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Transient targeting of hypothalamic orexin neurons alleviates seizures in a mouse model of epilepsy

Author

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  • Han-Tao Li

    (Swiss Federal Institute of Technology | ETH Zurich
    Chang Gung Memorial Hospital at Linkou Medical Center and Chang Gung University College of Medicine)

  • Paulius Viskaitis

    (Swiss Federal Institute of Technology | ETH Zurich)

  • Eva Bracey

    (Swiss Federal Institute of Technology | ETH Zurich)

  • Daria Peleg-Raibstein

    (Swiss Federal Institute of Technology | ETH Zurich)

  • Denis Burdakov

    (Swiss Federal Institute of Technology | ETH Zurich)

Abstract

Lateral hypothalamic (LH) hypocretin/orexin neurons (HONs) control brain-wide electrical excitation. Abnormally high excitation produces epileptic seizures, which affect millions of people and need better treatments. HON population activity spikes from minute to minute, but the role of this in seizures is unknown. Here, we describe correlative and causal links between HON activity spikes and seizures. Applying temporally-targeted HON recordings and optogenetic silencing to a male mouse model of acute epilepsy, we found that pre-seizure HON activity predicts and controls the electrophysiology and behavioral pathology of subsequent seizures. No such links were detected for HON activity during seizures. Having thus defined the time window where HONs influence seizures, we targeted it with LH deep brain stimulation (DBS), which inhibited HON population activity, and produced seizure protection. Collectively, these results uncover a feature of brain activity linked to seizures, and demonstrate a proof-of-concept treatment that controls this feature and alleviates epilepsy.

Suggested Citation

  • Han-Tao Li & Paulius Viskaitis & Eva Bracey & Daria Peleg-Raibstein & Denis Burdakov, 2024. "Transient targeting of hypothalamic orexin neurons alleviates seizures in a mouse model of epilepsy," Nature Communications, Nature, vol. 15(1), pages 1-12, December.
    • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-45515-5
    DOI: 10.1038/s41467-024-45515-5
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    References listed on IDEAS

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    1. Antoine R. Adamantidis & Feng Zhang & Alexander M. Aravanis & Karl Deisseroth & Luis de Lecea, 2007. "Neural substrates of awakening probed with optogenetic control of hypocretin neurons," Nature, Nature, vol. 450(7168), pages 420-424, November.
    2. J. Antonio González & Panagiota Iordanidou & Molly Strom & Antoine Adamantidis & Denis Burdakov, 2016. "Awake dynamics and brain-wide direct inputs of hypothalamic MCH and orexin networks," Nature Communications, Nature, vol. 7(1), pages 1-9, September.
    3. Ben Engelhard & Joel Finkelstein & Julia Cox & Weston Fleming & Hee Jae Jang & Sharon Ornelas & Sue Ann Koay & Stephan Y. Thiberge & Nathaniel D. Daw & David W. Tank & Ilana B. Witten, 2019. "Specialized coding of sensory, motor and cognitive variables in VTA dopamine neurons," Nature, Nature, vol. 570(7762), pages 509-513, June.
    4. Christin Kosse & Denis Burdakov, 2019. "Natural hypothalamic circuit dynamics underlying object memorization," Nature Communications, Nature, vol. 10(1), pages 1-8, December.
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