Recovery of centralities in medial prefrontal and sensory-related cortices associated with social behavior improvements in an autism mouse model
Abstract Anti-epileptics and diuretics, used for unapproved purposes, have been reported to ameliorate social deficits in individuals with autism spectrum disorder. However, the underlying neural mechanisms remain unclear. Here, we explored the effects of bumetanide, clonazepam, and phenytoin, all w...
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Nature Portfolio
2025-07-01
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| Online Access: | https://doi.org/10.1038/s41598-025-05996-w |
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| author | Hiroki Ueno Yusuke Iyanaga Katsuyuki Kunida Yuta Hara Hiroki Miura Yuka Nakai Masato Tanuma Misuzu Hayashida Rei Yokoyama Jin Ohkubo Kaoru Seiriki Atsuko Hayata-Takano Tomoka Ao Shun Yamaguchi Shiho Kitaoka Tomoyuki Furuyashiki Yukio Ago Takanobu Nakazawa Kazuhiro Takuma Junichiro Yoshimoto Hitoshi Hashimoto Atsushi Kasai |
| author_facet | Hiroki Ueno Yusuke Iyanaga Katsuyuki Kunida Yuta Hara Hiroki Miura Yuka Nakai Masato Tanuma Misuzu Hayashida Rei Yokoyama Jin Ohkubo Kaoru Seiriki Atsuko Hayata-Takano Tomoka Ao Shun Yamaguchi Shiho Kitaoka Tomoyuki Furuyashiki Yukio Ago Takanobu Nakazawa Kazuhiro Takuma Junichiro Yoshimoto Hitoshi Hashimoto Atsushi Kasai |
| author_sort | Hiroki Ueno |
| collection | DOAJ |
| description | Abstract Anti-epileptics and diuretics, used for unapproved purposes, have been reported to ameliorate social deficits in individuals with autism spectrum disorder. However, the underlying neural mechanisms remain unclear. Here, we explored the effects of bumetanide, clonazepam, and phenytoin, all with clinically reported properties for improving social deficits, in a prenatal valproic acid exposure male mouse model. By combining comprehensive behavioral analysis with brain-wide mapping of Arc, an immediate early gene, we found a correlation between social behaviors and Arc-positive cell counts across brain areas. Network analysis identified the medial prefrontal and sensory-related cortices as critical nodes with high centrality, playing critical roles in connecting other brain regions. These metrics are associated with both the decreased social behaviors and their recovery following drug treatment. Our findings suggest that restoring the centralities of the medial prefrontal and sensory-related cortices serve as a potential biomarker for evaluating drug efficacy in autism spectrum disorder. |
| format | Article |
| id | doaj-art-d0feb7dcfc0845c596e26f939524c44e |
| institution | Kabale University |
| issn | 2045-2322 |
| language | English |
| publishDate | 2025-07-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Scientific Reports |
| spelling | doaj-art-d0feb7dcfc0845c596e26f939524c44e2025-08-20T03:45:23ZengNature PortfolioScientific Reports2045-23222025-07-0115111310.1038/s41598-025-05996-wRecovery of centralities in medial prefrontal and sensory-related cortices associated with social behavior improvements in an autism mouse modelHiroki Ueno0Yusuke Iyanaga1Katsuyuki Kunida2Yuta Hara3Hiroki Miura4Yuka Nakai5Masato Tanuma6Misuzu Hayashida7Rei Yokoyama8Jin Ohkubo9Kaoru Seiriki10Atsuko Hayata-Takano11Tomoka Ao12Shun Yamaguchi13Shiho Kitaoka14Tomoyuki Furuyashiki15Yukio Ago16Takanobu Nakazawa17Kazuhiro Takuma18Junichiro Yoshimoto19Hitoshi Hashimoto20Atsushi Kasai21Laboratory of Molecular Neuropharmacology, Graduate School of Pharmaceutical Sciences, Osaka UniversityLaboratory of Molecular Neuropharmacology, Graduate School of Pharmaceutical Sciences, Osaka UniversitySchool of Medicine, Fujita Health UniversityDivision of Chemotherapy, Faculty of Pharmacy, Kindai UniversityLaboratory of Molecular Neuropharmacology, Graduate School of Pharmaceutical Sciences, Osaka UniversityLaboratory of Molecular Neuropharmacology, Graduate School of Pharmaceutical Sciences, Osaka UniversityLaboratory of Molecular Neuropharmacology, Graduate School of Pharmaceutical Sciences, Osaka UniversityLaboratory of Molecular Neuropharmacology, Graduate School of Pharmaceutical Sciences, Osaka UniversityLaboratory of Molecular Neuropharmacology, Graduate School of Pharmaceutical Sciences, Osaka UniversityLaboratory of Molecular Neuropharmacology, Graduate School of Pharmaceutical Sciences, Osaka UniversityLaboratory of Molecular Neuropharmacology, Graduate School of Pharmaceutical Sciences, Osaka UniversityLaboratory of Molecular Neuropharmacology, Graduate School of Pharmaceutical Sciences, Osaka UniversityLaboratory of Molecular Neuropharmacology, Graduate School of Pharmaceutical Sciences, Osaka UniversityDepartment of Morphological Neuroscience, Gifu University Graduate School of MedicineDepartment of Pharmacology, Hyogo College of MedicineDivision of Pharmacology, Graduate School of Medicine, Kobe UniversityDepartment of Cellular and Molecular Pharmacology, Graduate School of Biomedical and Health Sciences, Hiroshima UniversityLaboratory of Molecular Neuropharmacology, Graduate School of Pharmaceutical Sciences, Osaka UniversityDepartment of Pharmacology, Graduate School of Dentistry, Osaka UniversitySchool of Medicine, Fujita Health UniversityLaboratory of Molecular Neuropharmacology, Graduate School of Pharmaceutical Sciences, Osaka UniversityLaboratory of Molecular Neuropharmacology, Graduate School of Pharmaceutical Sciences, Osaka UniversityAbstract Anti-epileptics and diuretics, used for unapproved purposes, have been reported to ameliorate social deficits in individuals with autism spectrum disorder. However, the underlying neural mechanisms remain unclear. Here, we explored the effects of bumetanide, clonazepam, and phenytoin, all with clinically reported properties for improving social deficits, in a prenatal valproic acid exposure male mouse model. By combining comprehensive behavioral analysis with brain-wide mapping of Arc, an immediate early gene, we found a correlation between social behaviors and Arc-positive cell counts across brain areas. Network analysis identified the medial prefrontal and sensory-related cortices as critical nodes with high centrality, playing critical roles in connecting other brain regions. These metrics are associated with both the decreased social behaviors and their recovery following drug treatment. Our findings suggest that restoring the centralities of the medial prefrontal and sensory-related cortices serve as a potential biomarker for evaluating drug efficacy in autism spectrum disorder.https://doi.org/10.1038/s41598-025-05996-wAutism spectrum disordersNode centralityMedial prefrontal cortexSensorimotor cortexBrain-wide IEG mapping |
| spellingShingle | Hiroki Ueno Yusuke Iyanaga Katsuyuki Kunida Yuta Hara Hiroki Miura Yuka Nakai Masato Tanuma Misuzu Hayashida Rei Yokoyama Jin Ohkubo Kaoru Seiriki Atsuko Hayata-Takano Tomoka Ao Shun Yamaguchi Shiho Kitaoka Tomoyuki Furuyashiki Yukio Ago Takanobu Nakazawa Kazuhiro Takuma Junichiro Yoshimoto Hitoshi Hashimoto Atsushi Kasai Recovery of centralities in medial prefrontal and sensory-related cortices associated with social behavior improvements in an autism mouse model Scientific Reports Autism spectrum disorders Node centrality Medial prefrontal cortex Sensorimotor cortex Brain-wide IEG mapping |
| title | Recovery of centralities in medial prefrontal and sensory-related cortices associated with social behavior improvements in an autism mouse model |
| title_full | Recovery of centralities in medial prefrontal and sensory-related cortices associated with social behavior improvements in an autism mouse model |
| title_fullStr | Recovery of centralities in medial prefrontal and sensory-related cortices associated with social behavior improvements in an autism mouse model |
| title_full_unstemmed | Recovery of centralities in medial prefrontal and sensory-related cortices associated with social behavior improvements in an autism mouse model |
| title_short | Recovery of centralities in medial prefrontal and sensory-related cortices associated with social behavior improvements in an autism mouse model |
| title_sort | recovery of centralities in medial prefrontal and sensory related cortices associated with social behavior improvements in an autism mouse model |
| topic | Autism spectrum disorders Node centrality Medial prefrontal cortex Sensorimotor cortex Brain-wide IEG mapping |
| url | https://doi.org/10.1038/s41598-025-05996-w |
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