Sleep drive, not total sleep amount, increases seizure risk
Abstract Sleep loss has been associated with increased seizure risk since antiquity. Using automated video detection of spontaneous seizures in Drosophila epilepsy models, we show that seizures worsen only when sleep restriction raises homeostatic “sleep drive,” not simply when total sleep amount fa...
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| Format: | Article |
| Language: | English |
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Nature Portfolio
2025-07-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-025-62311-x |
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| author | Vishnu Anand Cuddapah Cynthia T. Hsu Fernanda Valle Sirias Yongjun Li Hrishit M. Shah Christopher Saul Samantha Killiany Camilo Guevara Joy Shon Zhifeng Yue Gabrielle L. Gionet Mary E. Putt Amita Sehgal |
| author_facet | Vishnu Anand Cuddapah Cynthia T. Hsu Fernanda Valle Sirias Yongjun Li Hrishit M. Shah Christopher Saul Samantha Killiany Camilo Guevara Joy Shon Zhifeng Yue Gabrielle L. Gionet Mary E. Putt Amita Sehgal |
| author_sort | Vishnu Anand Cuddapah |
| collection | DOAJ |
| description | Abstract Sleep loss has been associated with increased seizure risk since antiquity. Using automated video detection of spontaneous seizures in Drosophila epilepsy models, we show that seizures worsen only when sleep restriction raises homeostatic “sleep drive,” not simply when total sleep amount falls. This is supported by the paradoxical finding that acute activation of sleep-promoting circuits worsens seizures, because it increases sleep drive without changing sleep amount. Sleep-promoting circuits become hyperactive after sleep loss and are associated with increased whole-brain activity. During sleep restriction, optogenetic inhibition of sleep-promoting circuits to reduce sleep drive protects against seizures. Downregulation of the 5HT1A serotonin receptor in sleep-promoting cells mediates the effect of sleep drive on seizures, and we identify an FDA-approved 5HT1A agonist to mitigate seizures. Our findings demonstrate that while homeostatic sleep is needed to recoup lost sleep, sleep drive comes at the cost of increasing seizure susceptibility. |
| format | Article |
| id | doaj-art-9f3e1b4eda814c66ab1ca4e38a60799d |
| institution | DOAJ |
| issn | 2041-1723 |
| language | English |
| publishDate | 2025-07-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj-art-9f3e1b4eda814c66ab1ca4e38a60799d2025-08-20T03:05:15ZengNature PortfolioNature Communications2041-17232025-07-0116111410.1038/s41467-025-62311-xSleep drive, not total sleep amount, increases seizure riskVishnu Anand Cuddapah0Cynthia T. Hsu1Fernanda Valle Sirias2Yongjun Li3Hrishit M. Shah4Christopher Saul5Samantha Killiany6Camilo Guevara7Joy Shon8Zhifeng Yue9Gabrielle L. Gionet10Mary E. Putt11Amita Sehgal12Jan and Dan Duncan Neurological Research Institute, Texas Children’s HospitalHoward Hughes Medical Institute, University of PennsylvaniaJan and Dan Duncan Neurological Research Institute, Texas Children’s HospitalHoward Hughes Medical Institute, University of PennsylvaniaHoward Hughes Medical Institute, University of PennsylvaniaHoward Hughes Medical Institute, University of PennsylvaniaHoward Hughes Medical Institute, University of PennsylvaniaHoward Hughes Medical Institute, University of PennsylvaniaHoward Hughes Medical Institute, University of PennsylvaniaHoward Hughes Medical Institute, University of PennsylvaniaDepartment of Biostatistics, Epidemiology and Informatics University of PennsylvaniaDepartment of Biostatistics, Epidemiology and Informatics University of PennsylvaniaHoward Hughes Medical Institute, University of PennsylvaniaAbstract Sleep loss has been associated with increased seizure risk since antiquity. Using automated video detection of spontaneous seizures in Drosophila epilepsy models, we show that seizures worsen only when sleep restriction raises homeostatic “sleep drive,” not simply when total sleep amount falls. This is supported by the paradoxical finding that acute activation of sleep-promoting circuits worsens seizures, because it increases sleep drive without changing sleep amount. Sleep-promoting circuits become hyperactive after sleep loss and are associated with increased whole-brain activity. During sleep restriction, optogenetic inhibition of sleep-promoting circuits to reduce sleep drive protects against seizures. Downregulation of the 5HT1A serotonin receptor in sleep-promoting cells mediates the effect of sleep drive on seizures, and we identify an FDA-approved 5HT1A agonist to mitigate seizures. Our findings demonstrate that while homeostatic sleep is needed to recoup lost sleep, sleep drive comes at the cost of increasing seizure susceptibility.https://doi.org/10.1038/s41467-025-62311-x |
| spellingShingle | Vishnu Anand Cuddapah Cynthia T. Hsu Fernanda Valle Sirias Yongjun Li Hrishit M. Shah Christopher Saul Samantha Killiany Camilo Guevara Joy Shon Zhifeng Yue Gabrielle L. Gionet Mary E. Putt Amita Sehgal Sleep drive, not total sleep amount, increases seizure risk Nature Communications |
| title | Sleep drive, not total sleep amount, increases seizure risk |
| title_full | Sleep drive, not total sleep amount, increases seizure risk |
| title_fullStr | Sleep drive, not total sleep amount, increases seizure risk |
| title_full_unstemmed | Sleep drive, not total sleep amount, increases seizure risk |
| title_short | Sleep drive, not total sleep amount, increases seizure risk |
| title_sort | sleep drive not total sleep amount increases seizure risk |
| url | https://doi.org/10.1038/s41467-025-62311-x |
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