A ventral pallidum-locus coeruleus-lateral hypothalamus pathway modulates brain arousal in freely behaving and isoflurane-anesthetized male mice

Xiang-Ying Xu, Yue Xiao, Xu Liu, Yue Huang, Ying Ji, Yawei Ji, Yuan Gao, Su Liu, Jian-Jun Yang, Jun-Li Cao (), Chunyi Zhou () and Cheng Xiao ()
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Xiang-Ying Xu: School of Anesthesiology, Xuzhou Medical University
Yue Xiao: School of Anesthesiology, Xuzhou Medical University
Xu Liu: School of Anesthesiology, Xuzhou Medical University
Yue Huang: School of Anesthesiology, Xuzhou Medical University
Ying Ji: School of Anesthesiology, Xuzhou Medical University
Yawei Ji: School of Anesthesiology, Xuzhou Medical University
Yuan Gao: School of Anesthesiology, Xuzhou Medical University
Su Liu: Xuzhou Medical University
Jian-Jun Yang: The First Affiliated Hospital of Nanjing Medical University
Jun-Li Cao: School of Anesthesiology, Xuzhou Medical University
Chunyi Zhou: School of Anesthesiology, Xuzhou Medical University
Cheng Xiao: School of Anesthesiology, Xuzhou Medical University

Nature Communications, 2025, vol. 16, issue 1, 1-18

Abstract: Abstract Much progress has been made in the understanding of the neural circuits associated with sleep and anesthesia. As an important component among these circuits, the forebrain nuclei have been frequently interrogated. This study demonstrates that glutamatergic (Glu) neurons in the ventral pallidum (VP) enhance activity upon salient stimuli and state-dependently modulate brain arousal and motor activity in freely behaving male mice, and bidirectionally regulate the induction of and emergence from isoflurane general anesthesia. We delineate a neural pathway, consisting of VP Glu neurons→ noradrenergic (NA) neurons in the locus coeruleus (LC)→the lateral hypothalamus (LH) in male mice, controlling the release of noradrenaline in the LH and state-dependently modulated brain arousal, motor activity, and isoflurane general anesthesia through α2a receptors in the LH. Therefore, the VPGlu-LCNA-LH pathway and α2a receptors in the LH may be promising state-dependent regulators of brain arousal in both freely behaving and anesthetized states.

Date: 2025
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DOI: 10.1038/s41467-025-59857-1

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