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

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

  • Nat Commun. 2025 May 16;16(1):4560. doi: 10.1038/s41467-025-59857-1.
Xiang-Ying Xu 1 2 3,  Yue Xiao 1 4,  Xu Liu 1,  Yue Huang 1,  Ying Ji 1,  Yawei Ji 1,  Yuan Gao 1,  Su Liu 2 3 5,  Jian-Jun Yang 6,  Jun-Li Cao 7 8 9 10,  Chunyi Zhou 11 12 13,  Cheng Xiao 14 15 16
Affiliations

Affiliations

  • 1 Jiangsu Province Key Laboratory of Anesthesiology, School of Anesthesiology, Xuzhou Medical University, Xuzhou, Jiangsu, China.
  • 2 Jiangsu Province Key Laboratory of Anesthesia and Analgesia Application Technology, Xuzhou Medical University, Xuzhou, Jiangsu, China.
  • 3 NMPA Key Laboratory for Research and Evaluation of Narcotic and Psychotropic Drugs, School of Anesthesiology, Xuzhou Medical University, Xuzhou, Jiangsu, China.
  • 4 Department of Anesthesiology, Affiliated Hospital of Nantong University, Nantong, Jiangsu, China.
  • 5 Department of Anesthesia, Affiliated Hospital of Xuzhou Medical University, Xuzhou, Jiangsu, China.
  • 6 Department of Anesthesiology and Perioperative Medicine, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, China.
  • 7 Jiangsu Province Key Laboratory of Anesthesiology, School of Anesthesiology, Xuzhou Medical University, Xuzhou, Jiangsu, China. Cao0310@aliyun.com.
  • 8 Jiangsu Province Key Laboratory of Anesthesia and Analgesia Application Technology, Xuzhou Medical University, Xuzhou, Jiangsu, China. Cao0310@aliyun.com.
  • 9 NMPA Key Laboratory for Research and Evaluation of Narcotic and Psychotropic Drugs, School of Anesthesiology, Xuzhou Medical University, Xuzhou, Jiangsu, China. Cao0310@aliyun.com.
  • 10 Department of Anesthesia, Affiliated Hospital of Xuzhou Medical University, Xuzhou, Jiangsu, China. Cao0310@aliyun.com.
  • 11 Jiangsu Province Key Laboratory of Anesthesiology, School of Anesthesiology, Xuzhou Medical University, Xuzhou, Jiangsu, China. chunyi.zhou@xzhmu.edu.cn.
  • 12 Jiangsu Province Key Laboratory of Anesthesia and Analgesia Application Technology, Xuzhou Medical University, Xuzhou, Jiangsu, China. chunyi.zhou@xzhmu.edu.cn.
  • 13 NMPA Key Laboratory for Research and Evaluation of Narcotic and Psychotropic Drugs, School of Anesthesiology, Xuzhou Medical University, Xuzhou, Jiangsu, China. chunyi.zhou@xzhmu.edu.cn.
  • 14 Jiangsu Province Key Laboratory of Anesthesiology, School of Anesthesiology, Xuzhou Medical University, Xuzhou, Jiangsu, China. xchengxj@xzhmu.edu.cn.
  • 15 Jiangsu Province Key Laboratory of Anesthesia and Analgesia Application Technology, Xuzhou Medical University, Xuzhou, Jiangsu, China. xchengxj@xzhmu.edu.cn.
  • 16 NMPA Key Laboratory for Research and Evaluation of Narcotic and Psychotropic Drugs, School of Anesthesiology, Xuzhou Medical University, Xuzhou, Jiangsu, China. xchengxj@xzhmu.edu.cn.
PMID: 40379709 DOI: 10.1038/s41467-025-59857-1
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.

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