Characterization of early communicative behavior in mouse models of neurofibromatosis type 1 / Susan E. MALONEY in Autism Research, 11-1 (January 2018)  

Public ISBD [article]  inAutism Research > 11-1 (January 2018) . - p.44-58 Titre : Characterization of early communicative behavior in mouse models of neurofibromatosis type 1 Type de document : texte imprimé Auteurs : Susan E. MALONEY, Auteur ; Krystal C. CHANDLER, Auteur ; Corina ANASTASAKI, Auteur ; Michael A. RIEGER, Auteur ; David H. GUTMANN, Auteur ; Joseph D. DOUGHERTY, Auteur Article en page(s) : p.44-58 Langues : Anglais (eng) Index. décimale : PER Périodiques Résumé : Neurofibromatosis type 1 (NF1) is a monogenic neurodevelopmental disease caused by germline loss‐of‐function mutations in the NF1 tumor suppressor gene. Cognitive impairments are observed in approximately 80% of children with this disease, with 45–60% exhibiting autism spectrum disorder (ASD) symptomatology. In light of the high comorbidity rate between ASD and NF1, we assessed early communicative behavior by maternal‐separation induced pup ultrasonic vocalizations (USV) and developmental milestones in two distinct Nf1 genetically engineered models, one modeling clinical germline heterozygous loss of Nf1 function (Nf1+/– mice), and a second with somatic biallelic Nf1 inactivation in neuroglial progenitor cells (Nf1GFAPCKO mice). We observed altered USV production in both models: Nf1+/– mice exhibited both increased USVs across development and alterations in aspects of pitch, while Nf1GFAPCKO mice demonstrated a decrease in USVs. Developmental milestones, such as weight, pinnae detachment, and eye opening, were not disrupted in either model, indicating the USV deficits were not due to gross developmental delay, and likely reflected more specific alterations in USV circuitry. In this respect, increased whole‐brain serotonin was observed in Nf1+/– mice, but whole‐brain levels of dopamine and its metabolites were unchanged at the age of peak USV disruption, and USV alterations did not correlate with overall level of neurofibromin loss. The early communicative phenotypes reported herein should motivate further studies into the risks mediated by haploinsufficiency and biallelic deletion of Nf1 across a full battery of ASD‐relevant behavioral phenotypes, and a targeted analysis of underlying circuitry disruptions. Autism Res 2018, 11: 44–58. © 2017 International Society for Autism Research, Wiley Periodicals, Inc. Lay Summary Neurofibromatosis type 1 (NF1) is a common neurogenetic disorder caused by mutation of the NF1 gene, in which 80% of affected children exhibit cognitive and behavioral issues. Based on emerging evidence that NF1 may be an autism predisposition gene, we examined autism spectrum disorder (ASD)‐relevant early communicative behavior in Nf1 mouse models and observed alterations in both models. The changes in early communicative behavior in Nf1 mutant mice should motivate further studies into the causative factors and potential treatments for ASD arising in the context of NF1. En ligne : https://doi.org/10.1002/aur.1853 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=333 [article] Characterization of early communicative behavior in mouse models of neurofibromatosis type 1 [texte imprimé] / Susan E. MALONEY, Auteur ; Krystal C. CHANDLER, Auteur ; Corina ANASTASAKI, Auteur ; Michael A. RIEGER, Auteur ; David H. GUTMANN, Auteur ; Joseph D. DOUGHERTY, Auteur . - p.44-58. Langues : Anglais (eng) in Autism Research > 11-1 (January 2018) . - p.44-58 Index. décimale : PER Périodiques Résumé : Neurofibromatosis type 1 (NF1) is a monogenic neurodevelopmental disease caused by germline loss‐of‐function mutations in the NF1 tumor suppressor gene. Cognitive impairments are observed in approximately 80% of children with this disease, with 45–60% exhibiting autism spectrum disorder (ASD) symptomatology. In light of the high comorbidity rate between ASD and NF1, we assessed early communicative behavior by maternal‐separation induced pup ultrasonic vocalizations (USV) and developmental milestones in two distinct Nf1 genetically engineered models, one modeling clinical germline heterozygous loss of Nf1 function (Nf1+/– mice), and a second with somatic biallelic Nf1 inactivation in neuroglial progenitor cells (Nf1GFAPCKO mice). We observed altered USV production in both models: Nf1+/– mice exhibited both increased USVs across development and alterations in aspects of pitch, while Nf1GFAPCKO mice demonstrated a decrease in USVs. Developmental milestones, such as weight, pinnae detachment, and eye opening, were not disrupted in either model, indicating the USV deficits were not due to gross developmental delay, and likely reflected more specific alterations in USV circuitry. In this respect, increased whole‐brain serotonin was observed in Nf1+/– mice, but whole‐brain levels of dopamine and its metabolites were unchanged at the age of peak USV disruption, and USV alterations did not correlate with overall level of neurofibromin loss. The early communicative phenotypes reported herein should motivate further studies into the risks mediated by haploinsufficiency and biallelic deletion of Nf1 across a full battery of ASD‐relevant behavioral phenotypes, and a targeted analysis of underlying circuitry disruptions. Autism Res 2018, 11: 44–58. © 2017 International Society for Autism Research, Wiley Periodicals, Inc. Lay Summary Neurofibromatosis type 1 (NF1) is a common neurogenetic disorder caused by mutation of the NF1 gene, in which 80% of affected children exhibit cognitive and behavioral issues. Based on emerging evidence that NF1 may be an autism predisposition gene, we examined autism spectrum disorder (ASD)‐relevant early communicative behavior in Nf1 mouse models and observed alterations in both models. The changes in early communicative behavior in Nf1 mutant mice should motivate further studies into the causative factors and potential treatments for ASD arising in the context of NF1. En ligne : https://doi.org/10.1002/aur.1853 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=333

Characterization of early markers of disease in the mouse model of mucopolysaccharidosis IIIB / Katherine B. MCCULLOUGH in Journal of Neurodevelopmental Disorders, 16 (2024)  

Public ISBD [article]  inJournal of Neurodevelopmental Disorders > 16 (2024) Titre : Characterization of early markers of disease in the mouse model of mucopolysaccharidosis IIIB Type de document : texte imprimé Auteurs : Katherine B. MCCULLOUGH, Auteur ; Amanda TITUS, Auteur ; Kate REARDON, Auteur ; Sara CONYERS, Auteur ; Joseph D. DOUGHERTY, Auteur ; Xia GE, Auteur ; Joel R. GARBOW, Auteur ; Patricia DICKSON, Auteur ; Carla M. YUEDE, Auteur ; Susan E. MALONEY, Auteur Langues : Anglais (eng) Mots-clés : Humans  Animals  Adult  Child  Mucopolysaccharidosis III/genetics/pathology  Diffusion Tensor Imaging  Brain  Disease Models, Animal  Treatment Outcome  Aggression  Dominance  Fear conditioning  Gait  Lysosomal storage disorder  Mri/dti  Mucopolysaccharidosis IIIB  Sanfilippo B  Startle response  Ultrasonic vocalization Index. décimale : PER Périodiques Résumé : BACKGROUND: Mucopolysaccharidosis (MPS) IIIB, also known as Sanfilippo Syndrome B, is a devastating childhood disease. Unfortunately, there are currently no available treatments for MPS IIIB patients. Yet, animal models of lysosomal storage diseases have been valuable tools in identifying promising avenues of treatment. Enzyme replacement therapy, gene therapy, and bone marrow transplant have all shown efficacy in the MPS IIIB model systems. A ubiquitous finding across rodent models of lysosomal storage diseases is that the best treatment outcomes resulted from intervention prior to symptom onset. Therefore, the aim of the current study was to identify early markers of disease in the MPS IIIB mouse model as well as examine clinically-relevant behavioral domains not yet explored in this model. METHODS: Using the MPS IIIB mouse model, we explored early developmental trajectories of communication and gait, and later social behavior, fear-related startle and conditioning, and visual capabilities. In addition, we examined brain structure and function via magnetic resonance imaging and diffusion tensor imaging. RESULTS: We observed reduced maternal isolation-induced ultrasonic vocalizations in MPS IIIB mice relative to controls, as well as disruption in a number of the spectrotemporal features. MPS IIIB also exhibited disrupted thermoregulation during the first two postnatal weeks without any differences in body weight. The developmental trajectories of gait were largely normal. In early adulthood, we observed intact visual acuity and sociability yet a more submissive phenotype, increased aggressive behavior, and decreased social sniffing relative to controls. MPS IIIB mice showed greater inhibition of startle in response to a pretone with a decrease in overall startle response and reduced cued fear memory. MPS IIIB also weighed significantly more than controls throughout adulthood and showed larger whole brain volumes and normalized regional volumes with intact tissue integrity as measured with magnetic resonance and diffusion tensor imaging, respectively. CONCLUSIONS: Together, these results indicate disease markers are present as early as the first two weeks postnatal in this model. Further, this model recapitulates social, sensory and fear-related clinical features. Our study using a mouse model of MPS IIIB provides essential baseline information that will be useful in future evaluations of potential treatments. En ligne : https://dx.doi.org/10.1186/s11689-024-09534-z Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=575 [article] Characterization of early markers of disease in the mouse model of mucopolysaccharidosis IIIB [texte imprimé] / Katherine B. MCCULLOUGH, Auteur ; Amanda TITUS, Auteur ; Kate REARDON, Auteur ; Sara CONYERS, Auteur ; Joseph D. DOUGHERTY, Auteur ; Xia GE, Auteur ; Joel R. GARBOW, Auteur ; Patricia DICKSON, Auteur ; Carla M. YUEDE, Auteur ; Susan E. MALONEY, Auteur. Langues : Anglais (eng) in Journal of Neurodevelopmental Disorders > 16 (2024) Mots-clés : Humans  Animals  Adult  Child  Mucopolysaccharidosis III/genetics/pathology  Diffusion Tensor Imaging  Brain  Disease Models, Animal  Treatment Outcome  Aggression  Dominance  Fear conditioning  Gait  Lysosomal storage disorder  Mri/dti  Mucopolysaccharidosis IIIB  Sanfilippo B  Startle response  Ultrasonic vocalization Index. décimale : PER Périodiques Résumé : BACKGROUND: Mucopolysaccharidosis (MPS) IIIB, also known as Sanfilippo Syndrome B, is a devastating childhood disease. Unfortunately, there are currently no available treatments for MPS IIIB patients. Yet, animal models of lysosomal storage diseases have been valuable tools in identifying promising avenues of treatment. Enzyme replacement therapy, gene therapy, and bone marrow transplant have all shown efficacy in the MPS IIIB model systems. A ubiquitous finding across rodent models of lysosomal storage diseases is that the best treatment outcomes resulted from intervention prior to symptom onset. Therefore, the aim of the current study was to identify early markers of disease in the MPS IIIB mouse model as well as examine clinically-relevant behavioral domains not yet explored in this model. METHODS: Using the MPS IIIB mouse model, we explored early developmental trajectories of communication and gait, and later social behavior, fear-related startle and conditioning, and visual capabilities. In addition, we examined brain structure and function via magnetic resonance imaging and diffusion tensor imaging. RESULTS: We observed reduced maternal isolation-induced ultrasonic vocalizations in MPS IIIB mice relative to controls, as well as disruption in a number of the spectrotemporal features. MPS IIIB also exhibited disrupted thermoregulation during the first two postnatal weeks without any differences in body weight. The developmental trajectories of gait were largely normal. In early adulthood, we observed intact visual acuity and sociability yet a more submissive phenotype, increased aggressive behavior, and decreased social sniffing relative to controls. MPS IIIB mice showed greater inhibition of startle in response to a pretone with a decrease in overall startle response and reduced cued fear memory. MPS IIIB also weighed significantly more than controls throughout adulthood and showed larger whole brain volumes and normalized regional volumes with intact tissue integrity as measured with magnetic resonance and diffusion tensor imaging, respectively. CONCLUSIONS: Together, these results indicate disease markers are present as early as the first two weeks postnatal in this model. Further, this model recapitulates social, sensory and fear-related clinical features. Our study using a mouse model of MPS IIIB provides essential baseline information that will be useful in future evaluations of potential treatments. En ligne : https://dx.doi.org/10.1186/s11689-024-09534-z Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=575

Erroneous inference based on a lack of preference within one group: Autism, mice, and the social approach task / Kayla R. NYGAARD in Autism Research, 12-8 (August 2019)  

Public ISBD [article]  inAutism Research > 12-8 (August 2019) . - p.1171-1183 Titre : Erroneous inference based on a lack of preference within one group: Autism, mice, and the social approach task Type de document : texte imprimé Auteurs : Kayla R. NYGAARD, Auteur ; Susan E. MALONEY, Auteur ; Joseph D. DOUGHERTY, Auteur Article en page(s) : p.1171-1183 Langues : Anglais (eng) Mots-clés : autism spectrum disorder  mice  social behavior  social preference index  statistics  three-chambered social approach task Index. décimale : PER Périodiques Résumé : The Social Approach Task is commonly used to identify sociability deficits when modeling liability factors for autism spectrum disorder (ASD) in mice. It was developed to expand upon existing assays to examine distinct aspects of social behavior in rodents and has become a standard component of mouse ASD-relevant phenotyping pipelines. However, there is variability in the statistical analysis and interpretation of results from this task. A common analytical approach is to conduct within-group comparisons only, and then interpret a difference in significance levels as if it were a group difference, without any direct comparison. As an efficient shorthand, we named this approach EWOCs: Erroneous Within-group Only Comparisons. Here, we examined the prevalence of EWOCs and used simulations to test whether this approach could produce misleading inferences. Our review of Social Approach studies of high-confidence ASD genes revealed 45% of papers sampled used only this analytical approach. Through simulations, we then demonstrate how a lack of significant difference within one group often does not correspond to a significant difference between groups, and show this erroneous interpretation increases the rate of false positives up to 25%. Finally, we define a simple solution: use an index, like a social preference score, with direct statistical comparisons between groups to identify significant differences. We also provide power calculations to guide sample size in future studies. Overall, elimination of EWOCs and adoption of direct comparisons should result in more accurate, reliable, and reproducible data interpretations from the Social Approach Task across ASD liability models. Autism Res 2019, 12: 1171-1183. (c) 2019 International Society for Autism Research, Wiley Periodicals, Inc. LAY SUMMARY: The Social Approach Task is widely used to assess social behavior in mice and is frequently used in studies modeling autism. However, reviewing published studies showed nearly half do not use correct comparisons to interpret these data. Using simulated and original data, we argue the correct statistical approach is a direct comparison of scores between groups. This simple solution should reduce false positives and improve consistency of results across studies. En ligne : http://dx.doi.org/10.1002/aur.2154 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=405 [article] Erroneous inference based on a lack of preference within one group: Autism, mice, and the social approach task [texte imprimé] / Kayla R. NYGAARD, Auteur ; Susan E. MALONEY, Auteur ; Joseph D. DOUGHERTY, Auteur . - p.1171-1183. Langues : Anglais (eng) in Autism Research > 12-8 (August 2019) . - p.1171-1183 Mots-clés : autism spectrum disorder  mice  social behavior  social preference index  statistics  three-chambered social approach task Index. décimale : PER Périodiques Résumé : The Social Approach Task is commonly used to identify sociability deficits when modeling liability factors for autism spectrum disorder (ASD) in mice. It was developed to expand upon existing assays to examine distinct aspects of social behavior in rodents and has become a standard component of mouse ASD-relevant phenotyping pipelines. However, there is variability in the statistical analysis and interpretation of results from this task. A common analytical approach is to conduct within-group comparisons only, and then interpret a difference in significance levels as if it were a group difference, without any direct comparison. As an efficient shorthand, we named this approach EWOCs: Erroneous Within-group Only Comparisons. Here, we examined the prevalence of EWOCs and used simulations to test whether this approach could produce misleading inferences. Our review of Social Approach studies of high-confidence ASD genes revealed 45% of papers sampled used only this analytical approach. Through simulations, we then demonstrate how a lack of significant difference within one group often does not correspond to a significant difference between groups, and show this erroneous interpretation increases the rate of false positives up to 25%. Finally, we define a simple solution: use an index, like a social preference score, with direct statistical comparisons between groups to identify significant differences. We also provide power calculations to guide sample size in future studies. Overall, elimination of EWOCs and adoption of direct comparisons should result in more accurate, reliable, and reproducible data interpretations from the Social Approach Task across ASD liability models. Autism Res 2019, 12: 1171-1183. (c) 2019 International Society for Autism Research, Wiley Periodicals, Inc. LAY SUMMARY: The Social Approach Task is widely used to assess social behavior in mice and is frequently used in studies modeling autism. However, reviewing published studies showed nearly half do not use correct comparisons to interpret these data. Using simulated and original data, we argue the correct statistical approach is a direct comparison of scores between groups. This simple solution should reduce false positives and improve consistency of results across studies. En ligne : http://dx.doi.org/10.1002/aur.2154 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=405

Shared developmental gait disruptions across two mouse models of neurodevelopmental disorders / Rachel M. RAHN in Journal of Neurodevelopmental Disorders, 13 (2021)  

Public ISBD [article]  inJournal of Neurodevelopmental Disorders > 13 (2021) Titre : Shared developmental gait disruptions across two mouse models of neurodevelopmental disorders Type de document : texte imprimé Auteurs : Rachel M. RAHN, Auteur ; Claire T. WEICHSELBAUM, Auteur ; David H. GUTMANN, Auteur ; Joseph D. DOUGHERTY, Auteur ; Susan E. MALONEY, Auteur Langues : Anglais (eng) Mots-clés : Animals  Disease Models, Animal  Gait  Humans  Mice  Neurodevelopmental Disorders/genetics  Neurofibromatosis Type 1  Williams Syndrome  neurodevelopmental disorders  precision medicine Index. décimale : PER Périodiques Résumé : BACKGROUND: Motor deficits such as abnormal gait are an underappreciated yet characteristic phenotype of many neurodevelopmental disorders (NDDs), including Williams Syndrome (WS) and Neurofibromatosis Type 1 (NF1). Compared to cognitive phenotypes, gait phenotypes are readily and comparably assessed in both humans and model organisms and are controlled by well-defined CNS circuits. Discovery of a common gait phenotype between NDDs might suggest shared cellular and molecular deficits and highlight simple outcome variables to potentially quantify longitudinal treatment efficacy in NDDs. METHODS: We characterized gait using the DigiGait assay in two different murine NDD models: the complete deletion (CD) mouse, which models hemizygous loss of the complete WS locus, and the Nf1(+/R681X) mouse, which models a NF1 patient-derived heterozygous germline NF1 mutation. Longitudinal data were collected across four developmental time points (postnatal days 21-30) and one early adulthood time point. RESULTS: Compared to wildtype littermate controls, both models displayed markedly similar spatial, temporal, and postural gait abnormalities during development. Developing CD mice also displayed significant decreases in variability metrics. Multiple gait abnormalities observed across development in the Nf1(+/R681X) mice persisted into early adulthood, including increased stride length and decreased stride frequency, while developmental abnormalities in the CD model largely resolved by adulthood. CONCLUSIONS: These findings suggest that the subcomponents of gait affected in NDDs show overlap between disorders as well as some disorder-specific features, which may change over the course of development. Our incorporation of spatial, temporal, and postural gait measures also provides a template for gait characterization in other NDD models and a platform to examining circuits or longitudinal therapeutics. En ligne : https://dx.doi.org/10.1186/s11689-021-09359-0 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=573 [article] Shared developmental gait disruptions across two mouse models of neurodevelopmental disorders [texte imprimé] / Rachel M. RAHN, Auteur ; Claire T. WEICHSELBAUM, Auteur ; David H. GUTMANN, Auteur ; Joseph D. DOUGHERTY, Auteur ; Susan E. MALONEY, Auteur. Langues : Anglais (eng) in Journal of Neurodevelopmental Disorders > 13 (2021) Mots-clés : Animals  Disease Models, Animal  Gait  Humans  Mice  Neurodevelopmental Disorders/genetics  Neurofibromatosis Type 1  Williams Syndrome  neurodevelopmental disorders  precision medicine Index. décimale : PER Périodiques Résumé : BACKGROUND: Motor deficits such as abnormal gait are an underappreciated yet characteristic phenotype of many neurodevelopmental disorders (NDDs), including Williams Syndrome (WS) and Neurofibromatosis Type 1 (NF1). Compared to cognitive phenotypes, gait phenotypes are readily and comparably assessed in both humans and model organisms and are controlled by well-defined CNS circuits. Discovery of a common gait phenotype between NDDs might suggest shared cellular and molecular deficits and highlight simple outcome variables to potentially quantify longitudinal treatment efficacy in NDDs. METHODS: We characterized gait using the DigiGait assay in two different murine NDD models: the complete deletion (CD) mouse, which models hemizygous loss of the complete WS locus, and the Nf1(+/R681X) mouse, which models a NF1 patient-derived heterozygous germline NF1 mutation. Longitudinal data were collected across four developmental time points (postnatal days 21-30) and one early adulthood time point. RESULTS: Compared to wildtype littermate controls, both models displayed markedly similar spatial, temporal, and postural gait abnormalities during development. Developing CD mice also displayed significant decreases in variability metrics. Multiple gait abnormalities observed across development in the Nf1(+/R681X) mice persisted into early adulthood, including increased stride length and decreased stride frequency, while developmental abnormalities in the CD model largely resolved by adulthood. CONCLUSIONS: These findings suggest that the subcomponents of gait affected in NDDs show overlap between disorders as well as some disorder-specific features, which may change over the course of development. Our incorporation of spatial, temporal, and postural gait measures also provides a template for gait characterization in other NDD models and a platform to examining circuits or longitudinal therapeutics. En ligne : https://dx.doi.org/10.1186/s11689-021-09359-0 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=573

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