Zona incerta somatostatin⁺ neurons modulate seizure progression through hypothalamic circuits.
6 affiliations
- 1Zhejiang Collaborative Innovation Center for the Brain Diseases with Integrative Medicine, Zhejiang Key Laboratory of Neuropsychopharmacology, School of Pharmaceutical Sciences, The First Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou, China.
- 2Medical Research Center, Shandong Medical and Pharmaceutical University Hospital, Binzhou, China.
- 3College of Pharmaceutical Sciences, Zhejiang Pharmaceutical University, Ningbo, China.
- 4Zhejiang Collaborative Innovation Center for the Brain Diseases with Integrative Medicine, Zhejiang Key Laboratory of Neuropsychopharmacology, School of Pharmaceutical Sciences, The First Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou, China. [email protected].
- 5Zhejiang Collaborative Innovation Center for the Brain Diseases with Integrative Medicine, Zhejiang Key Laboratory of Neuropsychopharmacology, School of Pharmaceutical Sciences, The First Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou, China. [email protected].
- 6Zhejiang Collaborative Innovation Center for the Brain Diseases with Integrative Medicine, Zhejiang Key Laboratory of Neuropsychopharmacology, School of Pharmaceutical Sciences, The First Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou, China. [email protected].
Abstract
GABAergic neurons critically regulate epileptic seizures, yet circuit mechanisms mediated by subtype-specific GABAergic neurons in the zona incerta (ZI) remain unclear. Here we reveal the essential role of ZI somatostatin⁺ GABAergic neurons in seizure modulation in the mouse hippocampal kindling model. In vivo Ca²⁺ fiber photometry and optogenetics show that ZI GABAergic neurons are gradually activated during seizure progression. Opto-activation inhibits seizure progression, especially the spread of generalized seizures at the later phase, whereas opto-inhibition accelerates it. Although both somatostatin⁺ and parvalbumin⁺ neurons are dynamically recruited during seizure progression, only somatostatin⁺ neurons exert bidirectional seizure modulation. Circuitry mapping and functional modulation demonstrate that ZI somatostatin⁺ neurons projecting to the ventromedial hypothalamus (VMH) glutamatergic neurons suppress the spread of generalized seizures by inhibiting the excitability of VMH-related downstream seizure-spread regions. These findings uncover a cell-type-specific circuit mechanism for seizure regulation by ZI somatostatin⁺ neurons, highlighting these neurons as a potential therapeutic target for epilepsy.
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BibTeX
@article{zhang2026zona,
title = {{Zona incerta somatostatin⁺ neurons modulate seizure progression through hypothalamic circuits.}},
author = {Mengdi Zhang and Lin Yang and Yuan Zhou and Yeping Ruan and Dongxiao Jiang and Lilong Yu and Jiajia Ying and Wenjing Wang and Tianyu Tang and Menghan Li and Zhong Chen and Fan Fei and Cenglin Xu and Yi Wang},
journal = {Nature communications},
year = {2026},
month = sep,
doi = {10.1038/s41467-026-78174-9},
url = {https://europepmc.org/article/MED/42957689},
note = {CC BY},
}
RIS
TY - JOUR
TI - Zona incerta somatostatin⁺ neurons modulate seizure progression through hypothalamic circuits.
AU - Mengdi Zhang
AU - Lin Yang
AU - Yuan Zhou
AU - Yeping Ruan
AU - Dongxiao Jiang
AU - Lilong Yu
AU - Jiajia Ying
AU - Wenjing Wang
AU - Tianyu Tang
AU - Menghan Li
AU - Zhong Chen
AU - Fan Fei
AU - Cenglin Xu
AU - Yi Wang
PY - 2026
DA - 2026/09/29
JO - Nature communications
DO - 10.1038/s41467-026-78174-9
UR - https://europepmc.org/article/MED/42957689
AB - GABAergic neurons critically regulate epileptic seizures, yet circuit mechanisms mediated by subtype-specific GABAergic neurons in the zona incerta (ZI) remain unclear. Here we reveal the essential role of ZI somatostatin⁺ GABAergic neurons in seizure modulation in the mouse hippocampal kindling model. In vivo Ca²⁺ fiber photometry and optogenetics show that ZI GABAergic neurons are gradually activated during seizure progression. Opto-activation inhibits seizure progression, especially the spread of generalized seizures at the later phase, whereas opto-inhibition accelerates it. Although both somatostatin⁺ and parvalbumin⁺ neurons are dynamically recruited during seizure progression, only somatostatin⁺ neurons exert bidirectional seizure modulation. Circuitry mapping and functional modulation demonstrate that ZI somatostatin⁺ neurons projecting to the ventromedial hypothalamus (VMH) glutamatergic neurons suppress the spread of generalized seizures by inhibiting the excitability of VMH-related downstream seizure-spread regions. These findings uncover a cell-type-specific circuit mechanism for seizure regulation by ZI somatostatin⁺ neurons, highlighting these neurons as a potential therapeutic target for epilepsy.
SN - 2041-1723
ER -