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

Han-Tao Li, Paulius Viskaitis, Eva Bracey, Daria Peleg-Raibstein and Denis Burdakov ()
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Han-Tao Li: Swiss Federal Institute of Technology | ETH Zurich
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

Nature Communications, 2024, vol. 15, issue 1, 1-12

Abstract: 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.

Date: 2024
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DOI: 10.1038/s41467-024-45515-5

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