People with epilepsy experience daily oscillations in seizure risk. Using a video-tracking model to automate detection, we explored mechanisms underlying spontaneous seizures in Drosophila and find that flies, like people, exhibit daily oscillations in seizure risk. These rhythms are absent in flies lacking a molecular circadian clock and are independent of sleep.
Thermogenetic screening and cell-specific clock perturbations reveal that the ventrolateral neurons, including “morning cells”, and dorsolateral neurons, comprising the “evening cells”, modulate diurnal oscillations in seizure risk. Pigment-dispersing factor and short neuropeptide F from morning cells increase seizure risk during the day. During this time, morning cell activity increases whole-brain activity.
At night, morning cells switch to glycine signaling likely acting on evening cells to decrease seizure risk. Optogenetic inhibition of clock neurons suppresses seizure risk. Our findings reveal an unexpected role for brain clock neurons in modulating daily seizure risk.
We thank Kiet Luu for assistance with fly maintenance. We thank Joy Shon, Christopher Saul, and Zhifeng Yue for technical assistance. Gabrielle Gionet and Antoneta Karaj assisted with statistical analyses.
Schematics were created with Biorender (biorender.com). The article is subject to HHMI’s Open Access to Publications policy. HHMI lab heads have previously granted a nonexclusive CC BY 4.0 license to the public and a sublicensable license to HHMI in their research articles.
Pursuant to those licenses, the author-accepted manuscript of this article can be made freely available under a CC BY 4.0 license immediately upon publication. The content is the sole responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. Stocks obtained from the Bloomington Drosophila Stock Center (NIH P40OD018537) were used in this study.
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