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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)
[article]
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
in Autism Research > 15-4 (April 2022) . - p.614-627[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 Female-specific association of NOS1 genotype with white matter microstructure in ADHD patients and controls / Hanneke VAN EWIJK in Journal of Child Psychology and Psychiatry, 58-8 (August 2017)
[article]
Titre : Female-specific association of NOS1 genotype with white matter microstructure in ADHD patients and controls Type de document : Texte imprimé et/ou numérique Auteurs : Hanneke VAN EWIJK, Auteur ; Janita B. BRALTEN, Auteur ; Esther D. A. VAN DUIN, Auteur ; Marina HAKOBJAN, Auteur ; Jan K. BUITELAAR, Auteur ; Dirk J. HESLENFELD, Auteur ; Pieter J. HOEKSTRA, Auteur ; Catharina A. HARTMAN, Auteur ; Martine HOOGMAN, Auteur ; Jaap OOSTERLAAN, Auteur ; Barbara FRANKE, Auteur Article en page(s) : p.958-966 Langues : Anglais (eng) Mots-clés : attention-deficit/hyperactivity disorder NOS1 imaging genetics diffusion tensor imaging Index. décimale : PER Périodiques Résumé : Background The nitric oxide synthase gene (NOS1) exon 1f (ex1f) VNTR is a known genetic risk factor for Attention-Deficit/Hyperactivity Disorder (ADHD), particularly in females. NOS1 plays an important role in neurite outgrowth and may thus influence brain development, specifically white matter (WM) microstructure, which is known to be altered in ADHD. The current study aimed to investigate whether NOS1 is associated with WM microstructure in (female) individuals with and without ADHD. Methods Diffusion Tensor Imaging (DTI) scans were collected from 187 participants with ADHD (33% female) and 103 controls (50% female), aged 8–26 years, and NOS1-ex1f VNTR genotype was determined. Whole-brain analyses were conducted for fractional anisotropy (FA) and mean diffusivity (MD) to examine associations between NOS1 and WM microstructure, including possible interactions with gender and diagnosis. Results Consistent with previous literature, NOS1-ex1f was associated with total ADHD and hyperactivity-impulsivity symptoms, but not inattention; this effect was independent of gender. NOS1-ex1f was also associated with MD values in several major WM tracts in females, but not males. In females, homozygosity for the short allele was linked to higher MD values than carriership of the long allele. MD values in these regions did not correlate with ADHD symptoms. Results were similar for participants with and without ADHD. Conclusions NOS1-ex1f VNTR is associated with WM microstructure in females in a large sample of participants with ADHD and healthy controls. Whether this association is part of a neurodevelopmental pathway from NOS1 to ADHD symptoms should be further investigated in future studies. En ligne : http://dx.doi.org/10.1111/jcpp.12742 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=317
in Journal of Child Psychology and Psychiatry > 58-8 (August 2017) . - p.958-966[article] Female-specific association of NOS1 genotype with white matter microstructure in ADHD patients and controls [Texte imprimé et/ou numérique] / Hanneke VAN EWIJK, Auteur ; Janita B. BRALTEN, Auteur ; Esther D. A. VAN DUIN, Auteur ; Marina HAKOBJAN, Auteur ; Jan K. BUITELAAR, Auteur ; Dirk J. HESLENFELD, Auteur ; Pieter J. HOEKSTRA, Auteur ; Catharina A. HARTMAN, Auteur ; Martine HOOGMAN, Auteur ; Jaap OOSTERLAAN, Auteur ; Barbara FRANKE, Auteur . - p.958-966.
Langues : Anglais (eng)
in Journal of Child Psychology and Psychiatry > 58-8 (August 2017) . - p.958-966
Mots-clés : attention-deficit/hyperactivity disorder NOS1 imaging genetics diffusion tensor imaging Index. décimale : PER Périodiques Résumé : Background The nitric oxide synthase gene (NOS1) exon 1f (ex1f) VNTR is a known genetic risk factor for Attention-Deficit/Hyperactivity Disorder (ADHD), particularly in females. NOS1 plays an important role in neurite outgrowth and may thus influence brain development, specifically white matter (WM) microstructure, which is known to be altered in ADHD. The current study aimed to investigate whether NOS1 is associated with WM microstructure in (female) individuals with and without ADHD. Methods Diffusion Tensor Imaging (DTI) scans were collected from 187 participants with ADHD (33% female) and 103 controls (50% female), aged 8–26 years, and NOS1-ex1f VNTR genotype was determined. Whole-brain analyses were conducted for fractional anisotropy (FA) and mean diffusivity (MD) to examine associations between NOS1 and WM microstructure, including possible interactions with gender and diagnosis. Results Consistent with previous literature, NOS1-ex1f was associated with total ADHD and hyperactivity-impulsivity symptoms, but not inattention; this effect was independent of gender. NOS1-ex1f was also associated with MD values in several major WM tracts in females, but not males. In females, homozygosity for the short allele was linked to higher MD values than carriership of the long allele. MD values in these regions did not correlate with ADHD symptoms. Results were similar for participants with and without ADHD. Conclusions NOS1-ex1f VNTR is associated with WM microstructure in females in a large sample of participants with ADHD and healthy controls. Whether this association is part of a neurodevelopmental pathway from NOS1 to ADHD symptoms should be further investigated in future studies. En ligne : http://dx.doi.org/10.1111/jcpp.12742 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=317 The oxytocin receptor gene predicts brain activity during an emotion recognition task in autism / F. UZEFOVSKY in Molecular Autism, 10 (2019)
[article]
Titre : The oxytocin receptor gene predicts brain activity during an emotion recognition task in autism Type de document : Texte imprimé et/ou numérique Auteurs : F. UZEFOVSKY, Auteur ; Richard A. I. BETHLEHEM, Auteur ; S. SHAMAY-TSOORY, Auteur ; A. RUIGROK, Auteur ; R. HOLT, Auteur ; M. SPENCER, Auteur ; L. CHURA, Auteur ; V. WARRIER, Auteur ; Bhismadev CHAKRABARTI, Auteur ; Edward T. BULLMORE, Auteur ; J. SUCKLING, Auteur ; D. FLORIS, Auteur ; Simon BARON-COHEN, Auteur Article en page(s) : 12 p. Langues : Anglais (eng) Mots-clés : Autism Imaging genetics Oxytocin receptor Supramarginal gyrus fMRI the relevant national and institutional committees on human experimentation and with the Declaration of Helsinki of 1975, as revised in 2008.Not applicable.The authors declare that they have no competing interests.Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. Index. décimale : PER Périodiques Résumé : Background: Autism is a highly varied and heritable neurodevelopmental condition, and common variants explain approximately 50% of the genetic variance of autism. One of the genes implicated in autism is the oxytocin receptor (OXTR). The current study combined genetic and brain imaging (fMRI) data to examine the moderating effect of genotype on the association between diagnosis and brain activity in response to a test of cognitive empathy. Methods: Participants were adolescents (mean age = 14.7 +/- 1.7) who were genotyped for single nucleotide polymorphisms (SNPs) within the OXTR and underwent functional brain imaging while completing the adolescent version of the 'Reading the Mind in the Eyes' Test (Eyes Test). Results: Two (rs2254298, rs53576) of the five OXTR SNPs examined were significantly associated with brain activity during the Eyes Test, and three of the SNPs (rs2254298, rs53576, rs2268491) interacted with diagnostic status to predict brain activity. All of the effects localized to the right supramarginal gyrus (rSMG) and an overlap analysis revealed a large overlap of the effects. An exploratory analysis showed that activity within an anatomically defined rSMG and genotype can predict diagnostic status with reasonable accuracy. Conclusions: This is one of the first studies to investigate OXTR and brain function in autism. The findings suggest a neurogenetic mechanism by which OXTR-dependent activity within the rSMG is related to the aetiology of autism. En ligne : https://dx.doi.org/10.1186/s13229-019-0258-4 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=389
in Molecular Autism > 10 (2019) . - 12 p.[article] The oxytocin receptor gene predicts brain activity during an emotion recognition task in autism [Texte imprimé et/ou numérique] / F. UZEFOVSKY, Auteur ; Richard A. I. BETHLEHEM, Auteur ; S. SHAMAY-TSOORY, Auteur ; A. RUIGROK, Auteur ; R. HOLT, Auteur ; M. SPENCER, Auteur ; L. CHURA, Auteur ; V. WARRIER, Auteur ; Bhismadev CHAKRABARTI, Auteur ; Edward T. BULLMORE, Auteur ; J. SUCKLING, Auteur ; D. FLORIS, Auteur ; Simon BARON-COHEN, Auteur . - 12 p.
Langues : Anglais (eng)
in Molecular Autism > 10 (2019) . - 12 p.
Mots-clés : Autism Imaging genetics Oxytocin receptor Supramarginal gyrus fMRI the relevant national and institutional committees on human experimentation and with the Declaration of Helsinki of 1975, as revised in 2008.Not applicable.The authors declare that they have no competing interests.Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. Index. décimale : PER Périodiques Résumé : Background: Autism is a highly varied and heritable neurodevelopmental condition, and common variants explain approximately 50% of the genetic variance of autism. One of the genes implicated in autism is the oxytocin receptor (OXTR). The current study combined genetic and brain imaging (fMRI) data to examine the moderating effect of genotype on the association between diagnosis and brain activity in response to a test of cognitive empathy. Methods: Participants were adolescents (mean age = 14.7 +/- 1.7) who were genotyped for single nucleotide polymorphisms (SNPs) within the OXTR and underwent functional brain imaging while completing the adolescent version of the 'Reading the Mind in the Eyes' Test (Eyes Test). Results: Two (rs2254298, rs53576) of the five OXTR SNPs examined were significantly associated with brain activity during the Eyes Test, and three of the SNPs (rs2254298, rs53576, rs2268491) interacted with diagnostic status to predict brain activity. All of the effects localized to the right supramarginal gyrus (rSMG) and an overlap analysis revealed a large overlap of the effects. An exploratory analysis showed that activity within an anatomically defined rSMG and genotype can predict diagnostic status with reasonable accuracy. Conclusions: This is one of the first studies to investigate OXTR and brain function in autism. The findings suggest a neurogenetic mechanism by which OXTR-dependent activity within the rSMG is related to the aetiology of autism. En ligne : https://dx.doi.org/10.1186/s13229-019-0258-4 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=389