Analysis of neuroanatomical differences in mice with genetically modified serotonin transporters assessed by structural magnetic resonance imaging / Jacob ELLEGOOD in Molecular Autism, 9 (2018)  

Public ISBD [article]  inMolecular Autism > 9 (2018) . - 24p. Titre : Analysis of neuroanatomical differences in mice with genetically modified serotonin transporters assessed by structural magnetic resonance imaging Type de document : texte imprimé Auteurs : Jacob ELLEGOOD, Auteur ; Yohan YEE, Auteur ; Travis KERR, Auteur ; Christopher L. MULLER, Auteur ; Randy D. BLAKELY, Auteur ; R. Mark HENKELMAN, Auteur ; Jeremy VEENSTRA-VANDERWEELE, Auteur ; Jason P. LERCH, Auteur Article en page(s) : 24p. Langues : Anglais (eng) Mots-clés : Animals  Brain/diagnostic imaging/metabolism  Female  Magnetic Resonance Imaging  Male  Mice  Mice, Inbred C57BL  Mutation  Neurons/metabolism  Serotonin/metabolism  Serotonin Plasma Membrane Transport Proteins/genetics/metabolism  5-ht  5htt  Brain  Dorsal raphe  Magnetic resonance imaging  Neurodevelopment  Serotonin  Slc6a4 Index. décimale : PER Périodiques Résumé : Background: The serotonin (5-HT) system has long been implicated in autism spectrum disorder (ASD) as indicated by elevated whole blood and platelet 5-HT, altered platelet and brain receptor and transporter binding, and genetic linkage and association findings. Based upon work in genetically modified mice, 5-HT is known to influence several aspects of brain development, but systematic neuroimaging studies have not previously been reported. In particular, the 5-HT transporter (serotonin transporter, SERT; 5-HTT) gene, Slc6a4, has been extensively studied. Methods: Using a 7-T MRI and deformation-based morphometry, we assessed neuroanatomical differences in an Slc6a4 knockout mouse on a C57BL/6 genetic background, along with an Slc6a4 Ala56 knockin mouse on two different genetic backgrounds (129S and C57BL/6). Results: Individually (same sex, same background, same genotype), the only differences found were in the female Slc6a4 knockout mouse; all the others had no significant differences. However, an analysis of variance across the whole study sample revealed a significant effect of Slc6a4 on the amygdala, thalamus, dorsal raphe nucleus, and lateral and frontal cortices. Conclusions: This work shows that an increase or decrease in SERT function has a significant effect on the neuroanatomy in 5-HT relevant regions, particularly the raphe nuclei. Notably, the Slc6a4 Ala56 knockin alone appears to have an insignificant, but suggestive, effect compared to the KO, which is consistent with Slc6a4 function. Despite the small number of 5-HT neurons and their localization to the brainstem, it is clear that 5-HT plays an important role in neuroanatomical organization. En ligne : https://dx.doi.org/10.1186/s13229-018-0210-z Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=371 [article] Analysis of neuroanatomical differences in mice with genetically modified serotonin transporters assessed by structural magnetic resonance imaging [texte imprimé] / Jacob ELLEGOOD, Auteur ; Yohan YEE, Auteur ; Travis KERR, Auteur ; Christopher L. MULLER, Auteur ; Randy D. BLAKELY, Auteur ; R. Mark HENKELMAN, Auteur ; Jeremy VEENSTRA-VANDERWEELE, Auteur ; Jason P. LERCH, Auteur . - 24p. Langues : Anglais (eng) in Molecular Autism > 9 (2018) . - 24p. Mots-clés : Animals  Brain/diagnostic imaging/metabolism  Female  Magnetic Resonance Imaging  Male  Mice  Mice, Inbred C57BL  Mutation  Neurons/metabolism  Serotonin/metabolism  Serotonin Plasma Membrane Transport Proteins/genetics/metabolism  5-ht  5htt  Brain  Dorsal raphe  Magnetic resonance imaging  Neurodevelopment  Serotonin  Slc6a4 Index. décimale : PER Périodiques Résumé : Background: The serotonin (5-HT) system has long been implicated in autism spectrum disorder (ASD) as indicated by elevated whole blood and platelet 5-HT, altered platelet and brain receptor and transporter binding, and genetic linkage and association findings. Based upon work in genetically modified mice, 5-HT is known to influence several aspects of brain development, but systematic neuroimaging studies have not previously been reported. In particular, the 5-HT transporter (serotonin transporter, SERT; 5-HTT) gene, Slc6a4, has been extensively studied. Methods: Using a 7-T MRI and deformation-based morphometry, we assessed neuroanatomical differences in an Slc6a4 knockout mouse on a C57BL/6 genetic background, along with an Slc6a4 Ala56 knockin mouse on two different genetic backgrounds (129S and C57BL/6). Results: Individually (same sex, same background, same genotype), the only differences found were in the female Slc6a4 knockout mouse; all the others had no significant differences. However, an analysis of variance across the whole study sample revealed a significant effect of Slc6a4 on the amygdala, thalamus, dorsal raphe nucleus, and lateral and frontal cortices. Conclusions: This work shows that an increase or decrease in SERT function has a significant effect on the neuroanatomy in 5-HT relevant regions, particularly the raphe nuclei. Notably, the Slc6a4 Ala56 knockin alone appears to have an insignificant, but suggestive, effect compared to the KO, which is consistent with Slc6a4 function. Despite the small number of 5-HT neurons and their localization to the brainstem, it is clear that 5-HT plays an important role in neuroanatomical organization. En ligne : https://dx.doi.org/10.1186/s13229-018-0210-z Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=371

Brain abnormalities in a Neuroligin3 R451C knockin mouse model associated with autism / Jacob ELLEGOOD in Autism Research, 4-5 (October 2011)  

Public ISBD [article]  inAutism Research > 4-5 (October 2011) . - p.368-376 Titre : Brain abnormalities in a Neuroligin3 R451C knockin mouse model associated with autism Type de document : texte imprimé Auteurs : Jacob ELLEGOOD, Auteur ; Jason P. LERCH, Auteur ; R. Mark HENKELMAN, Auteur Année de publication : 2011 Article en page(s) : p.368-376 Langues : Anglais (eng) Mots-clés : animal models  magnetic resonance imaging  diffusion tensor imaging  neuroligin3  volume assessment Index. décimale : PER Périodiques Résumé : Magnetic resonance imaging (MRI) has been used quite extensively for examining morphological changes in human and animal brains. One of the many advantages to examining mouse models of human autism is that we are able to examine single gene targets, like that of Neuroligin3 R451C knockin (NL3 KI), which has been directly implicated in human autism. The NL3 KI mouse model has marked volume differences in many different structures in the brain: gray matter structures, such as the hippocampus, the striatum, and the thalamus, were all found to be smaller in the NL3 KI. Further, many white matter structures were found to be significantly smaller, such as the cerebral peduncle, corpus callosum, fornix/fimbria, and internal capsule. Fractional anisotropy measurements in these structures were also measured, and no differences were found. The volume changes in the white matter regions, therefore, are not due to a general breakdown in the microstructure of the tissue and seem to be caused by fewer axons or less mature axons. A larger radial diffusivity was also found in localized regions of the corpus callosum and cerebellum. The corpus callosal changes are particularly interesting as the thinning (or reduced volume) of the corpus callosum is a consistent finding in autism. This suggests that the NL3 KI model may be useful for examining white matter changes associated with autism. Autism Res2011,4:368–376. © 2011 International Society for Autism Research, Wiley Periodicals, Inc. En ligne : http://dx.doi.org/10.1002/aur.215 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=145 [article] Brain abnormalities in a Neuroligin3 R451C knockin mouse model associated with autism [texte imprimé] / Jacob ELLEGOOD, Auteur ; Jason P. LERCH, Auteur ; R. Mark HENKELMAN, Auteur . - 2011 . - p.368-376. Langues : Anglais (eng) in Autism Research > 4-5 (October 2011) . - p.368-376 Mots-clés : animal models  magnetic resonance imaging  diffusion tensor imaging  neuroligin3  volume assessment Index. décimale : PER Périodiques Résumé : Magnetic resonance imaging (MRI) has been used quite extensively for examining morphological changes in human and animal brains. One of the many advantages to examining mouse models of human autism is that we are able to examine single gene targets, like that of Neuroligin3 R451C knockin (NL3 KI), which has been directly implicated in human autism. The NL3 KI mouse model has marked volume differences in many different structures in the brain: gray matter structures, such as the hippocampus, the striatum, and the thalamus, were all found to be smaller in the NL3 KI. Further, many white matter structures were found to be significantly smaller, such as the cerebral peduncle, corpus callosum, fornix/fimbria, and internal capsule. Fractional anisotropy measurements in these structures were also measured, and no differences were found. The volume changes in the white matter regions, therefore, are not due to a general breakdown in the microstructure of the tissue and seem to be caused by fewer axons or less mature axons. A larger radial diffusivity was also found in localized regions of the corpus callosum and cerebellum. The corpus callosal changes are particularly interesting as the thinning (or reduced volume) of the corpus callosum is a consistent finding in autism. This suggests that the NL3 KI model may be useful for examining white matter changes associated with autism. Autism Res2011,4:368–376. © 2011 International Society for Autism Research, Wiley Periodicals, Inc. En ligne : http://dx.doi.org/10.1002/aur.215 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=145

Genetic Effects on Cerebellar Structure Across Mouse Models of Autism Using a Magnetic Resonance Imaging Atlas / Patrick E. STEADMAN in Autism Research, 7-1 (February 2014)  

Public ISBD [article]  inAutism Research > 7-1 (February 2014) . - p.124-137 Titre : Genetic Effects on Cerebellar Structure Across Mouse Models of Autism Using a Magnetic Resonance Imaging Atlas Type de document : texte imprimé Auteurs : Patrick E. STEADMAN, Auteur ; Jacob ELLEGOOD, Auteur ; Kamila U. SZULC, Auteur ; Daniel H. TURNBULL, Auteur ; Alexandra L. JOYNER, Auteur ; R. Mark HENKELMAN, Auteur ; Jason P. LERCH, Auteur Article en page(s) : p.124-137 Langues : Anglais (eng) Mots-clés : animal models  neuroimaging  neuroanatomy  structural MRI  genetics Index. décimale : PER Périodiques Résumé : Magnetic resonance imaging (MRI) of autism populations is confounded by the inherent heterogeneity in the individuals' genetics and environment, two factors difficult to control for. Imaging genetic animal models that recapitulate a mutation associated with autism quantify the impact of genetics on brain morphology and mitigate the confounding factors in human studies. Here, we used MRI to image three genetic mouse models with single mutations implicated in autism: Neuroligin-3 R451C knock-in, Methyl-CpG binding protein-2 (MECP2) 308-truncation and integrin β3 homozygous knockout. This study identified the morphological differences specific to the cerebellum, a structure repeatedly linked to autism in human neuroimaging and postmortem studies. To accomplish a comparative analysis, a segmented cerebellum template was created and used to segment each study image. This template delineated 39 different cerebellar structures. For Neuroligin-3 R451C male mutants, the gray (effect size (ES) = 1.94, FDR q = 0.03) and white (ES = 1.84, q = 0.037) matter of crus II lobule and the gray matter of the paraflocculus (ES = 1.45, q = 0.045) were larger in volume. The MECP2 mutant mice had cerebellar volume changes that increased in scope depending on the genotype: hemizygous males to homozygous females. The integrin β3 mutant mouse had a drastically smaller cerebellum than controls with 28 out of 39 cerebellar structures smaller. These imaging results are discussed in relation to repetitive behaviors, sociability, and learning in the context of autism. This work further illuminates the cerebellum's role in autism. En ligne : http://dx.doi.org/10.1002/aur.1344 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=227 [article] Genetic Effects on Cerebellar Structure Across Mouse Models of Autism Using a Magnetic Resonance Imaging Atlas [texte imprimé] / Patrick E. STEADMAN, Auteur ; Jacob ELLEGOOD, Auteur ; Kamila U. SZULC, Auteur ; Daniel H. TURNBULL, Auteur ; Alexandra L. JOYNER, Auteur ; R. Mark HENKELMAN, Auteur ; Jason P. LERCH, Auteur . - p.124-137. Langues : Anglais (eng) in Autism Research > 7-1 (February 2014) . - p.124-137 Mots-clés : animal models  neuroimaging  neuroanatomy  structural MRI  genetics Index. décimale : PER Périodiques Résumé : Magnetic resonance imaging (MRI) of autism populations is confounded by the inherent heterogeneity in the individuals' genetics and environment, two factors difficult to control for. Imaging genetic animal models that recapitulate a mutation associated with autism quantify the impact of genetics on brain morphology and mitigate the confounding factors in human studies. Here, we used MRI to image three genetic mouse models with single mutations implicated in autism: Neuroligin-3 R451C knock-in, Methyl-CpG binding protein-2 (MECP2) 308-truncation and integrin β3 homozygous knockout. This study identified the morphological differences specific to the cerebellum, a structure repeatedly linked to autism in human neuroimaging and postmortem studies. To accomplish a comparative analysis, a segmented cerebellum template was created and used to segment each study image. This template delineated 39 different cerebellar structures. For Neuroligin-3 R451C male mutants, the gray (effect size (ES) = 1.94, FDR q = 0.03) and white (ES = 1.84, q = 0.037) matter of crus II lobule and the gray matter of the paraflocculus (ES = 1.45, q = 0.045) were larger in volume. The MECP2 mutant mice had cerebellar volume changes that increased in scope depending on the genotype: hemizygous males to homozygous females. The integrin β3 mutant mouse had a drastically smaller cerebellum than controls with 28 out of 39 cerebellar structures smaller. These imaging results are discussed in relation to repetitive behaviors, sociability, and learning in the context of autism. This work further illuminates the cerebellum's role in autism. En ligne : http://dx.doi.org/10.1002/aur.1344 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=227

Magnetic Resonance Imaging as a Tool for the Study of Mouse Models of Autism / Jacob ELLEGOOD in Autism - Open Access, 2-S ([01/12/2012])  

Public ISBD [article]  inAutism - Open Access > 2-S [01/12/2012] . - 8 p. Titre : Magnetic Resonance Imaging as a Tool for the Study of Mouse Models of Autism Type de document : texte imprimé Auteurs : Jacob ELLEGOOD, Auteur ; R. Mark HENKELMAN, Auteur ; Jason P. LERCH, Auteur Article en page(s) : 8 p. Langues : Anglais (eng) Index. décimale : PER Périodiques Résumé : Autism is a heterogeneous disorder, in both its behaviour and genetics. This heterogeneity has led to inconsistencies in the neuroanatomical findings in human autistic patients. The benefit of a model system, such as the mouse, is that there could be a decrease in the heterogeneity of the genetics and standardization of the environment could be done, in order to determine a specific anatomical phenotype, which is representative of a specific genotype. Magnetic Resonance Imaging (MRI) has been used quite extensively to examine morphological changes in the mouse brain; however, examining volume and tissue microstructure changes in mouse models of autism with MRI, is just in its infancy. This review will discuss the current research on anatomical phenotyping in mouse models of autism. En ligne : https://dx.doi.org/10.4172/2165-7890.S1-008 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=409 [article] Magnetic Resonance Imaging as a Tool for the Study of Mouse Models of Autism [texte imprimé] / Jacob ELLEGOOD, Auteur ; R. Mark HENKELMAN, Auteur ; Jason P. LERCH, Auteur . - 8 p. Langues : Anglais (eng) in Autism - Open Access > 2-S [01/12/2012] . - 8 p. Index. décimale : PER Périodiques Résumé : Autism is a heterogeneous disorder, in both its behaviour and genetics. This heterogeneity has led to inconsistencies in the neuroanatomical findings in human autistic patients. The benefit of a model system, such as the mouse, is that there could be a decrease in the heterogeneity of the genetics and standardization of the environment could be done, in order to determine a specific anatomical phenotype, which is representative of a specific genotype. Magnetic Resonance Imaging (MRI) has been used quite extensively to examine morphological changes in the mouse brain; however, examining volume and tissue microstructure changes in mouse models of autism with MRI, is just in its infancy. This review will discuss the current research on anatomical phenotyping in mouse models of autism. En ligne : https://dx.doi.org/10.4172/2165-7890.S1-008 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=409

Neuroanatomical Phenotypes Are Consistent With Autism-Like Behavioral Phenotypes in the 15q11-13 Duplication Mouse Model / Jacob ELLEGOOD in Autism Research, 8-5 (October 2015)  

Public ISBD [article]  inAutism Research > 8-5 (October 2015) . - p.545-555 Titre : Neuroanatomical Phenotypes Are Consistent With Autism-Like Behavioral Phenotypes in the 15q11-13 Duplication Mouse Model Type de document : texte imprimé Auteurs : Jacob ELLEGOOD, Auteur ; Nobuhiro NAKAI, Auteur ; Jin NAKATANI, Auteur ; R. Mark HENKELMAN, Auteur ; Toru TAKUMI, Auteur ; Jason P. LERCH, Auteur Article en page(s) : p.545-555 Langues : Anglais (eng) Mots-clés : animal models  structural MRI  neuroanatomy  copy number variation  molecular genetics  15q11-13 duplication Index. décimale : PER Périodiques Résumé : Paternally and maternally inherited deletions and duplications of human chromosome 15q11-13 are relatively common in the human population. Furthermore, duplications in the 15q region are often associated with autism. Both maternal and paternal interstitial 15q11-13 duplication mouse models have been previously created, where several behavioral differences were found in the paternal duplication (patDp/+) mouse but not in the maternal duplication (matDp/+). These included decreased sociability, behavioral inflexibility, abnormal ultrasonic vocalizations, decreased spontaneous activity, and increased anxiety. Similarly, in the current study, we found several anatomical differences in the patDp/+ mice that were not seen in the matDp/+ mice. Regional differences that are evident only in the paternal duplication are a smaller dentate gyrus and smaller medial striatum. These differences may be responsible for the behavioral inflexibility. Furthermore, a smaller dorsal raphe nucleus could be responsible for the reported serotonin defects. This study highlights consistency that can be found between behavioral and anatomical phenotyping. Autism Res 2015, 8: 545–555. © 2015 International Society for Autism Research, Wiley Periodicals, Inc. En ligne : http://dx.doi.org/10.1002/aur.1469 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=270 [article] Neuroanatomical Phenotypes Are Consistent With Autism-Like Behavioral Phenotypes in the 15q11-13 Duplication Mouse Model [texte imprimé] / Jacob ELLEGOOD, Auteur ; Nobuhiro NAKAI, Auteur ; Jin NAKATANI, Auteur ; R. Mark HENKELMAN, Auteur ; Toru TAKUMI, Auteur ; Jason P. LERCH, Auteur . - p.545-555. Langues : Anglais (eng) in Autism Research > 8-5 (October 2015) . - p.545-555 Mots-clés : animal models  structural MRI  neuroanatomy  copy number variation  molecular genetics  15q11-13 duplication Index. décimale : PER Périodiques Résumé : Paternally and maternally inherited deletions and duplications of human chromosome 15q11-13 are relatively common in the human population. Furthermore, duplications in the 15q region are often associated with autism. Both maternal and paternal interstitial 15q11-13 duplication mouse models have been previously created, where several behavioral differences were found in the paternal duplication (patDp/+) mouse but not in the maternal duplication (matDp/+). These included decreased sociability, behavioral inflexibility, abnormal ultrasonic vocalizations, decreased spontaneous activity, and increased anxiety. Similarly, in the current study, we found several anatomical differences in the patDp/+ mice that were not seen in the matDp/+ mice. Regional differences that are evident only in the paternal duplication are a smaller dentate gyrus and smaller medial striatum. These differences may be responsible for the behavioral inflexibility. Furthermore, a smaller dorsal raphe nucleus could be responsible for the reported serotonin defects. This study highlights consistency that can be found between behavioral and anatomical phenotyping. Autism Res 2015, 8: 545–555. © 2015 International Society for Autism Research, Wiley Periodicals, Inc. En ligne : http://dx.doi.org/10.1002/aur.1469 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=270

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