Disruption of Circadian Rhythms by Ambient Light during Neurodevelopment Leads to Autistic-like Molecular and Behavioral Alterations in Adult Mice
Although circadian rhythms are thought to be essential for maintaining body health, the effects of chronic circadian disruption during neurodevelopment remain elusive. Here, using the “Short Day” (SD) mouse model, in which an 8 h/8 h light/dark (LD) cycle was applied from embryonic day 1 to postnata...
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MDPI AG
2021-11-01
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| Online Access: | https://www.mdpi.com/2073-4409/10/12/3314 |
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| author | Kun Fang Dong Liu Salil S. Pathak Bowen Yang Jin Li Ramanujam Karthikeyan Owen Y. Chao Yi-Mei Yang Victor X. Jin Ruifeng Cao |
| author_facet | Kun Fang Dong Liu Salil S. Pathak Bowen Yang Jin Li Ramanujam Karthikeyan Owen Y. Chao Yi-Mei Yang Victor X. Jin Ruifeng Cao |
| author_sort | Kun Fang |
| collection | DOAJ |
| description | Although circadian rhythms are thought to be essential for maintaining body health, the effects of chronic circadian disruption during neurodevelopment remain elusive. Here, using the “Short Day” (SD) mouse model, in which an 8 h/8 h light/dark (LD) cycle was applied from embryonic day 1 to postnatal day 42, we investigated the molecular and behavioral changes after circadian disruption in mice. Adult SD mice fully entrained to the 8 h/8 h LD cycle, and the circadian oscillations of the clock proteins, PERIOD1 and PERIOD2, were disrupted in the suprachiasmatic nucleus and the hippocampus of these mice. By RNA-seq widespread changes were identified in the hippocampal transcriptome, which are functionally associated with neurodevelopment, translational control, and autism. By western blotting and immunostaining hyperactivation of the mTOR and MAPK signaling pathways and enhanced global protein synthesis were found in the hippocampi of SD mice. Electrophysiological recording uncovered enhanced excitatory, but attenuated inhibitory, synaptic transmission in the hippocampal CA1 pyramidal neurons. These functional changes at synapses were corroborated by the immature morphology of the dendritic spines in these neurons. Lastly, autistic-like animal behavioral changes, including impaired social interaction and communication, increased repetitive behaviors, and impaired novel object recognition and location memory, were found in SD mice. Together, these results demonstrate molecular, cellular, and behavioral changes in SD mice, all of which resemble autistic-like phenotypes caused by circadian rhythm disruption. The findings highlight a critical role for circadian rhythms in neurodevelopment. |
| first_indexed | 2024-03-10T04:26:10Z |
| format | Article |
| id | doaj.art-c8ec39bbe3704d0e8a3f71545d37d0fa |
| institution | Directory Open Access Journal |
| issn | 2073-4409 |
| language | English |
| last_indexed | 2024-03-10T04:26:10Z |
| publishDate | 2021-11-01 |
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| series | Cells |
| spelling | doaj.art-c8ec39bbe3704d0e8a3f71545d37d0fa2023-11-23T07:36:04ZengMDPI AGCells2073-44092021-11-011012331410.3390/cells10123314Disruption of Circadian Rhythms by Ambient Light during Neurodevelopment Leads to Autistic-like Molecular and Behavioral Alterations in Adult MiceKun Fang0Dong Liu1Salil S. Pathak2Bowen Yang3Jin Li4Ramanujam Karthikeyan5Owen Y. Chao6Yi-Mei Yang7Victor X. Jin8Ruifeng Cao9Department of Molecular Medicine, University of Texas Health San Antonio, San Antonio, TX 78229, USADepartment of Biomedical Sciences, University of Minnesota Medical School, Duluth, MN 55812, USADepartment of Biomedical Sciences, University of Minnesota Medical School, Duluth, MN 55812, USADepartment of Molecular Medicine, University of Texas Health San Antonio, San Antonio, TX 78229, USADepartment of Biomedical Sciences, University of Minnesota Medical School, Duluth, MN 55812, USADepartment of Biomedical Sciences, University of Minnesota Medical School, Duluth, MN 55812, USADepartment of Biomedical Sciences, University of Minnesota Medical School, Duluth, MN 55812, USADepartment of Biomedical Sciences, University of Minnesota Medical School, Duluth, MN 55812, USADepartment of Molecular Medicine, University of Texas Health San Antonio, San Antonio, TX 78229, USADepartment of Biomedical Sciences, University of Minnesota Medical School, Duluth, MN 55812, USAAlthough circadian rhythms are thought to be essential for maintaining body health, the effects of chronic circadian disruption during neurodevelopment remain elusive. Here, using the “Short Day” (SD) mouse model, in which an 8 h/8 h light/dark (LD) cycle was applied from embryonic day 1 to postnatal day 42, we investigated the molecular and behavioral changes after circadian disruption in mice. Adult SD mice fully entrained to the 8 h/8 h LD cycle, and the circadian oscillations of the clock proteins, PERIOD1 and PERIOD2, were disrupted in the suprachiasmatic nucleus and the hippocampus of these mice. By RNA-seq widespread changes were identified in the hippocampal transcriptome, which are functionally associated with neurodevelopment, translational control, and autism. By western blotting and immunostaining hyperactivation of the mTOR and MAPK signaling pathways and enhanced global protein synthesis were found in the hippocampi of SD mice. Electrophysiological recording uncovered enhanced excitatory, but attenuated inhibitory, synaptic transmission in the hippocampal CA1 pyramidal neurons. These functional changes at synapses were corroborated by the immature morphology of the dendritic spines in these neurons. Lastly, autistic-like animal behavioral changes, including impaired social interaction and communication, increased repetitive behaviors, and impaired novel object recognition and location memory, were found in SD mice. Together, these results demonstrate molecular, cellular, and behavioral changes in SD mice, all of which resemble autistic-like phenotypes caused by circadian rhythm disruption. The findings highlight a critical role for circadian rhythms in neurodevelopment.https://www.mdpi.com/2073-4409/10/12/3314circadian rhythmneurodevelopmental disordertranslational controlmTORMAPKautism |
| spellingShingle | Kun Fang Dong Liu Salil S. Pathak Bowen Yang Jin Li Ramanujam Karthikeyan Owen Y. Chao Yi-Mei Yang Victor X. Jin Ruifeng Cao Disruption of Circadian Rhythms by Ambient Light during Neurodevelopment Leads to Autistic-like Molecular and Behavioral Alterations in Adult Mice Cells circadian rhythm neurodevelopmental disorder translational control mTOR MAPK autism |
| title | Disruption of Circadian Rhythms by Ambient Light during Neurodevelopment Leads to Autistic-like Molecular and Behavioral Alterations in Adult Mice |
| title_full | Disruption of Circadian Rhythms by Ambient Light during Neurodevelopment Leads to Autistic-like Molecular and Behavioral Alterations in Adult Mice |
| title_fullStr | Disruption of Circadian Rhythms by Ambient Light during Neurodevelopment Leads to Autistic-like Molecular and Behavioral Alterations in Adult Mice |
| title_full_unstemmed | Disruption of Circadian Rhythms by Ambient Light during Neurodevelopment Leads to Autistic-like Molecular and Behavioral Alterations in Adult Mice |
| title_short | Disruption of Circadian Rhythms by Ambient Light during Neurodevelopment Leads to Autistic-like Molecular and Behavioral Alterations in Adult Mice |
| title_sort | disruption of circadian rhythms by ambient light during neurodevelopment leads to autistic like molecular and behavioral alterations in adult mice |
| topic | circadian rhythm neurodevelopmental disorder translational control mTOR MAPK autism |
| url | https://www.mdpi.com/2073-4409/10/12/3314 |
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