior. Testing under task or social conditions would reveal more information about behavioral dynamics and variability. CONCLUSIONS: Our automated pipeline for deep phenotyping successfully captures model-specific deviations in adaptation and movement as well as differences in the detailed structure of behavioral dynamics. The reported deficits indicate that deep phenotyping constitutes a robust set of ASD symptoms that may be considered for implementation in clinical settings as quantitative diagnosis criteria. En ligne : http://dx.doi.org/10.1186/s13229-022-00492-8 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=477 Deletion of Fmr1 in parvalbumin-expressing neurons results in dysregulated translation and selective behavioral deficits associated with fragile X syndrome / Magdalena KALINOWSKA in Molecular Autism, 13 (2022)
PermalinkDifferential effects by sex with Kmt5b loss / R. N. WICKRAMASEKARA in Autism Research, 14-8 (August 2021)
PermalinkSynaptic vesicle dynamic changes in a model of fragile X / Jantine A.C. BROEK in Molecular Autism, 7 (2016)
PermalinkExperience-dependent changes in hippocampal spatial activity and hippocampal circuit function are disrupted in a rat model of Fragile X Syndrome / Antonis ASIMINAS in Molecular Autism, 13 (2022)
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