A Sleep‐Specific Midbrain Target for Sevoflurane Anesthesia

Yi, Tingting; Wang, Na; Huang, Jing; Wang, Yaling; Ren, Shuancheng; Hu, Yiwen; Xia, Jianxia; Liao, Yixiang; Li, Xin; Luo, Fenlan; Ouyang, Qin; Liu, Yü; Zheng, Ziyi; Qin, Xiao; Ren, Rong; Yao, Zhong-Xiang; Tang, Xiangdong; Wang, Yanjiang; Chen, Xiaowei; He, Chao; Li, Hong; Hu, Zhian

doi:10.1002/advs.202300189

Cited by 8 publications

(6 citation statements)

References 78 publications

(138 reference statements)

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“…Activation of the perirhinal area (PERI) ( Yang and Naya, 2023 ), and nucleus of reuniens (RE) ( Huang et al, 2021 ) pointed to a potential impact on cognitive processes and memory systems. Our study also revealed ISO activates the EW, a finding that aligned with observations under sevoflurane anesthesia ( Yi et al, 2023 ). The bed nuclei of the stria terminalis (BST), associated with stress responses and emotional regulation, exhibited significant activation ( Daniel and Rainnie, 2016 ).…”

Section: Resultssupporting

confidence: 91%

“…To quantitatively assess brain states across the four groups, we utilized electroencephalography (EEG) and electromyography (EMG) recordings (Figure 1-figure supplement 1). The depth of anesthesia was evaluated based on the power ratio of the EEG within the delta (0.5-4 Hz) and theta (6-10 Hz) frequency bands, combined with the changes in the EMG (Luo et al, 2023). Our findings showed that ISO and KET elevated EEG power ratio while reducing EMG power, suggesting both drugs induced a loss of consciousness.…”

Section: Iso and Ketmentioning

confidence: 78%

“…The only activated nucleus in the midbrain was the Edinger-Westphal nucleus (EW). Recent research has found that sevoflurane activates EW and is involved in sleep induction and maintenance of anesthesia, suggesting its crucial role in general anesthesia (Yi et al, 2023). By comparing the ISO and KET induced c-Fos expression, we summarized the brain regions activated by both anesthetics in Figure 5D.…”

Section: Resultsmentioning

confidence: 99%

“…EEG and EMG recordings were conducted as previously described (Luo et al, 2023). Specifically, a stainless steel electrode was positioned over the frontal cortex for EEG measurements, while an insulated EMG electrode was inserted into the neck muscles.…”

Section: Anesthesia Depth Measurementmentioning

confidence: 99%

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Comparative Brain-Wide Mapping of Ketamine and Isoflurane-Activated Nuclei and Functional Networks

Wang

et al. 2023

Preprint

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Ketamine (KET) and isoflurane (ISO) are two widely used general anesthetics, yet their distinct and shared neurophysiological mechanisms remain elusive. In this study, we conducted a comparative analysis of KET and ISO effects on c-Fos expression across the brain, utilizing principal component analysis (PCA) and c-Fos-based functional network analysis to evaluate the responses of individual brain regions to each anesthetic. Our findings demonstrate that KET significantly activates cortical and subcortical arousal-promoting nuclei, with the somatosensory cortex (SS) serving as a hub node, corroborating the top-down general anesthesia theory for dissociative anesthesia. In contrast, ISO activates the nuclei in the hypothalamus and brainstem, with the locus coeruleus (LC) as a hub node, implying a bottom-up mechanism for anesthetic-induced unconsciousness. Notably, the coactivation of sleep-wakefulness regulation, analgesia-related, neuroendocrine-related nuclei (e.g., prelimbic area (PL) and infralimbic areas (ILA), and the anterior paraventricular nucleus (aPVT), Edinger-Westphal nucleus (EW), locus coeruleus (LC), parabrachial nucleus (PB), solitary tract nucleus (NTS)) by both anesthetics underscores shared features such as unconsciousness, analgesia, and autonomic regulation, irrespective of their specific molecular targets. In conclusion, our results emphasize the distinct actions of KET and ISO while also uncovering the commonly activated brain regions, thus contributing to the advancement of our understanding of the mechanisms underlying general anesthesia.

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Section: Resultssupporting

confidence: 91%

Section: Iso and Ketmentioning

confidence: 78%

Section: Resultsmentioning

confidence: 99%

Section: Anesthesia Depth Measurementmentioning

confidence: 99%

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Comparative Brain-Wide Mapping of Ketamine and Isoflurane-Activated Nuclei and Functional Networks

Wang

et al. 2023

Preprint

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“…TRAP was used to label ciprofol-activated neurons through the cfos-CRE-ERT2 system [ 44 , 45 ]. AAV-cfos-CRE-ERT2 and Cre-dependent AAV encoding the caspase-3/hM3Dq/hM4Di receptor were first injected (1:1 uniform mixing) into the LHb region in WT mice, followed by intraperitoneal injection of 4-OH tamoxifen (H6278, Sigma-Aldrich, Merck KGaA, Darmstadt, Germany) prepared in a mixed oil solution (of nine parts corn oil and 1 part ethanol) at 1 week after the virus injection (50 mg/kg).…”

Section: Methodsmentioning

confidence: 99%

A Common Neuronal Ensemble in the Lateral Habenula Regulates Ciprofol Anesthesia in Mice

Zhou,

Zhang,

Zhu

et al. 2024

Pharmaceuticals

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General anesthetics were first used over 170 years ago; however, the mechanisms of how general anesthetics induce loss of consciousness (LOC) remain unclear. Ciprofol, a novel intravenous anesthetic, has been developed by incorporating cyclopropyl into the chemical structure of propofol. This modification offers the benefits of rapid onset and minimal injection pain. Recent studies have revealed that the glutamatergic neurons of the lateral habenula (LHb) play a crucial role in modulating the LOC induced by propofol and sevoflurane. Nevertheless, the specific involvement of LHb in the anesthetic effects of ciprofol remains uncertain. Here, using targeted recombination in active populations (TRAP) combined with electroencephalogram/electromyography recordings and the righting reflex behavioral test, our study revealed that intravenous infusion of ciprofol for 1 h could lead to the induction of c-Fos expression in the LHb in mice. The combination of TRAP and gene ablation, aimed at selectively ablating ciprofol-activated neurons in the LHb, has been shown to facilitate the emergence of ciprofol anesthesia and decrease the proportion of delta waves during the emergence phase. Chemogenetic inhibition of these neurons produced a comparable effect, whereas chemogenetic activation resulted in the opposite outcome. Chemogenetic activation of ciprofol-activated neurons in the LHb delays the emergence of anesthesia and induces a deep hypnotic state during the emergence phase. Taken together, our findings suggest that LHb ciprofol-activated neurons modulate the state of consciousness and could potentially be targeted to manipulate consciousness during ciprofol anesthesia.

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A Sleep‐Specific Midbrain Target for Sevoflurane Anesthesia

Wang

Huang

et al. 2023

Advanced Science

Self Cite

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Sevoflurane has been the most widely used inhaled anesthetics with a favorable recovery profile; however, the precise mechanisms underlying its anesthetic action are still not completely understood. Here the authors show that sevoflurane activates a cluster of urocortin 1 (UCN1+)/cocaine‐ and amphetamine‐regulated transcript (CART+) neurons in the midbrain involved in its anesthesia. Furthermore, growth hormone secretagogue receptor (GHSR) is highly enriched in sevoflurane‐activated UCN1+/CART+ cells and is necessary for sleep induction. Blockade of GHSR abolishes the excitatory effect of sevoflurane on UCN1+/CART+ neurons and attenuates its anesthetic effect. Collectively, their data suggest that anesthetic action of sevoflurane necessitates the GHSR activation in midbrain UCN1+/CART+ neurons, which provides a novel target including the nucleus and receptor in the field of anesthesia.

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A Sleep‐Specific Midbrain Target for Sevoflurane Anesthesia

Cited by 8 publications

References 78 publications

Comparative Brain-Wide Mapping of Ketamine and Isoflurane-Activated Nuclei and Functional Networks

Comparative Brain-Wide Mapping of Ketamine and Isoflurane-Activated Nuclei and Functional Networks

A Common Neuronal Ensemble in the Lateral Habenula Regulates Ciprofol Anesthesia in Mice

A Sleep‐Specific Midbrain Target for Sevoflurane Anesthesia

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